CZ20003528A3 - Macrolide compounds acting as LHRH antagonists - Google Patents

Abstract

Derivatives comprising 3'-N-demethyl-3'-N-substituted-6-Omethyl-11-deoxy-1 1,12- (cyclic carbamate) -erythromycins A of formula I which act as hormone antagonists releasing luteinizing hormone (LHRH). They are described pharmaceutical compositions comprising these compounds, methods the use of these compounds as well as the methods for preparing these compounds compounds.

Description

The present invention relates to a class of macrolide compounds that act as luteinizing hormone releasing hormone (LHRH) antagonists, pharmaceutical compositions containing the compounds, methods of using the compounds, and methods of preparing the same. In particular, the invention relates to derivatives comprising 3'-N-demethyl-3'-N-substituted-6-O-methyl-11-deoxy-11,12- (cyclic carbamate) -erythromycins A which act as LHRH antagonists.

BACKGROUND OF THE INVENTION

Gonadotropins, follicle stimulating hormone (FSH), luteinizing hormone (LH) and choriogonadotropin (CG) are required for ovulation, spermatogenesis, and sex hormone biosynthesis. One of the hypothalamic hormones, gonadotropin releasing hormone (GnRH), also referred to as LHRH, regulates the secretion of both FSH and LH in mammals.

LHRH is a decapeptide having the following structure: pyro-Glu ¹ -His ² -Trp ³ -Ser ⁴ -Tyr ⁵ -Gly ⁶ -Leu ⁷ -Arg ⁸ -Pro ⁹ -Gly ¹⁰ -NH2, where superscripts indicate the position of each amino acid residue in the the decapeptide chain.

LHRH is released from the hypothalamus and binds to the pituitary gland receptor, causing the release of LH and FSH, which then stimulate the gonads to produce sex hormones. Thus, pulsating release of LH and FSH controls the reproductive cycle in animals and humans. Acute doses of LHRH agonists increase LH and steroid sex hormone levels in both animals and humans. Paradoxically, however, chronic LHRH agonist treatment leads to suppression of LH and steroid sex hormone levels.

Thus, the effect of repeated doses of LHRH agonists results in suppression of estrocene production in women and testosterone production in men. The same phenomenon occurs in both animals and humans after acute or chronic administration of LHRH antagonists.

In recent years, considerable research efforts have been made to find LHRH antagonists. As a result, HH / peptide LHRH antagonists have been shown to inhibit LH production and reproductive hormones in mammals by acute or chronic administration. See, for example, M.J. Karten, Modes of Action of GnRH and GnRH analogs, edited by W. F. Crowley and P. M. Conn, pp. 277 (1992). LHRH antagonists are reported to be useful in the treatment of various conditions in which the inhibition of sex steroid production plays a key role, including contraception, puberty delay, treatment of benign prostatic hyperplasia, palliative treatment or remission of hormone-dependent prostate tumors, cryptorchism, hirsutism women, gastric motility disorders, dysmenorrhea and endometriosis.

Common LHRH antagonists are decapeptides and, because of their low oral bioavailability, are administered intravenously or subcutaneously. Non-peptidic heterocyclic structure antagonists have also been reported in the literature, see for example WO 95/29900, WO 77/22707 and WO 97/21704. Non-peptide LHRH antagonists have the potential advantage in improved oral bioavailability and have a smaller molecule size.

However, there are no data in the literature on macrolide compounds acting as LHRH antagonists. Macrolia antibiotics and macrolide prokinetics are known in the art.

For example, EP 248 279 A2 discloses macrolide antibiotics derived from erythromycin containing cyclic 11,12 carbamate groups. EP 0 559 896 A1 discloses 3'-N substituted erythromycin derivatives which are potent antibacterial agents. Prokinetics in the form of macrocyclic lactones (macrolides) are also known. See J. S. Gidda et al., European Patent Application No. 0349100, published Jan. 3, 1990, which discloses 12-membered macrolides suitable for use as gastrointestinal motility promoting agents. Derivatives of erythromycin A, B, C, and D useful as agents for stimulating digestive tract contractility are disclosed in U.S. Pat. Nos. 4,677,097, S.Omura and Z.Itoh, issued June 30, 1987; European Patent Application No. 215,355, published March 25, 1987; and European Patent Application No. 213,617, published March 11, 1987. In addition, in the work of T.Suzanaka et al., Chem.Pharm.Bull. 37 (10): 2701-2709 (1989) disclose quaternary derivatives of 8,9-anhydroerythromycin A6,9-hemiacetal and 9,9-dihydro-erythromycin A-6,9-epoxide stimulating gastrointestinal motor activity.

None of the above cited works disclose novel derivatives comprising 3'-N-demethyl-3'-N-substituted-6-O-methyl-11-deoxy-11,12-cyclic carbamate-erythromycins A of the invention, which are potent antagonists LHRH.

SUMMARY OF THE INVENTION

According to one aspect of the invention, the invention includes a compound of the formula:

or a pharmaceutically acceptable salt or ester thereof, wherein

A represents a group selected from the group consisting of:

a) -C,

b) -N, and

c) -O;

X and Y independently and at each occurrence are z

groups including and) hydrogen, (b) halide, C) trifluoromethyl, (d) alkoxy, E) alkyl, F) aryl, and G) substituted aryl;

R is selected from the group consisting of:

(a) alkyl;

b) cycloalkyl,

(c) a heterocyclic group;

d) substituted heterocyclic group,

(e) alkylcycloalkyl;

f) substituted alkylcycloalkyl,

(g) alkylaryl;

h) alkyl heterocyclic group,

(i) alkenyl;

j) alkynyl,

k) -C (S) -NHR ₄ , C (NR ₄ ) -NHR ₄ , wherein R ₄ is hydrogen, alkyl or aryl; and

l) - (CH ₂ ) -C (CH ₂ ) _m -R 5 where m is 2, 3, 4, or 5 and R 5 is alkyl, alkoxy, aryl or substituted aryl;

R ₂ and R ₃ are independently at each occurrence

(a) hydrogen,

(b) a methyl group; or

R ₂ and R _3, when A is C, together form a cyclic group;

R ₃ , when A is N, has no meaning; and n = 1, 2 or 3.

In another aspect, the invention relates to a process for the preparation of a compound of formula I. The process comprises the following steps:

a) reacting a compound of the formula

with hexamethyldisilazide and compounds of general formula carbonyldiimidazole to give

b) reacting a compound prepared with an amino compound of the general formula:

in step (a)

(CH ₂ ) _o -NH _; from 2 ', 4-protected general formulas:

followed by deprotection of the hydroxyl groups to give the compound

c) demeunylation of the 3'-amino group by treating the compound prepared in step (b) with iodine in the presence of a base to prepare a compound of the formula:

d) alkylating the 3'-N-demethylated compound prepared in step (c) with an alkylating agent.

The compounds of the invention have little or no antibacterial activity, but bind to the LHRH recpetor and are potent LHRH antagonists. Thus, these compounds are effective in the treatment of prostate cancer, endometriosis, premature puberty and other choreoids in which sex hormones play a role.

In another aspect of the invention, the invention relates to pharmaceutical compositions that act as LHRH antagonists and suppress the production of LH, testosterone, estradiol and estrogen in mammals.

In yet another aspect, the invention includes a method of reducing sex hormone levels in both male and female mammals, comprising administering a therapeutically effective amount of a LHRH affecting compound in combination with a therapeutically effective amount of an antiandrogen to a host in need of treatment.

The term lower alkyl or alkyl as used herein denotes straight or branched chain alkyl radicals containing 1 to 20 carbon atoms, in some cases represented as C 1 -C 7 -alkyl, where x and y are respectively the minimum and maximum number of carbon atoms in the alkyl radical . Examples of lower alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2 , 2-dimethylpropyl, hexyl and the like.

The term alkoxy or lower alkoxy as used herein refers to the lower alkyl group described above, which is attached to the oxygen atom by an ether bond. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, pentyloxy, tert-butoxy, octyloxy, and the like. Said alkoxy radical may also include a ring _; containing, but not limited to, five or six carbon atoms, and which may contain one or two heteroatoms such as nitrogen or oxygen.

»* · ·

The term alkenyl as used herein denotes a straight or branched chain hydrocarbon chain of two to twenty, three carbon atoms, preferably four to twelve carbon atoms, especially eight to ten carbon atoms, containing one or more carbon-carbon double bonds, preferably about one to three double bonds. The compounds of the invention may either be in a certain known configuration or may be a mixture of isomers.

The term alkynyl as used herein denotes a straight or branched hydrocarbon chain of two to two. three carbon atoms, preferably four to twelve carbon atoms, in particular eight to ten carbon atoms, containing one or more carbon-carbon triple bonds, preferably one triple bond. The compounds of the invention may either be in a certain known configuration or may be a mixture of isomers.

The term cycloalkyl as used herein means a saturated monocyclic hydrocarbon group containing three to seven ring carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. This cyclic group may be optionally substituted with, for example, a lower alkyl, hydroxy, halogen or amino group.

The term alkylcycloalkyl as used herein refers to the cycloalkyl group described above attached to the lower alkyl radical described above. Said alkylcycloalkyl is attached to the parent group via an alkyl radical, wherein said alkyl radical contains one to six carbon atoms. Examples of such groups include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl and the like.

The term aryl as used herein means a mono-, fused-cyclic or fused tricyclic carbocyclic ring system containing one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, phenanthryl, biphenylenyl, indalyl, indethyl, and the like.

The term substituted aryl as used herein means an aryl group as described above in which one, two or three hydrogen atoms are independently replaced by a group selected from Cl, Br, F, I, OH, cyano, mercapto, nitro,

C 1 -C ₃ -alkyl, h = logene-C 1 -C ₃ -alkyl, C 1 -C ₆ -alkoxy, thio-C 1 -C 6 -alkoxy, methoxymethoxy, amino, C 1 -C ₃ -alkylamino, di (C 1 -C ₃ -alkyloxy) C ₃ -alkyl-amino, formyl, carboxy, alkoxycarbonyl, C 1 -C ₃ -alkyl-CC-O-, C 1 -C ₃ -alkyl-CO-NH, and carboxamide; except that the substituted aryls include tetrafluorophenyl and pentafluorophenyl.

The term arylalkyl as used herein means an aryl group as described above appended to the alkyl group described above. The arylalkyl group is attached to the parent group by an alkyl group wherein the alkyl group contains one to six carbon atoms. The aryl group in said arylalkyl group may be substituted as described above. Examples of such groups include, but are not limited to, [3- (4-hydroxy) phenyl] propyl, [3- (1-methyl) (4-hydroxy) phenyl] propyl, (4-hydroxybenzyl) methyl, and the like.

The term heterocyclic ring or heterocyclic or heterocycle used herein refers to each of 3 or 3

A 4-membered ring containing a heteroatom selected from the group consisting of oxygen, sulfur nitrogen; or a 5-, 6-, or 7-membered ring containing gelatin, two or three nitrogen atoms; one nitrogen atom * · • · · ·

Jeden and one sulfur atom; or one nitrogen atom and one oxygen atom. Said 5-membered ring contains 0-2 double bonds and said 6-membered ring contains 0-3 double bonds. The nitrogen atoms may optionally be in quaternary form. The term heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or to another heterocyclic ring (e.g., indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl and the like). Said heterocyclic groups include: azetidinyl, benzimidazolyl,

1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, o / benzthiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, isothinyl, indolyl, indolyl, indolyl, indolyl, indolyl, indolyl, indolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridil, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, thiazolyl, and thienyl.

The heterocycles may be unsubstituted or may be monosubstituted or disubstituted by a group independently selected from the group consisting of hydroxy, halogen, oxo (= O), alkylimino (R'N = where R * represents lower alkyl), cycloalkyl, aryl, arylalkyl, and lower alkyl . In addition, the nitrogen-containing heterocycles may be N-protected.

The term (heterocycle) alkyl) as used herein means a heterocyclic group described above attached to a lower alkyl group also described above. This (heterocycle) alkyl group is attached to the parent group by an alkyl group, wherein the alkyl group contains one to one alkyl group also described above. This (heterocycle) alkyl group is attached to the parent group by an alkyl group, wherein an alkyl group containing one to six carbon atoms, examples of which include, but are not limited to, 2-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, 2-pyridylpropyl, 4-pyridylpropyl, 2-furylmethyl and the like.

The term substituted (heterocycle) alkyl as used herein means a heterocycloalkyl group as described above, wherein the heterocyclic group or alkyl group is substituted with an independently selected replacement of one, two, or three hydrogen atoms with a group selected from Cl, Br, F, I, OH , cyano, mercapto, nitro, C 1 -C ₃ -alkyl, halogen-C 1 -C ₃ -alkyl, C 1 -C ₆ -alkoxy, thio-C 1 -C 6 -alkoxy, hydroxyalkyl, methoxymethoxy, amino,

C 1 -C 3 -alkyl-amino, di (C 1 -C ₃ -alkyl-) amino, carboxaldehyde, carboxy, alkoxycarbonyl, C 1 -C ₃ -alkyl-CO-O-, C 1 -C ₃ -alkyl-CO-NH, and carboxamide. Examples of this group include, but are not limited to, 3 - [(5-methyl) -2-pyridyl] propyl, 3 - [(6-methyl) -2-pyridyl] propyl, 4 - [(β-methyl) -2] -pyridyl] propyl

4 - [(6-methyl) -2-pyridyl] butyl, (5-nitro) -2-thienylmethyl and the like.

The term heteroaryl as used herein means a cyclic aromatic radical of five to ten ring atoms, wherein one ring atom is selected from the group consisting of S, O and N; none, one or two of the ring atoms may be other heteroatoms independently selected from the group consisting of S, O and N;

the remaining ring atoms are carbon, said radical being attached to the remainder of the molecule via any of the ring atoms and said radical may be, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,

The term substituted heteroaryl as used herein means a heteroaryl group as described above which is substituted with an independently selected replacement of one, two or three hydrogen atoms with a group selected from Cl, Br, F, I, OH, C 1 -C ₃ -alkyl, C 1 -C 6 -alkoxy, methoxymethoxy, amino, and amino-C ₃ -arr.ino or it may also mean a mono-oxo substituted heteroaryl compound such as 4-oxo-lH-quinoline.

The term "arrotic solvent" as used herein means a solvent that is relatively proton-inert, i.e., does not act as a proton-donor. Examples of such solvents include, but are not limited to, hydrocarbons such as hexane and toluene, halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform and the like, heterocyclic compounds such as tetrahydrofuran and N-methylpyrrolidinone, ethers such as diethyl ether and bismethoxymethyl ether, as well as other miscellaneous compounds such as dimethylformamide, acetonitrile, acetone and ethyl acetate. These compounds are well known to those skilled in the art, and will readily select preferred individual solvents or mixtures thereof for specific compounds and reaction conditions depending on factors such as solubility of reagents, reagent reactivity, and preferred temperature ranges. Further details regarding aprotic solvents can be found in organic chemistry textbooks or in detailed monographs on the subject, for example in Organic Solvents Physical Properties yes Methods of Purification, 4th edition, ed. John A. Riddick et al. , Vol. II, Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term "pharmaceutically acceptable salt" as used herein means salts that, according to medical judgment, are suitable for:

contact with tissues of humans and lower animals without causing undesirable toxic, irritant, allergic and similar responses, and their use is commensurate with a justified benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art, for example, S. M. Berge et al. disclose in detail the pharmaceutically acceptable salts in their work published in J. Pharmaceutical Sciences, 66: 1-19 (1977), which is incorporated herein by reference. These salts may be prepared in situ during the final separation and purification of the compounds of the invention, or may be prepared separately by reacting the free basic functionality with a suitable organic or inorganic acid. Examples of pharmaceutically acceptable non-toxic acid addition salts are those formed with an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and chloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malic acid, or using other methods known in the art, for example using ion exchangers. Other pharmaceutically acceptable salts include adipate, alginate, aspartate, benzenesulfone; benzoate, hydrogen sulphate, borate, butyrate, camphate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dedecylsulfate, ethanesulfonate, formate, fumarate, glucose phosphate, glucoheptonate, glucoheptonate, glucoheptonate, glucoheptonate 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmieat, pamoate, pectinate, phosphate, persulfate , pivlatate, propionate, stearate, succinate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Typical alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where possible, nontoxic ammonium, quaternary ammonium, and amine cations with counterions including nalogenide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and arylsulfonate.

The term pharmaceutically acceptable ester means esters that hydrolyze in vivo, and includes esters readily degradable in the human body to release the parent compound or salt thereof. Suitable ester groups include, for example, esters derived from pharmaceutically acceptable aliphatic carboxylic acids, especially alkanoic, alkenic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety preferably contains less than 6 carbon atoms. Examples of suitable esters include formates, acetates, proplonates, butyrates, acrylates and ethyl succinates.

The compounds of the invention may contain multiple asymmetric centers. Unless otherwise indicated, the invention includes various stereoisomers and mixtures thereof. If the bond is indicated by a wavy line, the compound is believed to be in the form of a mixture of stereoisomers or is a single isomer with a determined or unspecified orientation.

Preferred embodiments

Preferred compounds of the invention include those wherein R is alkyl, alkenyl, cyclsalkyl, heterocycle, (heterocycle) alkyl, or alkyleycloalkyl; X and Y are independently chloro, fluoro, dioxalano, hydrogen, or alkoxy; A is -C, or N; R? and R 3 is hydrogen or cyclopropyl and n is 1.

Typical compounds of the invention are selected from the group consisting of:

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-cyclopropyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A 11,12 (cyclic carbamate);

<713'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-cyclohexyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-isovaleryl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) );

3'-N-demethyl-3'-N- (3-methylthiopropyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A 11,12- (cyclic carbamate);

• · ♦ ·

3'-N-demethyl-3'-N- (3-tetrahydrothienyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12- ( cyclic carbamate);

3'-N-demethyl-3'-N- (3,4-dimethylcyclopentyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 - (cyclic carbamate);

3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11 12- (cyclic carbamate);

3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 - (cyclic carbamate);

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethylamino)) - 6-O-methyl-erythromycin A, 11,12 - (cyclic carbamate);

3'-N-demethyl-3'-N-cyclohexyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11 12- (cyclic carbamate);

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3,4-dioxolanopheneahylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ;

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3,4-dioxolanophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (4-chloro-3-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic caroamate) :

3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (4-chloro-3-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ;

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (4-chloro-3-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12, ( cyclic caramate);

3'-N-demethyl-3'-N-cyclobutylmethyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic caroamate);

^{3'-N-demethyl-N-R} 3 cyklobutylmethy 1-11-deoxy-11- [carboxy- (4-chlorophenethylamine)] - 6-0-methyl-erythromycin A 11,12 (cyclic karoamat);

3'-N-demethyl-3'-N-ethyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-ervthromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3-chlorophenethylamino)) - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate):

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic caroamate) );

3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ;

3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) );

3'-N-demethyl-3'-N-cyclopropylmethyl-11-deoxy-11- (carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A,

11,12- (cyclic carbamate);

3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carramate);

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] - β-O-methyl-erythromycin A,

11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- (4-pyridylmethyl) -11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - β-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ;

3'-N-demethyl-3'-N- (2-butyl) -11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - β-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ;

3'-N-demethyl-3'-N- (3-pentyl) -11-deoxy-11- [carboxy- (4-chlorophenethylamino)) - β-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ;

3'-N-demethyl-3'-N- (cyclopropylmethyl) -11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - β-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N- (2-cyclopropylethyl) -11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ;

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (4-methoxyphenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (4-methoxyphenetbylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carcinoma);

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3,4-

(dimethylphenezhylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3-bromo-4-methoxyphenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ;

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3-bromo-4-methoxyphenetbylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ;

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ;

3'-N-demethyl-3'-N- (2-furyl) methyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A,

11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- [2- (5-hydroxymethyl) furyl) methyl-11-deoxy-11- (carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl- erythromycin A, 11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- (2-pyridyl) methyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A,

11,12- (cyclic carbamate);

• ·

3'-N-demethyl-3'-N- [2- (6-methyl) pyridyl] methyl-11-deoxy-11- (carboxy- (3-chloro-4-fluorophenethylamino)) - 6-O- methyl-erythromycir. A, 11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- (4-hydroxyethoxybenzyl) -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylmino)] -6-O-methyl-erythromycir. 1111,12- (cyclic carbamate);

3'-N-demethyl-3'-N- (3-methylthio) butyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A,

11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- (4,4,4-trifluorobutyl) -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A ,

11,12- (cyclic carbamate);

3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (4-chloro-3-fluorophenethylamino)] -6-O-methyl-erythromycin, δ 11.12 (cyclic caroamate) ;

3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (3,4-

(difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic caramate);

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- [3,4- (1,4-dioxano) phenethylamino)] - 6-O-methyl-erythromycin A, 11, 12 (cyclic caramate);

3'-N-demethyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy- (3,4-dichloroethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carramate);

3'-N-demethyl-3'-N- [3- (methylsulfoxy) propyl] -11-deoxy-l- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A 11,12- (cyclic carbamate);

3'-N-demethyl-3'-N-ethylthiourea-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N- [2- (5-hydroxymethyl) furyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A , 11,12- (cyclic carbamate):

3'-N-demethyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 - (cyclic carbamate);

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (4-chloroanilinoethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (4-chloroanilinoethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 [cyclic carbamate];

3'-N-demethyl-3'-N- (2-imidazolo) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 ( cyclic carbamate);

3'-N-demethyl-3'-N- (3-pyridyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N- (2-pyridyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N - [(5-nitro) -2-thienyl] methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- [5- (4-chlorophenyl) -2-furyl] methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methylerythromycin 11 11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- [5-nitro-2-furyl] methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11.12 (cyclic carbamate);

3'-N-demethyl-3'-N- [2,5-dimethoxy-3-tetrahydrofuryl] methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methylerythromycin A11 12- (cyclic carbamate);

3'-N-demethyl-3'-N- [6-methyl-2-pyridyl] methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A 11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- (4,4,4-trifluorobutyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)) - 6-O-methyl-erythromycin A,

11,12- (cyclic carbamate);

• ·

• ··· ···· · · ····· ·· ··

3'-N-demethyl-3'-N- (1-bromo-2-napthyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- (4-methyl-1-napthyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- (4-dimethyl amino-1-napthyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methylerythromycin A, 11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- (2-furyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 ( cyclic carbamate);

3'-N-demethyl-3'-N- [3- (4-pyridyl) propyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11.12 (cyclic carbamate);

3'-N-demethyl-3'-N- [3- (2-pyridyl) propyl] -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11.12 (cyclic carbamate);

3'-N-demethyl-3'-N-3- [4- (4-pyridyl) butyl] -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11.12 (cyclic carbamate);

3'-N-demethyl-3'-N- [3- (3-pyridyl) propyl] -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11.12 (cyclic carbamate);

3'-N-demethyl-3'-N - [(3- (3-pyridyl) propyl] -11-deoxy-11- (carboxy- (3-chloro-4-fluorophenethylamino)) - 6-O-methyl- erythromycin A,

11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- [3- (4-pyridyl) propyl] -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin AND,

11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- [3- (2-pyridyl) propyl] -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin AND,

11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- [4- (4-pyridyl) butyl] -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin AND,

11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- [4- (β-methyl-2-pyridyl)] butyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-0 -methyl-erythromycin A, 11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- [1-methyl-3- (4-hydroxyphenyl) propyl] -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl -erythromycin A, 11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- [(1-methyl) -3- (4-hydroxyphenyl) propyl] -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-0 -methyl-erythromycin A, 11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- [3- (6-methyl-2-pyridyl) propyl] -11-deoxy-11 [carboxy- (3-thloro-4-fluorophenethylamino)] - 6-0- methyl erythromycir A 11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- [3- (5-methyl-2-pyridyl) propyl] -11-deoxy-1- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycir. A, 11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- (2-pyridylethyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic caramate);

3'-N-demethyl-3'-N- (2-pyridylethyl) -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A,

11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- (4-hydroxybenzyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic) carbamate);

3'-N-demethyl-3'-N- (4-pyridyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11, 12- (cyclic carbamate);

3'-N-demethyl-3'-N - [(3-methylthio) butyl] -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11 12 (cyclic carbamate);

3'-N-demethyl-3'-N- (1-methylcyclopropane) methyl 11-11-deoxy-1- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl- erythromycin-A, 11,12- (cyclic carbamate);

3'-N-demethyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-l- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-0 -methyl-erythromycin A, 11,12- (cyclic carbamate);

n · * · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

3'-N-demethyl-3'-N-oxiranylmethyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carramate) ;

3'-N-demethyl-3'-guanidino-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carramate); and

3'-N-demethyl-3'-N-2- (4,5-dihydroimidazolyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11 12- (cyclic carbamate).

Even more preferred compounds of the invention are selected from the group consisting of:

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-cyclopropyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ;

3'-N-demethyl-2'-N-isopropyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ;

«· · ·

3'-N-demethyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)) - 6-O-methyl-erythromycin A,

11,12- (cyclic carbamate);

3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate);

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-l- [carboxy- {3,4-

-difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate):

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); and

3'-N-demethyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate).

Effect and use of LHRH agonists and antagonists

The compounds of the invention acting as LHRH agonists and antagonists are useful for the treatment of premature puberty, benign prostatic hyperlasia (BPH), endometriosis, uterine fibroids, breast cancer, acne, premenstrual syndrome, polycystic ovarian syndrome, and abnormal gonadal hormone deficiency in both human and animal sexes. The LHRH antagonists of the invention are also compositions suitable for controlling reproduction in both women and men. The compounds of the invention are useful for suppressing hlaoin testosterone and dihydrotestosterone (DHT) in men and estrogen and estradiol in women.

· · V V V V V V V V V V V V ► ► ► ► ► ► ► ► ► ► ► ► ► ► ► ► ► ► ► ·

In applying the method of the invention, an effective amount of a compound of the invention or a pharmaceutical composition comprising an effective amount of a compound of the invention is administered to a human or animal in need of such treatment or desirable. The compounds or compositions may be administered in a variety of ways depending on the end use targeted, including oral, parenteral (including subcutaneous, intramuscular and intravenous), vaginal (especially in the case of contraception), rectal, buccal (including sublingual administration), transdermal or intranasal administration. The most suitable method in each case depends on the use, in particular the active ingredient, on the patient and the judgment of the attending physician. The compound of the invention may be administered in the form of slow release formulations, depot formulations and implant formulations as detailed below.

In general, for modulating sex hormone levels in male or female mammals, it is desirable to administer the active ingredient in amounts between about 1 to 200 mg / kg body weight per day, preferably between 1 to 30 mg / kg body weight per day. Administration of the drug may be in the form of a single daily dose, divided into several applications, or in a slow release manner to ensure maximum efficacy.

The actual dosage and mode of administration of the compounds of the invention and the compositions containing them always depend on the needs of the subject to be treated, the degree of disability or the need for treatment, and the judgment of the attending physician. For parenteral administration, lower doses are generally used than for other modes of administration that are more dependent on absorption.

·· · ·· «·

·· · · ·

Another aspect of the invention relates to pharmaceutical compositions comprising as active ingredient a compound of the invention, wherein said compositions comprise a compound of the invention in admixture with a pharmaceutically acceptable non-toxic carrier. As mentioned above, said compositions may be formulated dc forms suitable for parenteral (subcutaneous, intramuscular or intravenous) administration, in particular in the form of liquid solutions or suspensions; in a form suitable for vaginal or rectal administration, in particular in semi-solid forms such as creams and suppositories; in a form suitable for oral or buccal administration, in particular in the form of tablets or capsules, or in a form suitable for intranasal administration, in particular in the form of powders, nasal drops or aerosols.

Said compositions may preferably be administered in a single dosage form and may be prepared by any suitable method known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, Easton, PA. 1970. Formulations for parenteral administration may contain any conventional ingredients. sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, hydrogenated naphthalenes and the like. Formulations for administration by inhalation may be in solid form, where they may contain ingredients such as lactose, or may be in the form of aqueous or oily solutions intended for administration as nasal carp. Common additives for buccal administration include sugars, calcium stearate, magnesium stearate, pregelatinized starch, and the like.

It is particularly desirable that the intake of the compounds of the invention to a given subject is ensured by a prolonged period of time, for example from one week to one year, by a single administration. Various slow release forms, depot forms or implants can be used for this purpose. For example, the dosage form may comprise a pharmaceutically acceptable non-toxic salt of a compound of the invention that is only slightly soluble in body fluids, for example a) an acid addition salt which is a polybasic acid such as phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid; pamic acid, alginic acid, polyglutamic acid, naphthalene-mono- or disulfonic acids, polygalacturonic acid and the like; b) a salt with a multivalent metal cation such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, and the like, or a salt with an organic cation formed from, for example, N, N'-debenzylethylenediamine or ethylenediamine; or c) combinations of (a) and (b) for example, zinc tannate. In addition, the compounds of the invention, or preferably their relatively insoluble salts such as those described above, may be formulated in a gel, for example, with an aluminum monostearate gel with sesame oil, which form is suitable for injection. Particularly preferred salts are zinc salts, zinc tannate salts, pamoate salts and the like. Another type of slow release depot suitable for injection comprises a compound of the invention or a salt thereof dispersed or encapsulated in a slowly degrading, nontoxic, non-antigenic polymer such as the polylactic acid / polyglycolic acid polymer disclosed in U.S. Patent 3,773,919. The compounds of the invention, or preferably their relatively insoluble salts of the type described above, can also be formulated as cholesterol matrix pellets, particularly for veterinary use. Other slow release, depot release or implant formulations, such as liposomes, are well known in the literature. See, for example, Sustained and Controlled Release Drug Delivery Systems, JR Robinson ed., Marcel Dekker Inc., New York, 1978. Specific Data Concerning *: · · · · · · · ....

For example, compounds having an LHRH relationship can be found, for example, in U.S. Patent No. 4,010,125.

LHRH antagonist activity

Typical compounds of the invention were evaluated in in vitro binding assays to the rat pituitary LHRH receptor (pru) and in assays for inhibiting LH from rat pituitary cells for antagonist activity (pA?). In these tests, the methods previously described by F.Haviv et al.

J. Med. Chem., 32: 2340-2344 (1989). Receptor Binding Affinity (pKi) is the negative logarithm of the equilibrium dissociation constant.

The results of the pK _r determination of typical compounds of the invention are shown in Table 1.

Table 1

Example pK _z Example pKi Example pKi 1 9.09 13 8.10 25 8.38 2 9.24 14 8.75 26 8.83 3 9, 13 15 Dec 8.20 27 Mar: 8.81 4 8.49 16 8.40 28 9.49 5 8.44 17 8.37 29 9.27 6 8,09 18 8.23 30 9.29 7 8.33 19 Dec 8.80 31 9.57 8 8.13 20 May 8.49 32 10,08 9 8.36 21 8.21 33 9, 17 10 8.76 22nd 8.35 34 8.00 11 8.51 23 8.17 35 8.12 12 8.68 24 8.56 36 8.04

• ·

• ·

Table 1 (continued)

Example pKí Example pKx Example pKi 37 8.04 57 8.04 77 8.21 38 8.17 58 8.81 78 8.10 39 8.29 59 8.43 79 8, 11 40 8.24 60 8.57 80 8.40 41 8.07 61 8.57 81 8.3 6 42 8, 14 62 8.52 82 8, 64 43 8.45 63 8.13 83 8.46 44 8.84 64 8.16 84 8.15 45 8.45 65 8, 13 85 8.23 46 8.94 66 8.86 86 8.75 47 8.60 67 8, 11 87 8.65 48 8.72 68 8.29 88 8.68 49 8.50 69 8.21 89 8.38 50 9, 01 70 8.23 90 8.39 51 8.20 71 8.21 91 8.02 52 8.10 72 9, 17 92 8.20 53 8.52 73 9, 67 93 8.30 54 8.39 74 8.50 55 8.14 75 8, 90 56 8.75 76 8.04

The cA ₂ value is the negative logarithm of the antagonist concentration, it shifts the response curve observed with the leuprolide agonist to its twice-higher concentration range, lauprolide is an LHRH agonist having the structure pyro-Glu ¹ -His ^; Rp ³ -Ser ⁴ -Tyr ⁵ -D-Leu ⁶ -Leu ⁷ -Arg ⁸ -Pro ⁹ -NHEt and this compound is disclosed and protected by US Patent No. 4,005,063. The pA ₂ values of typical compounds of the invention are shown in bullet 2 below.

Table 2

Example pA ₂ Example pA ₂ 1 9, 10 26 8.66 3 8, 60 27 Mar: 8.42 16 7.49 28 , 52 20 May 7, 53 29 8.97 21 7.26 30 8.28 22nd 7.52 31 8.24 23 7.30 32 7.58 25 7, 43 33 8.40

Methods of preparation

The compounds of the invention and their methods of preparation will be more readily apparent in conjunction with the following synthetic schemes 1 and 2, which illustrate possible methods of preparing the compounds of the invention. Said compounds may be prepared using commercially available or prepared reagents.

Abbreviations used

The following abbreviations are used in the description of the schemes and in the following examples: Ac for acetyl; APCI for atmospheric pressure chemical ionization; CDI for carbonyldiimidazole; CH ₃ CN for acetonitrile; Cl or DCI desorption chemical ionization; DMF for dimethylformamide; ESI for electrosprayionization; EtOAo for ethyl acetate; FAB for fast atom bombardment; FTIR for Fourier transform infrared spectroscopy; HPLC for high performance liquid chromatography; IR for infrared spectroscopy; MeOH for methanol; MHz for megaherz; MIC for micro resolution; MS for mass spectra; NaHMDS for sodium hexamethyldisilazide; NMR

for nuclear magnetic resonance; Rf for retention factor; ; _T R for reteční time; TBAF for tetrabutylammonium fluoride; THF for tetrahydrofuran; TLC for thin layer chromatography; TMS for trimethylsilyl; TMS Cl for trimethylsilyl chloride; and DCM for dichloromethane.

The starting material, 6-O-methyl-erythromycin A1 (clarithromycin, commercially available as Biaxin® from Abbot Laboratories) is protected at the 2 'and 4' positions by reaction with a suitable hydroxy-protecting agent as described, for example, in TWGreene. and PGMWuts, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Son, Inc., 1991. Suitable reagents for introducing a hydroxy protecting group include, for example, acetic anhydride, benzoic anhydride, benzyl chloroformate, hexamethyldisilazane or trialkylsilyl chloride in an aprotic solvent.

• ·

Scheme 1

^u degree

• · • ·

The protection of the hydroxy groups at the 2'- and 4-, 6-O-methyl-erythromycin A 1 positions shown in Scheme 1 can be accomplished sequentially or simultaneously to form a compound 2 wherein R p is a hydroxy protecting group. A preferred protecting group Rp is trimethylsilyl or acetyl.

Examples of aprotic solvents include dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methylpyrrolidine, dimethylsulfoxide, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, hexamethylenetriamide phosphoric acid, mixtures thereof or a mixture of one of these with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like. Aprotic solvents do not adversely affect the reaction, and preferred solvents include dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methylpyrrolidinone, and mixtures thereof.

The protected compound 2 is then treated with sodium hexamethyldisilazide or sodium hydride in an aprotic solvent at 0-25 ° C, and carbonydiimidazole to give compound 3.

Treatment of compound 3 with an amino compound of general formula (I)

X. Λ of formula —f

R 2 -ar ₃ (CH ₂ ) _o -NH _: either solvent-free or with acetonitrile at 25-80 ° C, followed by deprotection to give the N-substituted cyclic carbamate which depicts the compound of formula 4. Removal of hydroxy protecting groups at positions 2 'and 4

By the methods described by T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Son, Inc. 1991.

Demethylation of the 3'-N-dimethyl group is accomplished by treating compound 4 with iodine in the presence of a suitable base such as sodium acetate and using a light or heat source, followed by quenching with sodium thiosulfate and further processing to give compound 5. N-dealkylation can also be performed with using chloroformate agents such as benzyl chloroformate, allyl chloroformate, vinyl chloroformate and the like.

Alkylation of the 3'-N-demethylated compound 5 is accomplished by treatment with a suitable aldehyde or ketone in the presence of a metal hydride such as sodium cyanoborohydride or sodium triacethoxytetraborohydride in the presence of a Pd / C catalyst and in a protic or aprotic solvent and hydrogen atmosphere. Said aldehydes or ketones which can be used in the preparation of compound 5 include, for example, cyclopropylcarboxaldehyde, acetone, propanal, cyclohexanone, cyclopentanone, isovaleraldehyde, cyclobutanone, isopropylaldehyde,

2'-pyridinecarboxaldehyde, 4-thiazolecarboxaldehyde.

Alkylation of the 3'-N-demethylated compound 5 can also be accomplished by reaction with a suitable alkylating agent in the presence of a base by methods known in the art to provide compound 6. Alkylating agents that can be used in the preparation of compound 5 include lower alkyl halides such as ethyl bromide, halogen-substituted lower alkyl halides, cyano-substituted lower alkyl halides, hydroxy-substituted lower alkyl halides, other lower alkynyl halides such as propargyl bromide, lower cycloalkyl halides, lower cycloalkylmethyl halides such as lower cyclopropylmethyl halides, and benzyl methyl halides; .

Scheme 2 depicts a specific embodiment of Example 1 which comprises treating 2'-acetyl-6-O-methyl-erythromycin A 7 with trimethylsilyl chloride to give compound 8. Compound 8 is then treated with sodium hexamethylcisilazide and carbonyldiimidazole to form 12. -O-α-allimidazole derivative, which subsequently reacts with 3,4-dichloroethylene amine to form a derivative containing

11,12-cyclic carbamate. The 11,12-cyclic carbamate thus obtained is then treated with methanol to form compound 9.

Deprotection of the 4-protected hydroxy group by methods known in the art yields compound 10. Treatment of compound 10 with iodine in the presence of sodium acetate followed by quenching with sodium bisulfite yields compound 11. Alkylation at 3'-nitrogen is accomplished by reaction with cyclopentanene. in the presence of sodium cyanoborohydride in methanol with the addition of a few drops of acetic acid to give the final product, compound 12.

£ • · · ·

The foregoing description of the invention is further elucidated by o

However, the scope and spirit of the invention are not limited thereto.

Examples

Example 1

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate), ( Compound 12, Scheme 2)

6-O-methyl-erythromycin (commercially available from Abbott Laboratories as BIAXIN® is protected by an acetyl protecting group at the 2'-position by methods known in the literature.

Step 1: 2'-O-acetyl-4-O-trimethylsilyl-6-O-methyl-erythromycin A (Compound 8, Scheme 2)

2'-O-acetyl-6-O-methyl-erythromycin A (45 g, 57 mmol) was dissolved in 453 mL of CH ₂ Cl ₂ and cooled to 0 ° C in an ice / water bath. Then pyridine (13.8 mL, 171 mmol) was added in one portion, followed by dropwise addition over 15 minutes, TMS-C1 (14.5 mL, 114 mmol). The reaction mixture was stirred for 1 hour, protected by a drying tube, after which time TLC (CH ₂ Cl ₂ : MeOH, 9: 1) indicated complete conversion to the less polar component. The reaction was quenched by the addition of 500 mL of 5 M NaH ₂ PO ₄ , the organic layer was separated and washed with H ₂ C (300 mL), NaHCO ₃ (saturated) (300 mL), H ₂ O (300 mL), and brine. solution (100 ml), then the solution is dried (Na ₂ SO ₄ ), filtered and concentrated. Crystallization of the residue from CH ₃ CN gave 48 g of compound 8 (98%); mp 235-237 ° C (CH ₃ CN); _Rf; 5 (CH ₂ C1 _2: MeOH, 9: 1); MS ESI (M + H) &lt; + &gt;

8 62; ¹³ C NMR 75 MHz, CDCl3) δ 80, 5, 80,3, 13.3, 77.8, 76, 4, 65.2, 62,7, 50, 3, 4, 9, 4 45, 1, 35, 6 _; 30,9, 22.1, 21.5, 21, 4, 15,8, 12,1, 10.4, 8.9, 0.8.

··· ·

221.0, 175.6, 169.9, 100.0

74.1, 73.2, 72.0, 69,0, 67 44,9, 40,5, 38.7, 38,6, 37 20,9, 19,7, 19,2, 17,8, 15 Dec

Step 2: 4'-O-trimethylsilyl-11-deoxy-11- [carboxy- (3-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) (Compound 9, Scheme 2)

Compound 8, prepared in Step 1 (20.4 g, 24.2 mmol) was dissolved in 20 mL of anhydrous THF and then diluted with 200 mL of DMF. The resulting solution was cooled in an ice / water bath and then treated with 1,1'-carbonyldiimidazole (19.6 g, 120.9 mmol) added in one portion and then treated dropwise with 1.45 g (36 mmol). NaH (60% oil suspension). The reaction mixture was then allowed to warm to room temperature and stirred for 1 hour at room temperature under nitrogen atmosphere where TLC analysis [EtOAc: MeOH, 95: 5, visual detection by Ce (IV)] indicated complete conversion to the more polar component. The reaction was carefully quenched by the addition of water and then partitioned between EtOAc (400 mL) and water (300 m). The organic phase was separated and washed with 1N NaOH (300 mL), water (2 x 300 mL), and brine (200 mL), then dried (Na 2 SO 4) and concentrated. A sample of the obtained colorless foam was analytically evaluated by MS, which showed (M + H) ⁺ @ ⁺ m / z 938 of the desired acylimidosol intermediate. This product was dissolved in CH ₃ CN (25 mL) and treated with 7.0 g (36 mmol).

3,4-dichlorophenethylamine, and stirred under N 2 at 55 ° C. After 48 hours. TLC analysis (EtOAzMeOH, 95: 5, visual indication with Ce IV)] indicated complete conversion of the starting compound to a less polar component which precipitated by cooling to room temperature. The precipitate obtained is then recrystallized from CH ₃ CN to yield 16.1 g of 2 ', 4-protected cyclic carbamate as colorless needles. This protected cyclic carbamate (16.1 g, 15.2 mmol) was suspended in 250 mL of methanol and the suspension was heated at 55 ° C with protection through a drying tube. After 24 hours TLC analysis [CH 2 Cl 2: MeOH, 9: 1, visual indication Ce (IV)] indicated complete conversion of the starting imidosol intermediate to a new less polar product that precipitated upon cooling to room temperature. The solid obtained is recrystallized from MeOH / water to give 13 g of compound 9. mp 112-114 ° C; R _f = _0; 65 (CH ₂ Cl ₂ : MeOH, 9: 1); MS (ESI) (M + H) &lt; + & gt ^; at m / z 1017; HRMS m / z (M + H) ⁺ calcd: 999-5176, found: 999-5151; ^{Τ Η} NMR (300 MHz,

CDCI3) δ 7.46 (d, J = 2 Hz, Ar Η), 7.35 (d, J = 8 Hz, Ar Η), 7.19 (dd, J = 8.2 Hz, Ar Η), 4.91 (d, J = 4.4 Hz, 1H), 4.56 (d, J = 7 Hz, 1H, Cl-CH), 3.75 (d, J = 10 Hz, 1H, C- 3 CH), 3.70 (s, 1H, C-11 CH), 3.67 (d, J = 8 Hz, 1H, C-5 CH), 3.31 (s, 3H, C-6 OCH3 ₎ ), 3.07 (s, 3H, C-6 OCH ₃ ), 2.38 (d, J = 15 Hz, 1H, C-2 CH), 2.28 (s, 6H, C-2'N ( CH ₃ ) ₂ ), 1.43 (s, 3H, C-6 CH ₃ ), 1.40 (s, 3H, C-12 CH ₃ ), 1.07 (d, J = 23 Hz, 3H, C -10 CH ₃ ), 0.82 (t, J = 7 Hz, 3 H, C-15 CH ₃ ), 0.16 (s, 9H, C-4 OSi (CH ₃ ) ₃ ); ⁿ C NMR (75 MHz, CDCl ₃ ) δ 216, 1, 176.5, 157.2, 139.3, 132, 1,

131.0 , 130, 2, 1 30, 0, 128 , 4, 102.4, 96,6, 82,8, 80, 6, 79, 9 79,0, 78,0, 76, b 73.1, 71.1, 68.0, 65.2, 64.7, 60.3, 50.6, 49,6, 45,5, 45, 3, 44,8, 40.0 (2C), 39,1, 38,9, 35, 6, 32.6, 28,6, 22,1, 21, 8, 21,7, 20.1, 19.2, 18,8, 16,0, 14.1, 14.0, 10.2, 9.0, 0.8. Degree 3: 11- • deoxy- 11- [carboxy- - (3,4-

-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) (compound 10, scheme 2)

Compound 9 prepared in the above step (2.51 g,

2.46 mmol) was dissolved in 20 mL THF, treated with 2.6 mL of THF

TBAF (1 M / THF, 2.6 mmol), and stirred at room temperature.

• · · · · · · · · · · · · · · · · · ·

· · ·

9 · * • ⁵ *

9

After 2 hours TLC analysis [CHCl ₃ : MeOH: NH 4 OH, 90: 8: 1, visualization with Ce (IV)] indicated complete conversion of the starting component to a new, less polar product. The reaction mixture was then partitioned between EtOAc (300 mL) and water (300 mL). The organic phase was washed with NaHCO 3 (saturated, 200 mL), water (200 mL), and brine (200 mL) and then dried (Na 2 SO ₄ ) and concentrated. The residue obtained is recrystallized from CH ₃ CN to give 1.5 g of product (64 L): mp 240-243 ° C; R _f = 0.45 (CHC1 _3: MeOH: NH ₄ 0H, 90: 8: 1); MS (EAB) (M + H) &lt; + & gt ^; at m / z = 945; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.45 (d, J = 2 Hz, 1H, Ar Η), 7.35 (d, J = 8 Hz, 1H, Ar Η), 7.19 ( dd, J = 8.2 Hz, 1 H, Ar Η), 4.44 (d, J = 7 Hz, 1 H,

C-1 (CH), 3.75 (d, J = 10 Hz, 1 H, C-3 CH), 3.69 (s, 1H, C-11 CH), 3.33 (s, 3H, C-3 OCH ₃ ), 3.07 (s, 3H, C-6 OCH3) 2 29 (s, 6H, C-3 'N _{(CH3) 2);} 2.19 (d, J = 10Hz, OH, C4 OH), 1.44 (s, 3H) C-6 _CH3), 1.40 (with, 3H, C-12 _CH3), 1.31 (d, J = 6Hz, 3H, C-6 CH ₃ ), 1.26 (s, 3H, C-3 CH ₃ ), 1.15 (d, J = 7 Hz, 3 H, C-8 ch ₃ ), 1.12 (d, J = 8 Hz, 3H, C-4 CHJ, 1.02 (d, J = 7Hz, 3H, C-10 CH ₃ ), 0.83 (t, J = 8 Hz 3H, C-15 CH ₃₎ ; ¹³ C NMR (75 MHz, CDCI3)

δ 216.2, 176.4, 157.2, 139.3, 132.1, 131.0, 130.2, 130.1, 128.4, 102.9, 96.2, 82.8, 80 , 1, 78.9, 77.9, 77.8, 76.2, 72.6,

70,9, 68,9, 65.8, 65.6, 60.3, 50.6, 49.5, 45.5, 45.3, 44.8, 40.2 (2C), 39.0, 38.9, 34.8, 32, 6, 28.5, 21.9, 21.5 (2C), 20,2, 18,9, 13.7, 16.0, 14.2, 14.1, 10.2, 9.0; IR (KBr) at 3430, 2970, 2940, 060, 1735, 1710, 1460, 1420 1380 1235 1170 1070, 1055, 1710, 1000 cm ^-1 ; analysis: : calculated for C47H74Cl2N2O1 ;: I · C 5 H ₂ 0: C, 59 11; H, 7, 91; N, 2.93 . Found: C, 59, 13 ; H, 8 , 12; N, 2.89.

Step 4: 3'-N-demethyl-11-deoxy-11- [carboxy- (3,4-dichlorophenetnylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carramate) (Compound 11, Scheme 2 ) · * · Φ

2.5 g of the compound prepared in Step 3 (2.65 mmol) was dissolved in 5C mL of methanol and treated with 1.80 g NaOAc-3H ₂ O (13.25 mmol) and 0.71 g of I ₂ (2.78 mmol). mmol). The solution was then irradiated with a 500 W halogen lamp and stirred at room temperature. After 2 hours TLC analysis indicated complete conversion of the starting compound to a new, more polar component. Excess I ₂ was removed by adding 1 M Na ₂ S ₂ O ₃ dropwise. The reaction mixture was concentrated and the residue was purified on a silica gel column (eluting with CHCl ₃ : MeOH: NH ₄ OH, 90: 8: 1) to give 1.75 g of compound 11 (71%) as an amorphous solid; mp 136-142 ° C (acetonitrile / water); R _f = 0.33 (CHCl _3: MeOH: NH ₄ OH, 90: 8: 1); MS (FAB) (M + H) &lt; + & gt ^; at m / z 931; ^: Η NMR (300 MHz, CDC1 ₃₎ δ 7.45 (d, J = 2 Hz, 1H, Ar Η), 7.35 (d, J = 8 Hz, 1H, Ar Η), 7.19 (dd J = 8.2 Hz, 1H, Ar = 4.42 (d, J = 7 Hz, 1H, C-1 &apos; CH), 3.74 (d, J = 9 Hz, 1H, C-3) CH), 3.69 (s, 1H, C-11CH), 3.32 (s, 3H, C-3CH ₃ ), 3.07 (s, 3H, C-6CH ₃ ), 2, 42 (s, 3H, C-3'NCH ₃ ), 1.44 (s, 3H, C-6 CH ₃ ), 1.41 (s, 3H, C-12 CH ₃ ), 1.31 (d, J = 6Hz, 3H, C-6 _CH3), 1.26 (s, 3H, C-3 CH _3), 1.16 (d, J = 7 Hz, 3H, C-8 CH _3), 1.07 (d, J = 8Hz, 3H, C-4)

CH ₃ ), C-15 1.03 CH _3); (d, J = 7 Hz, 3 H, C-10 CH ₃ ), (t, J = 7 Hz, 3H, 1, 139.2, ¹³ C NMR (75 MHz, CDC1 ₃ ) 216 216.2, 176.2, 157, 132.2 , 131, 0, 130 , 3, 130.2, 128.4 , 102,4, 96,2, 82.7. 80.5. 78,8, 77,8, ? \ 7, 76.3, 75, 0, 72, 7, 68.6, 65.7, 60.3, 50.7, 50, 6, 49,5, 45,4, 45, 3, 44 8, 39, 0, 38.9, 38,8, 37,3, 34,8, 33,3, 32, 6, 21, 9, 21.5, 21, 3, 20, 1, 18.9, 18,7, 16,0, 14,2, 14.1, 10.2, 9.6: IR (KBr) ν 3420, 2970 2940 1760 1735 1710 1460, 1420, 1330, 1235, 1170, 1065, 1010, 1000 < cm ^γ ;

Analysis: for C ₄₆ vypočeeno H72Cl ₂ N ₂ Oi3.0,75 H ₂ O: C, 56 39; H, 7.44; N, 2.81. Found: C, 56.63; H, 7.36; N, 2.78.

• ·

Step 5: 3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12- (cyclic carbamate) (Compound 12, Scheme 2)

Dissolve 0.2 g (C, 21 mmol) of the compound obtained in Step 4 in 3 mL of methanol and treat with cyclopentanone (88 mg, 1.05 mmol), sodium cyanoborohydride (20 mg, 0.32 mmol) and acetic acid (1 drop) and the mixture was stirred at room temperature. After 48 hours TLC analysis [CH ₂ Cl ₂ : MeOH,

9: 1, visualization using Ce (IV)] indicates complete conversion to a new, less polar product. The reaction mixture was then partitioned between ethyl acetate (300 mL) and 50% saturated sodium bicarbonate solution (300 mL). The organic layer was then washed with water (2 x 200 mL) and brine (200 mL) and then dried (Na ₂ SO ₄ ), filtered and concentrated. The residue obtained is filtered over silica gel (CH ₂ Cl _2: MeOH, 9: 1) and the product obtained is recrystallized from acetonitrile / water to yield 153 mg (73%) of compound 12 as colorless needles; R _f = 0.50 (CH ₂ C1 _2: MeOH, 9: 1); mp 145-147 ° C (CH ₃ CN / H ₂ O); MS (FAB) (M + H) &lt; + & gt ^; at m / z 999; HRMS m / z (M + H) ⁺ calcd 999.5166, found 999.5110; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.44 (d, J = 2 Hz, 1H), 7.33 (d, J = 8 Hz, 1H), 7.18 (dd, J = 8.2 Hz, 1 H), 4.91 (d, J = 4 Hz, 1 H), 4.88 (dd, J = 11.2 Hz, 1 H), 4.44 (d,

J = 7 Hz, 1H), 4.03-3.98 (m, 1H), 3.88-3.76 (m, 2H), 3.73 (d,

J = 10 Hz, 1 H, 3.68 (s, 1 H), 3.65 (d, J = 7 Hz, 1 H), 3.493.46 (m, 1 H), 3.32 (s, 3 H) 3.17 (dd, J = 10.7 Hz, 1H), 3.11 (q, J = 7 Hz, 1H), 3.05 (s, 3H), 3.02-2.95 (m, 2H), 2.93-2.83 (m, 3H), 2.64-2.60 (m, 2H), 2.36 (d, J = 15 Hz, 1H), 2.16 (s,

3H), 2.14 (d, J = 10 Hz, 1H) , 1.93-1.7 5 ( series m, 7H ), 1, 70- 1.41 (m series, 7H) , 1.41 (with, 3H), 1.38 (with , 3H), 1, 33 -1.32 (m, 2H), 1.28 (d, J = 6 Hz, 3H), 1,28-1,24 (m , (H), 1, 24 (with, 3H), 1.20 (d, J = 6Hz, 3H), 1.20 (d, J = 6) Hz , 3H), 1, 13 (d, J = 7 Hz, 3H), 1.11 (d, J = 8 Hz, 3H), 1.00 (d, J = 7 Hz t 3H), 0.81

• · · · · · · · · · · · · · · · ·

48 • 9 * • · · · · · · · (t, J = 7Hz, 3H) ; ¹³ C NMR (75 MHz, CDCI3) 6 216 , 2, 176.3, 157.1 , 139.3, 132 , 1, 131.0, 130.2, 130,0, 128.3 , 102.9, 96.0 82,8, 80.1, 72.8, 77, 9, 77.7, 76.1, 72.6, 70.2, 68.9, 65.7, 63, 5, 63.0, 61.3, 50.6, 49.4, 45.5, 45,2, 44,7, 39.0, 38.9 (2C), 34.8, 32.1, 32.5, 31.5, 30, 9, 30.1, 23.7, 23.6, 21.8, 21.4 (2C), 20.1, 18.8, 18.6, 15.9, 14.1, 14,0, 10.2, 8.9; IR

(KBr) ν 3440, 2930, 1760, 1740, 1715, 1460, 1380, 1235, 1170, 1070, 1055, 1215, 1000 cm ^-1 ; analysis: calcd for C 51 H 8 OCl 2 N 2 O 13: 2, 61.24; H, 8.06; N, 2.80. Found: C, 61.07; H, 8.18: N, 2.54.

Example 2

3'-N-demethyl-3'-N-cyclopropyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared according to the method for EXAMPLE 1, substituting [(1-ethoxy-cyclopropyl) oxy] trimethylsilane for cyclopentanone; R _f = 0.35 (CH ₂ C1 _2: MeOH, 95: 5);

m.p. 258-260 ^: C (CH3CN); IR (KBr) at 3450, 2970, 2940, 1750, 1740 1730, 1470, 1460, 1380 , 1240, 1170, 1070, 1010, 1000 cm ⁴ , ³ H NMR (300 MHz, CDCl ₃ ) δ 7, 46 (d, J = 2Hz, 1H); 7.36 (d, J = 8 Hz, 1H), 7.20 (dd, J = 8.2 Hz, 1H), 4.93 (d, J = 4 Hz, 1 H) 4.91 (db, J = 9.2 Hz), IH), 4.45 (d, J = 7Hz, 1H), 4.08- 3, 98 (m, 1H), 3.95-3.76 (m, 2H), 3.75 (d, J = 9 Hz, 1H), 3.70 (with, 1H), 3.67 (d, J = 7Hz, IH), 3.58-3.48 (m, 1H); 3.34 (s,

3H), 3.20-3.11 (m series, 2H), 3.08 (s, 3H), 3.04-2.82 (m series, 4H), 2.65-2.55 (m, 2H), 2.39 (d, J = 15Hz, 1H), 2.31 (s,

3H), 2.21 (d, J = 10Hz , 1H), 1.99-1, 81 ( series m  , 3H), 1,78- 1.75 (series r 3H), 1, 65-1,50 (series m, 3H), 1, 44 (s, 3H), 1.42 -1.38 (m, 1H), 1.40 (s, 3H) 1.32 (d, J = 6 Hz, 3H) , 1.27 (with, 3H), 1.25 _k d, J = 6 Hz, 3H), 1.23 (d, J = 6 Hz, 3H) , 1.16 (d, J = 7Hz, 3H), 1.11 (d, J = 7Hz, 3H) , 1.03 (d, J = : 7 Hz,

»·»

3H), 0.83 (t, J = 7Hz, 3H), 0.62-0.45 (m series, 3H), 0.360.28 (m, 1H): ¹³ C NMR (75 MHz, CDCl ₃ ) δ 216, 3, 176.4, 157.2,

139,4, , 132, 2 131 1, 130 , 3, 1 30.2 OF 128.4, 103, 1, 96,2, 82,8, 80,4, 79,0, 71,0, 77.6, 76,3, 72, 7, 70,5, 69,0, 65,8, 64.8, 60,5, 50.7, 42,5, 45, 6, 45,3, 44, 8, 39,2, 39, 1, 39,0, 37,0, 36, 6, 35,2, 32.7, 30.1, 22,0, 21, 6, 21,5, 20,2, 18,9, 18,7, 16, 1, 14,3, 14,2, 10.3, 9.1, 7.9, 6 , 8; MS (APCI) (M + H) &lt; + & gt ^;. at m / z

971; HRMS m / z (M + H) ⁺ calcd 971-4803, found 971-44837; Analysis: Calculated for C _{2 4} 9H76Cl2N 0i _3: C, 60.55: H, 7.88; N,

2.88. Found: C, 60.62; H, 7.82; N, 2.88.

Example 3

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3,4-dichlorophenetnylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared according to the method for EXAMPLE 1, substituting propanal in place of cyclopentanone; Rf = 0.45 (CHCl3: MeOH: Nr + OH, 90: 8: 1); IR (KBr) ν 3440, 2970, 2930, 1760, 1735, 1710, 1460, 1380, 1235, 1170, 1065, 1055, 1010,

1000 cm ^{_1: 3} H NMR (300 MH of, CDC1 ₃ ) δ 7.46 (d, J = 2 Hz, 1 Η) 7.36 (d J = 5 Hz , i Η), 7, 20 (dd , J = 8.2 Hz, 1 H), 4,93-4 , 88 (m, 2H) 4.45 (d, J = 7 Hz, 1H), 4.04-3.99 (m, 1H), 3,88-3, 81 (m, 2H) 3.75 (d, J = 9 Hz, 1H), 3.70 (s, 1 H), 3, 68 (d, J = 8 Hz, 1H) , 3.49-3.4 8 (m , i Η), 3.34 (s, 3H) 3.22 (dd, J = 10, 7 Hz, 1H) , 3.13 (q, J = 7 Hz, 1H), 3.0 58. (s, 3H) , 3.07 -2.82 (ser ie m, 5H), 2, 65-2 , 29 (with erie m, 5H), 2.27 (s, 3H) ), 2.19 (d, J = 10 Hz, 1 H ), i , 94 -and, 4 8 (s m, 9H), 1 , 44 (p , 3H), 1.40 (with, 3H), 2.31 (d, J = 7 Hz, 3 H), 1.27 (s, 3H), 1 , 25-1,1 3 (m, 2H) , 1.23 (d, J = 6 Hz, 3H), 1.22 (d, J = 7 Hz, 3H), 1, 16 (d, J = 7Hz, 3H) , 1, 12 (d, J = 7 Hz, 3H), 1.0 3 (d, J = 7 H; of, 3H), O, 91 (t, 7 H of, 2H) , 0.8 (t, J = 7Hz, 3H); ¹³ C NMR (75

MHz, CDC1 ₃₎ δ 116.3, 176, 4, 157.2, 139.3, 132.2, 131, 0, 130, 3,

130,2, 128.4 , 102 , 9, 96.2, 82 8, 80.1, 78, 9, 77 9, 77 , 8, 76.2 72.6, 70,6, 62,9, 65.8, 65.6, 60, 3, 55.0, 50.7, 49, 5, 45,5, 45,3, 44,8, 39.1, 39.0, 38, 9, 36.9, 34,8, 32,6, 29,5, 21,9, 21,5, 21,4, 21.3, 20.2, 18, 9, 18.7, 16,0, 14,2, 14, 1, 11,6, 10.2, 9.0: MS (APCI) (M &lt; + &gt;) H) ⁺ m / z 972 anal; ysis: v ypočteno for C ₅ iH ₈₀ C1 ₂ N ₂ C- ₃ · C > 5 _with H ₂ 0: C, 59 , 86 ; H, 8.10 ; n, 2.84. Found C, 59, 93; H, 8.24 ; 2,8, 2.88.

Example 4

3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) -hydrochloride

Step 1: The free base of the title compound was prepared according to the method of Example 1 except that cyclobutanone was used instead of cyclopentanone; _Rf = 0.55 (CH2Cl2: MeOH, 9: 1); IR (KBr) ν 3460, 2930, 1760, 1740, 1710, 1460, 1380, 1235, 1170, 1100,

1060 , 1005, 995 cm ^-1 : ¹ 1 H NMR (300 MHz, CDCl 3) δ 7.46 (d, J = 2 Hz, 1H), 7.35 (d, J = 8) Hz, 1H) 7.20 (dd, J = 8.2Hz, 1 H), 4.94 -4.88 (m, 2H), 4.45 (d, J = 7) Hz, 1H), 4.04-3.78 (m, 3H) t 3.75 (d, J = 10Hz, 1 H) , 3.70 (s, 1H), 3.67-3.64 (m, 1H); 66 (d, J = 8 Hz, 1H), 3.64 -3.45 (m, 1H), 3.33 (s, 3H), 3.28-3.1 2 (m, 3H), 3.05 (s, 3H), 3.06-2.82 (m, 4 H), 2.65-2.60 (m, 1 H), 2.49 -2.29 (m, 2H), 2.13 (d, J = 1) 0 Hz, 1H), 2.06 (s, 3H), 2.01 -1.48 (m-series, 14H ), 1.43 (p , 3H) 1.40 (s, 3H), 1.31 (s) d, J = 6 Hz, 3H), 1.25 (s, 3H), 1.24 (d, J = 5.9 Hz, 3H), 1.22 (d, J = 5.9 Hz, 3H), 1 16 (d, J = 8 Hz 3H), 1.13 (d, J = 8) Hz, 3H), 1.03 d, J = 7 Hz, 3H), 0.83 (t, J = 7Hz, 3H); ¹³ C

NMR (75 MHz, CDCl ₃ ) δ 216, 2, 176, 3, 157.1, 139.3, 132.2, 131.0,

130.2, 130.0, 128.4, 103.1, 96.1, 82.8, 80.4, 78.9, 77.9,

77.8, 76.3, 72.7, 70, 1, 68, 9, 65.8, 60.4, 60, 1, 56, 8, 50, 6,

49.4, 45.6, 45.3, 44.8, 39, 1, 39.0, 34.9, 32.7, 31.0, 29.7,

28.6, 28.2, 21.9, 21.5, 21.4, 20.2, 18.9, 18.7, 16.0, 14.2,

14.1, 14.0, 10.2, 9.0; MS (FAB) (M + H) &lt; + & gt ^; at m / z 985; HRMS m / z (M ⁺ H) calcd 985 ^ 4959, found 985 ^ 4949: Calcd for C5iH7 ₈ Cl ₂ N ₂ 0i3 · 075 H ₂ 0: C, 60.55; H, 7.92; N,

2.76. Found: C, 60.56; H, 7.97; N, 3.02.

Step 2: Preparation of 3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin HCl salt, 11,12 - (cyclic carbamate)

160 mg (3.16 mmol) of 3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy-3,4-dichlorophenethylamino)] -6-O-methylerythromycin A 11,12- ( of the cyclic carbamate) was dissolved in 5 mL of EtOAc and treated with 0.16 mL of 1 M HCl / ether. The mixture was stirred at room temperature for 0.5 hour, during which time a precipitate formed. The precipitate was filtered off to give 125 mg of 3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11 [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11, 12 (cyclic carbamate) hydrochloride: MS (Cl) (M) ⁺ at m / z 985; Analysis: Calculated for C5OH79CI3N2O13 'Q _F 5 H ₂ 0: C, 58.21; H, 7.81; N, 2.71; Cl, 10.31. Found: C, 58.24; H, 7.90; N, 2.66; Cl, 10.06; RP-HPLC R _f = 22 ^ 0 min (45-90% CH ₃ CN gradient 1% per minute).

Example 5

3'-N-demethyl-3'-N-cyclohexyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carhamate)

The title compound was prepared according to the procedure in Example 1, substituting cyclohexanone for cyclopentanone. The crude product was purified on a silica gel column (CH ₂ Cl ₂ : MeOH, 9: 1) to give an amorphous solid; R _f = 0.55 (CH ₂ C1 _2: MeOH,

9: 1); IR (KBr - v 3440, 2970, 2930, 1760, 1730, 1705, 1455) •

1380, 1235, 1100, 1070, 1010, 1000 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ )

δ 7 46 (d, J = 2 Hz, IH) 7.35 (d, J = 8Hz, (H), 7, 20 May (dd, J = 8.2 Hz, 1H ), 4 93 (d, J = 5 Hz 1H, 4.91 (dd, J = 11.2 Hz, 1 Η), 4.46 (d, J = 6 Hz, 1 Η) 4,08-3,98 ( m, 1H), 3 , 88- 3, 80 (m, 2H) 3.76 (d, J = 10Hz, 1 ,70), 3.70 ( s, 1 H) t 3.68 (d, J = 8Hz, 1 H) , 3,50- 3.46 (m, 1H) H), 3.34 ( s, 3H), 3 , 17- 3, 11 (m series, 2H) , 3.08 (s, 3H) 3 , 04-2.82 (m 5H), 2, 61-2,32 (m, 2H), 2.39 (d, J = 15 Hz, 1H), 2 25 (s, 3H) , 2.19 (d t J = 10 Hz, 1 H) , 1, 94-1.48 (m series, 17H), 1.44 (s, 3H) l), 1.40

(s, 3H), 1.36-1.34 (m, 2H), 1.31 (d, J = 7Hz, 3H), 1.27 (s, 3H), 1.23 (d, J = 6 Hz, 3 H), 1.22 (d, J = 6 Hz, 3 H), 1.16 (d,

J = 7Hz, 3H), 1.13 (d, J = 8Hz, 3H), 1.03 (d, J = 7Hz, 3H), 0.83 (t, J = 7Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 216.2, 176.3, 157.1, 139.3, 132.1, 131.0, 130.2, 130.1, 128.4, 103.0 , 96,2,

82,8, 80.1 , 78,9, 77.9 (2C), 76.2, 72.6, 70.4, 68.9, 65.8, 63,0, 61.2 , 60,3, 50.7, 49, 5, 45,5, 45,3, 44.8, 39.1, 39.0, 38,9, 34.8 , 33,5, 32,6, 31,8, 31,7, 30,9, 26, 0, 25.9, 21.9, 21,5, 20, 1 , 18,9, 18,7, 16,0, 14,2, 14.1, 10.2, 8.9; MS (FAB) (M + H) &lt; + & gt ^;. at m / z 1013; HRMS m / z (M + H) ⁺ calculated 1013 ^ 5272,

found 1013-5242; Calcd for C52H82Cl2N2O13: C, 61.58; H, 8.15; N, 2.76. Found: C, 61.31; H, 8.16; N, 2.76.

Example 6

3'-N-demethyl-3'-N-isovaleryl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared by the method of Example 1 except that isovaleraldehyde was used instead of cyclopentanone.

The crude product was purified on a silica gel column (CHCl 3: MeOH: NH 3 OH, 90: 8: 1) to give an amorphous solid; _Rf = C 33 _(CHCl3: MeOH, 94: 6); IR (KBr) v 3435, 2960, ·

2940, 1750, Z'35, 1460, 1165, 1105, 1065, 1055, 1030, 1010 cm ^-1 ; ^{Χ Η} NMR 300 MHz, CDC1 ₃₎ δ 7.46 (d, J = 2 Hz, IH), 7.34 (d, J = 8 Hz, IH), 7.19 (dd, J = 8.2 Hz (1H), 4.92-4.88 (m series, 2H), 4.44 d, J = 7 Hz, 1 Η), 4.03-4.00 (m, 1 Η), 3.87- 3.81 (m, 2H); 3.7; (d, J = 10 Hz, 1 Η), 3.69 (s, 1 Η), 3.67 (d, J = 8 Hz, 1 Η), Z, 64 (wide singlet, 1 Η), 3, 50-3.47 (m, 1 °),

3, 33 (s, 3H) 3.21 -3.17 (m, IH), 3.14-3, 11 (m, 1H); , 07 (s, 3H), 3,05-2,9 ' (sé rie m, [0100] 2H ), 2.94-2.86 (m series, 2H) , 2,64- 2.62 (m, 1H) 2.57 -2.52 (m, 1H), 2.38 (d J = 14 Hz 1H), 2,33- 2.30 (m, IH), 2.23 (with, 3H), 2.18 (d , J = 10, 1H) , 1,93- 1.86 (series r, 2H) , 1.77 51 (m series, 7H), 1.43 (s, 3H), 1.39 (s, 3H) 1.38 -1.21 (sé river m, 14H), 1.15 (d, J = 7 Hz, 3H), 1.12 (d, J = 8 Hz, 3H) 1.02 (d, J) = 7Hz, 3H) 0.90 (d, 6H), 0.82 (t, J = 7 Hz, 3H) ; ¹³ C NMR (75 MHz, CDCl ₃ ) δ 216,1, 176, 4 , 157,2, 139, 3, 132 , 2, 131.0, 130.1 , 128.4, 103, 0, 96.1, 82,8, 80.2, 73 , 9, 77,9, 77, 9, 76.22, 72, 63, 70, 6, 69 0, 65.8, 65,5, 60.3, 51 , 6, 50, 6, 49, 5, 45.3, 44.8 , 39.1, 39.0, 39,0, 37,5, 36.8, 34 , 8, 32,6, 29, 4, 26.1, 22.7 , 22.7, 21.9, 21,4, 20,1, 18.9, 13 , 7, 16,0, 14, 2, 14.1, 10.2 , 9.0; MS (FA , B) (M + H)

at m / z 1001; analysis: calcd for C 51 H 82 Cl 2 N 2 O 13. O 5 H ₂ O: C, 60.58; H, 8.2 '; N, 2.77. Found: C, 60.46; H, 8.11; N, 2.78.

Example 7

3'-N-demethyl-3'-N- (methylthiopropionyl) -11-deoxy-11- [carboxy- (3,4-dichloroethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared according to the method for EXAMPLE 1, substituting 3-methylthiopropionaldehyde for cyclopentanone. The crude product was purified on a silica gel column (CHCl ₃ : MeOH: NH ₄ OH, 90: 8: 1) to give an amorphous solid; IR (KBr) ν 3460, 2970, 2930, 1750, 1460, 1235, 1165, 1125, 1100, 1065, 1050, 1010, 995 cm ^-1 ; ¹ H NMR (300

MHz, CDC1 ₃₎ δ 7.44 (d, ΙΗ), 7.34 (d, H), 7.19 (dd, 1H), 4.91 4.87 (series of m, 2H), 4.43 ( d, 1H), 4.02-3.99 (m, 1H), 3.86-3.81

(m, 2H), 3.74 (d, 1H), 3, 69. (s, 1H), 3, 66 (d, 1H), 3.50-3.47 (m, 2H), 3.32 (s, 3H) 3.22-3.19 (m, ÍH), 3,13-3, 10 (m, ÍH), 3.06 (with, 3H), 3,04-2,99 (m series, 2H) , 2, 91-2.87 (series m, 2H), 2, 64 -2, 62 (series m, 2H), 2.54-2 , 43 (series m 4H), 2.37 (d, ÍH), 2.24 (s, 3H) 2.20 (d, 1H), 2.09 (s, 2H) , 1.99 (d,

1H), 1.90-1.86 (m, 2H series), 1.78-1.73 (m, 4H series), 1.65 (d, 1H), 1.60-1.50 (m series) (2H), 1.42 (s, 3H), 1.39 (s, 3H),

1.29 (d, 3H), 1.25-1.20 (m series, 1OH), 1.14 (d, 3H), 1.11 (d, 3H), 1.02 (d, 3H), 0.82 (t, 3 H); ¹³ C NMR (75 MHz, CDCl 3) δ 216.3, 176.4, 157.1, 139.3, 132.1, 131.0, 130.2, 130.1, 128.4,

102,9, 96.1, 82.8, 80.1, 78.9 , 77.8, 76.2, 72.6, 70.7, 68.8, 65.7, 65.7, 60.3, 52,2, 50, 6, 49.5, 45.5, 45.3, 44.8, 39, 1, 38,9, 36.7, 34.8, 32,6, 32,0, 29.5, 27.5, 21.9, 21.4, 21.4 20,1, 18.8, 18.6, 16,0, 15,6, 14.2, 14.1, 10.2, 8.9; MS (FAB) (M + H) &lt; + & gt ^;. at m / z 1019; analysis: calculated for C 50 H 80 Cl 2 N 2 O 13 S: C, 58.87; H, 7.90; N, 2.75. Found: C, 58.81; H, 7.76; N, 2.96.

Example 8

3'-N-demethyl-3'-N- (3-tetrahydrothienyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic) carbamat)

The title compound was prepared according to the method for EXAMPLE 1, substituting 1,2,3,4-tetrahydrothiophen-3-one for cyclopentanone. The crude product was purified on a silica gel column (CCl ₃ : MeOH: NH ₄ OH, 90: 8: 1) to give an amorphous solid; R _f = 0.45 _(CHCl3: MeOH, 94: 6); IR (KBr) ν 3440, 2965, 2930, 1760, 1735, 1460, 1165, 1130, 1100, 1065, 1050, 1030, 1010, 1000 cm ^-1 ; NMR NMR (300 MHz, CDCl ₃ ) δ 7.45 (d, J = 2 Hz, 1 H), 7.34 (d, J = 8 Hz, 1 Η), 7.19 (dd, J = 8, 2 Hz, 1 Η), 4.92-4.88 (m series, 2H), 4.46 (d, J = 7 Hz, 1 Η), 4.02-3.99 • ·

(m, 1 Η), 3, 9-3.77 (m, 2H) 3.74 (d, J = 10 Hz, 1H), 3.69 (with, IH), 3.52 -3.42 (m, 1H), 3.32 (d, J = 3 Hz (3H), 3.30-3.26 (m, IH), 3.21 (dd, J = 10.7 Hz, IH), 3, 12 (q < J = 7 Hz, 1H), 3 , 06 (with, 3H), 3,05-2,82 (m series, 7H), 2.78 -2, 61 (m series, 3H) 2.36 (d, J = 55Hz 1H), 2.2 8 (s, 3H), 2, 19-2,14 (m series,

2H), 1.93-1.49 (m series, 9H), 1.42 (s, 3H), 1.39 (s, 3H), 1.38-1.21 (m series, 13H), 1 15 (d, J = 7Hz, 3H); 1.10 (d,

J = 8Hz, 3H ', 1.02 (d, J = 7Hz, 3H), 0.82 (t, J = 7Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 216.2, 176.3, 157.1, 139.2, 132.1,

131,0, 130,2, 130.1, 128.4, 102.8, 96.1, 96.1, 82,8, 80,3, 80.2, 78,9, , 9, 77.8, 76 2, 72.7, 70,6, 70,5, 68,7, 68,7, 66.7, 65.8, 65 , 8, 65.8, 63, 9, 63.5, 60.3, 50.6, 49,5, 49,5, 45,5, 45.2, 45 , 2, 44.8, 39 0, 39.0, 38,9, 34,8, 34,2, 33,4, 33,2, 33.0, 22 , 6, 32.4, 31, 8, 31.3, 27,9, 27,9, 21,9, 21,4, 21,4, 20.1, 13 , 8, 18.6, 16, 0, 14.2, 14.1, 10.2, 9.0, 9.0 (more

signals than the number of carbon atoms are caused by a mixture of diastereomers); MS (FAB) (M + H) &lt; + & gt ^; at m / z 1017; analysis:

Calcd for C ₅ H _{7 8} Cl ₂ N ₂ O ₃ S: C, 58.99 / H, 7.72; N, 2.75.

Found: C, 58.85; H, 7.93; N, 2.67.

Example 9

3'-N-demethyl-3'-N- (3-dimethylcyclopentyl) -1-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamat)

The title compound was prepared according to the method for EXAMPLE 1, substituting 3,4-dimethyl-cyclopentan-1-one for cyclopentanone. The crude product was purified on silica gel column (CHS1 _3: MeOH: NH ₄ OH, 90: 8: 1) to afford an amorphous solid. IR (KBr) ν 3450, 2970, 2950, 1750, 1735, 1460, 1170, 1110, 1) 70, 1045, 1015, 1000 cm -1 ¹ : ¹ H NMR (300 MHz,

CDC1 ₃₎ δ 7.45 d, J = 2 Hz, 1 Η), 7.34 (d, J = 8 Hz, 1 Η), 7.18 (dd, J - 8.2 Hz, IH), 4 , 93-4.92 (m, 1Η), 4.89 (dd, J = 2.10) ·

1H), 4.45 (t, J = 7Hz, 1H, 4.03-4.00 (m, 1H), 3.88-3.77 (ra, 2H), 3.74 (d, J = 10Hz , 1H), 3.69 (s, 1H, 3.66 (d, J = 7 Hz, ÍH), 3.50-3.4 (m, 1H), 3.33 (s, 3H); 3.19-3.10 (m series, 2H), 3.06 (s, 3H) 3.04-2.94 (m series, 3H), 2.92-2.84 (m series, 2H), 2.65-2.55 (series m (2H), 2.36 (d, J = 15 Hz, 1H), 2.17 - 2.14 (series, 4 H), 1,94- 1.74 (m series, 6H), 1.63-1.44 (m series, 4H), 1.42 (s, 3H), 1.39 (s, 3H) 1.30 (d, J = 6Hz, 3H) , 27- 1.17 (m series, 1OH), 1, 14 (d, J = 7Hz) 3H), 1.12 (d, J = 8 Hz, 3H), 1.02 (d, J = 7) Hz, 3H), 0.98 (d, J = 6Hz, 3H) , 96

-0.94 (m, 3H), 0.82 (t, J = 7Hz, 3H); MS (APCI) (M + H) &lt; + & gt ^; at m / z 1027; Analysis: Calculated for C ₅ H ₈₂ Cl ₂ N ₂ 0i3: C, 61.91; H, 8.23;

N, 2.72. Found: C, 61.63; H, 8.22; N, 2.69.

Example 10

3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethylamino)] -6-O-methylerythromycin A, 11,12- (cyclic carbamate) )

Step 1: Preparation of α, α-cyclopropyl-3,4-dichlorophenethylamine

3,4-dichlorophenylacetonitrile (25 g, 134 mmol) in 50 mL of anhydrous ether was added dropwise to a suspension of NaNH ₂ (10.5 g, 268 mmol) in 220 mL of ether. After the addition was complete, the reaction mixture was heated at reflux for 4 hours and then cooled to 0 0. Then a solution of 1-bromo-2-chloroethane (11 mL, 134 mmol) in 25 mL of ether was added dropwise at 0 ° C. and then the reaction mixture is heated at reflux for an additional 18 hours. After cooling, the reaction was quenched carefully by addition of H 2 O and then partitioned between EtOAc (200 mL) and H ₂ O (200 mL). The organic layer was washed with brine (100 mL), then dried (Na ₂ SO ₄ ), filtered and concentrated. The desired product was obtained by kugelrohr distillation (165 ° C, 10 torr) as a colorless oil which solidified on standing. This solid was recrystallized from MeOH / H ₂ O to yield 11.75 g (44%) of α, α-cyclopropyl-3,4-dichlorophenylacetonitrile; MS (CI) (M) ⁺ at m / z 211; Anal Calcd for C 10 H 7 Cl 2 N: C, 56.63; H, 3.21; N, 6.60. Found: C, 56.48; H, 3.27; N, 6.55.

α, α-cyclopropyl-3,4-dichlorophenylacetonitrile (12.3 g,

57.8 mmol) was added dropwise to a suspension of lithium aluminum hydride (2.2 g, 58.0 mmol) in 50 mL THF at such a rate as to maintain a gentle reflux. After the addition, the reaction mixture was stirred at room temperature for 4 hours under N ₂ atmosphere. After this time, the reaction was carefully quenched by the gradual addition of H ₂ O dropwise (2 mL), 15% (aqueous) NaOH (2 mL), and H ₂ O (6 mL). The reaction mixture was filtered and the insolubles were washed with additional ether. The combined filtrates were dried (Na ₂ SO 4), filtered and concentrated to give α, α-cyclopropyl-3,4-dichlorophenethylamine as a colorless oil. MS Cl (M + H) ⁺ at m / z 216: RP-HPLC R f = 4.8 min (40-70% CH 3 CN, gradient 1% per minute); ³ H NMR (300 MHz, CDCl 3) δ 7.42 (d, J = 2 Hz, 1 Η),

7.37 (d, J = 8Hz, 1H), 7.17 (dd, J = 8.2Hz, IH), 2.78 (s,

2H), 1.17 (s, 2H), 0.81-0.77 (m, 4H).

Step 2: 3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12- (cyclic carbamate)

This compound was prepared according to the procedure of Example 1, substituting 3,4-dichlorophenethylamine (α, α-cyclopropyl-3,4-dichlorophenethylamine prepared in Step 1 above) and using acetone instead of cyclopentanone. from acetonitrile / water; mp 210-212 ° C (CH ₃ CN / H ₂ O); R _f = 0 → 95 (CHCl ₃ : MeOH: NH ₃ OH, 90: 8: 1); HPLC R _t = 19 → 7 min, column (C-18), 50-80-CH ₃ CN, gradient 1% / min IR (KBr) at 3440, 2960,

2930, 2880, l ~ 60, 1730, 1710 1460, 1440, 1380, 1230, 1165, 1100, 1060, 1210, 1000 cm ^-1 : ¹ 1 H NMR (300 MHz, CDCl3) δ 7.64 (d J = 2 Hz, 1 Η 7.44 (dd, J = 8.2 Hz, 1 Η), 7.33 (d, J = 8 Hz, 1 Η), 4, 98 (d, J = 4Hz, 1Η), 4.68 (dd, J = 11.3 Hz, 1 ohm), 4.47 (d, J = ^_ Hz, 1 Η), 4.35 (d, J = 15 Hz, 1 Η), 4.07-4.01

(m, 1 Η) 3,7 ' ‘-3.67 (m, 2H), 3 77 (s, 1H), 3.73 (d, J = 7 Hz, 1H, 3.68 (d, J = 7 Hz, 1H), 3 53-3,48 (m, ÍH), 3.34 (with, 3H), 3.32-3.13 (m, 2H), 3, 19 (s, 3H) , 3.06 (q, J = 8 Hz, ÍH), 2, 95- 2.87 (m, 2H), 2, 60- 256 (m, 2H) 2,40 ( d, J = 15 Hz, ÍH), 2.20 (s, 3H) 2.18 (d, J = 1 0 Hz, 1 H ), 1.90 (t, J = 7 Hz, ÍH) t 1.77-1.56 (sé: sie m, 7H) , 1,42-1 , 21 m 2H) , 1.42 (with, 3H) , 1.33 (d, J = 6) Hz, 3H), 1.32 (s, 3H) , 1.27 (with, 3H), 1 , 24 (d, J = 6 Hz, 3H), 1,22 (d, J = 6 Hz, 3H) , 1,14- 1.04 (ser e d, 12H :), O, 99-0.94 (m, 1H), 0, 91 (d, J = 7 Hz, 3H), 0.69 (t, J = 7 Hz,

3H), 0.63-0.53 (m, (H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 216.8, 175.3, 157.5 , 139.3, 132, 1, 131 , 5, 130.2, 130.0, 129.5 , 102.9, 96.2, 82,4, 80.2, 73.8, 78.1, 78.7 76.7 72.7 70.5 68.9, 65.8, 62,9, 61.9, 52.6, 51,3, 50.3, 49.5, 45.6, 45.0, 39,4, 39,3, 38.7, 34.9, 33.1, 30, 8, 24.1, 21.9, 21.5, 21.1, 20.5, 20,2, 19.5, 13.7, 16, 1, 15.2, 14.5, 12.0, 10.9, 9.7, 9.1; MS (FAB) (M + H) ⁺ at m / z 999; analysis: calculated for C51H80CI2N2O13: C, 61 , 24; H, 3.06; N, 2, 80. Found: C, 61.12; H, 8.28; N,

2.74.

Example 11

3'-N-demethyl-2'-N-cyclobutyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethyl amino)] -6-O-methyl-erythromycin Λ, 11,12- (cyclic carbamate)

The title compound was prepared as described in Example 10, substituting cyclobutanone for acetone.

• · • ·

The crude product is obtained by crystallization from acetonitrile / water; mp 148-150 ° C (CH ₃ CN / H ₂ O); Rf 0.6 (CHC1 _3: MeOH: NH OH, 90: 8: 1); HPLC R _t = 19.7 min. (C-18), 50-80% CH ₃ CN, gradient 1% / min; IR (KBr) ν 3440, 2970, 2930, 1760, 1735, 110, 1460, 1380, 1230, 1170, 1100, 1060, 1010, 1000 cm ^-1 ; ¹ H HMR (300 MHz, CDCl ₃ ) δ 7.64 (d, J = 2 Hz, 1 H), 7.44 (dd, J = 8.2 Hz, 1 H), 7.33 (d, J = 8) Hz, 1H), 4.99 (d,

J = 5 Hz ÍH) , 4.69 (dd, J = 11.3 Hz, 1H, 4.47 (d, J = 8 Hz, 1H, 4.35 (d, J = 15 Hz ÍH), 4.06-4.01 (m, 1H), 3.77 (with, ÍH), 3,74-3,72 (m, 2H), 3.69 (d, J = 4 Hz, 1 Η), 3.63 -3,60 (br with, 1 Η), 3, 52 -3, 46 (m, 1 H) , 3.34 (s , 3H) 3.22-3.12 (m, 3H), 3.19 (s, 3H). 3.04 (t, J = 10 Hz, ÍH), 2.96-2.90 (m, 1H), 2.65-2.55 (m, ÍH), 2,50- 2.40 (m, ÍH), 2.40 (d, J) = 15 Hz, ÍH), 2.13 (d, J) = 10 Hz, 1H), 2.06 (with, 3H), 1.95-1.53 (m series, 12H), 1.45 -and, 32 (m, ÍH), 1.43 (with, 3H), 1.33 (s, 3H), 1.33 (d, J = 6 Hz 3H) , 1.27 (with, 3H), 1,22 (d, J = 6 Hz 6H), 1.14 (d, J = 7Hz, 3H) , 1.12 (d, J = 7 Hz, 3H), 1.07 (d, J = 8 Hz, 3H), 4 1.00-0.96 (m, 1H), 0.91 (d, J = 7 Hz, 3H), 0.69 (t, J = 7 Hz,

3H), 0, 64- 0.58 (m, ÍH ); ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 216.8, 175.3 157.4 , 143 5 131 7, 13: L, 5, 130,2, 129.9, 129.4 , 102.9, 96.1, 82,4, 80.3 , 78,6, 77, 9, 76, 7, 72.7, 70, 1, 68.9, 65.7, 61.8, 60.1, 56, 8 , 51,3, 50, 3, 49, 5, 45.6, 45.0, 39.3, 39, 2, 38.6, 34,9, 31.0 , 29,9, 28, 5, 28, 1, 24.0, 21.5, 21.5, 20.2, 19.5, 18,7, 16, 0 , 15,2, 14, 5, 14, 1, 12.0, 10.9, 9.7, 9.1; MS (APCI) (M + H) at m / z 101 1 sec 2- -Cl; analysis : calculated; for

C ₅ 2H ₃₀ Cl ₂ N ₂ O _{1 3} ; O, 61.70; H, 7.96; N, 2.76. Found: C, 61.67; H, 7.89; N, 2.46.

Example 12

3'-N-demethyl-Ξ'-N-cyclopentyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 - (cyclic carbamate)

The title compound was prepared as described in Example 1C, substituting cyclopentanone for acetone. The crude product is obtained by crystallization from acetonitrile / water; mp 175-178 ° C (CH ₃ CN / H ₂ O); R _f = 0.65 (CHC1 _3: MeOH: NH ₄ OH, 90: 8: 1); IR (MIC) ν 3480, 2960, 2880, 1755, 1740, 1715, 1460, 1380, 1230, 1170, 1070, 1060, 1015, 1000 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.64 (d, J = 2 Hz, 1 Η), 7.45 (dd, J = 9.2 Hz, 1H), 7.33 (d, J = 9 Hz, 1H), 4.99 (d, J = 5)

Hz, 1H), 4.69 (dd, J = 11.3 Hz, 1H), 4.48 (d, J = 7Hz, 1H) 4.35 (d, J = 3) 5 Hz, 1H) , 4.07-4.02 (m, IH) , 3.7 Δ (s, 1H), 3.75 -3.68 (m, 4H), 3.55 -3.45 (m, 1 H), 3.35 (with, 3H), 3.22-3.10 (m, 2H), 3.19 (s, 3H) 3.05 (t, J = 10Hz) 1H), 2.96-2.88 (m, 2H), 2.70-2.53 (m, 2H) 2.40 (d, J = 15Hz) , 1H) 2.18 (s, 3H); 2.15 (d, J = 1) 0 Hz, 1H) , 1.94-1.58 (series m, 14 H), 1.43 (s, 3H), 1.34 (d, J = 5 Hz 3H), 1.33 (s, 3H), 1,28 (s, 3H) 1.25 (d, J = 5 Hz 3H), 1.23 (d, J = 4Hz, 3H) 1.15 (d, J = 3Hz, 3H), 1.12 (d, J = 4 Hz 3H), 1.08-1.06 (m, 3H), 1.00-0.96 (m, 2H), 0.91 (d, J = 7Hz, 3H), 0.70 (t, J = 7 Hz, 3H), 0.64-0.59 (m, 2H); ¹³ C NMR (75 MHz : CDCl ₃ ) δ 216.8, 17 5.3, 157.1, 143.5,

131.7, 131.5, 130, 1, 129, 9, 129, 4, 102.9, 96, 1, 82.4, 80.2,

78.7, 77,9, 76.7, 72.6, 70.3, 68, 9, 65, 7, 63,5, 63,0, 61, 8, 51,4, 50,3, 49,5, 45,7, 45,0, 39, 3, 39, 2, 38,6, 34,9, 33, 2, 31,7, 31,0, 24,5, 23,8, 23.7, 21, 9, 21, 5, 20,2, 19,5, 18,7, 16,0, 15.1, 14,5, 12,0, 10,9, 9.7 , 9.0; MS (FAB) (M + H) ⁺ at

m / z 1025; Calcd for C ₅₃ H ₈ Cl ₂ N ₂ O ₁₃ : C, 62.03; H, 8.05; N, 2.72. Found: C, 61.86; H, 7.86; N, 2.52.

Example 13

3'-N-demethyl-3'-N-cyclohexyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12- (cyclic carbamate) • ·

The title compound was prepared as described in Example IC, substituting cyclohexanone for acetone. The crude product is obtained by crystallization from hexane; ; mp 210-212 ° C; R _f = 0.80 SHCI3: MeOH: NH4OH 90: 8: 1); IR (KBr) ν 3440, 2965, 1770, 1760, 1335, 1710, 1460, 1380, 1230, 1165, 1100, 1055, 1010, 1000 cm-;; ³ H NMR (300 MHz, CDCl ₃ ) δ 7.63 (d, J = 2 Hz,

1H), 7.45 (dc, J = 9.2Hz, 1H), 7.33 (d, J = 9Hz, 1Η), 4.98 (d, J = 5Hz, 1 1), 4.68 (dd, J = 11.3 Hz, 1 Η), 4.47 (d, J =

Hz, 1H), 4.35 (d, J = 5 Hz, 1H), 4.07-4.02 (m, 1H), 3.777.67 (m, 2H), 3.77 (s, IH) ), 3.73 (d, J = 7Hz, 1 Η), 3.69 (d,

J = 7 Hz, 1 E, 3.53-3.48 (m, 1H), 3.35 (s, 3H), 3.32-3.11 (m, 2H), 3.15 (s, 3H), 3.05 (t, J = 10Hz, 1H), 2.95-2.90 (m,

2H), 2.60-2.52 (m, 2H), 2.43-2.38 (m, 2H), 2.36 (d, J = 15Hz, 1H), 2.25 (s, 3H) 1.20 (d, J = 10 Hz, 1H), 1.93-1.56 (m, 12H series), 1.43-1.28 (m, 4H series), 1.43 (s, 3H), 1.34 (d, J = 5Hz, 3H), 1.32 (s, 3H), 1.28 (s, 3H), 1.24 (d, J = 5Hz, 3H), 1 22 (d, J = 4Hz, 3H), 1.15-1.05 (m series, 3H), 1.14 (d, J =

Hz, 3H), 1.11 (d, J = 4Hz, 3H), 1.08-0.96 (m, 1H), 0.91 (d, J = 7Hz, 3H), 0.69 ( t, J = 7 Hz, 3H), 0.64-0.57 (m, 1H); ¹³ C

NMR (75 MHz) , ODCI3 ) δ 216.8, 175.3, 157, , 1, 143.6, 131, -7, 131 5 130 1, 129, 4, 102.9, 96.3, 82,4, 80.2, 78.8, 78 , 1, 78, 0, 77.2, 75,8, 72, 6, 70.5, 68.9 , 65, 8, 63.0, 61.9, 61,2, 51, 3, 50.3, 45,5, 45, 6, 45, 1, 39.4 , 38, 7, 34.9, 33.6 31, 9, 31, 8, 30.9, 25,9, 24, 0, 21.9, 21.5 , 21, 4, 20.3, 19.5, 18,7, 16, 1, 15.2, 14,5, 12, 0, 10.9, 9.7, 9.1; MS (ESI) [M + H] &lt; + &gt; ⁺ at m / z

1039; analysis: calcd for C 54 H 84 Cl 2 N 2 O 13; C, 62.35; H, 8.14; N, 2.69. Found: C, 62.45; H, 8.16; N, 2.67.

Example 14

3'-N-demethyl-Ξ'-N-propyl-11-deoxy-11- [carboxy- (3,4-dioxolanophenethylamino] -6-0-methyl-erythromycin A, 11,12- (cyclic carbamate) • ♦

The title compound was prepared as described in Example 3, substituting 3,4-dioxolanophenethylamine for 3,4-dichlorophenethylamine. The desired product is obtained by crystallization from CH 3 CN / H 2 O; R _f = 0.31 (8% MeOH / DCM + 0.1% NH4OH); IR (KBr) ν 3440, 2960, 2940, 2870, 1745, 1725, 1710,

1500, 1485, 1455, 1440, 1420, 1375, 1320, 1280, 1230, 1165, 1120, 1100, 1070, 1050, 1010, 995 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) δ 6.86-6.71 (m series, 3H), 5.91 (s, 2H), 4.97 (dd, J = 10.8,

2,0 Hz, (4) 91 (d, J = 4.8Hz) 1H, 4.06-3.96 (m, 1H), 3.86 -3, 73 (ser ie m, 3H), 3.70 (s, 1H), 3.66 (d, J = 7.5 Hz, ÍH), 3, 53-3,43 (m, 1H), 3.33 (s, 3H), 3.24-3.10 (ra, 2H); 08 / (with, 3H) , 3,08- 2.74 (m series, 5H), 2.69-2.58 (m, 1H, 2.55-2 , 40 (m, 2H) , 2.38 (d, J = 15.3 Hz, 1H) ), 2.34-2.25 (m (1H), 2.23 (with, 3H) , 2.19 (d, J = 10.5 Hz, 1H) ), 2.00-1.85 (m.) (2H), 1.80 - 1.74 (m 2H), 1.71-1.44 (m series, 7H), 1.43 (s, 3H), 1.40 ( with, 3H), 1, 30 (d, J = 6.4 Hz, 3H), 1 26 (s, 3H), 1.2 4-1.20 (m, 6H), 1, 15 (d, J = 7.1 Hz, 3H), 1 12 (d, J = 7.5) Hz, 3H), 1 02 / (d, J = 7.1 Hz 3H), 0.90 (t, J = 7.5 Hz, 3H) .84 (t, J = 7.1 Hz, 3H); ^{1 3} C NMR (75 MHz, CDCl ₃ ) δ 216.1, 176 , 3, 157.2, 147, 5, 145,9, 132.8, 121.9, 109.5 , 108.2, 103.0, 100.6, 96, 2,

82.7, 80.2, 78,9, 78,0, 77,9, 76.3, 72.7, 70.7, 69.0, 65.8, 65,6, 60,5, 55.1, 50.7, 49,5, 45.5 (2C), 45.3, 39.2 (2C), 39,1, 36,9, 34, 9, 33,2, 29,5, 22.0, 21.5, 21.4, 20.2, 18, 9, 18,7, 16,0, 14,3, 14.1, 11, 6, 10.3, 9.0; MS (FAB) (M + H) &lt; + &^gt;

m / z 949; Anal Calcd for C 50 H 80 N 2 O 15: C, 63.27; H, 8.49; N, 2.95. Found: C, 63.07; H, 8.65; N, 2.84.

Example 15

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3,4-

-dioxolanophenezhylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

119 1

The title compound was prepared as described in Example 1, substituting 3,4-dloxolanophenethylamine for 3,4-dichlorophenethylamine; MS (FAB) (M + H) &lt; + & gt ^; at m / z 975.

Example 16

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (4-chloro-3-fluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 ( cyclic carbamate)

The title compound was prepared as described in Example 3, substituting 4-chloro-3-fluoro-phenethylamine for 3,4-dichlorophenethylamine. The desired product is obtained by crystallization from CH 3 CN / H 2 O; mp 217-19 ° C (CH 3 CN / H 2 O); IR (KBr) ν 3440, 2965, 2940, 2880, 2830, 1755, 1730, 1710, 1580, 1490, 1460, 1425, 1380, 1360, 1325, 1285, 1235, 1170, 1130, 1110, 1070, 1055, 1015 1000 cm ^-1 ; ^Δ NMR (300 MHz, CDCl ₃ ) δ 7.32-7.26 (m, 1H), 7.16 (dd, J = 10.2, 2.1 Hz, 1H), 7.07 (dd, J = 8.1, 1.3 Hz, 1H), 4.93-4.88 (m, 2H), 4.45 (d, J = 7.2 Hz, 1H), 4.06-3.96 (m, 1H), 3.92-3.77 (m, 2H), 3.74 (d, J = 9.2 Hz, 1H), 3.69 (s, 1H), 3.67 (d, 1H); J = 7.4 Hz, 1H), 3.54-3.44 (m, 1H), 3.33 (s, 3H), 3.27-3.08 (m series, 2H), 3, 07 (s, 3H), 3.06-2.82 (m series, 5H), 2.68-2.41 (sera m, 3H), 2.37 (d, J = 15.3 Hz, 1H) 2.37-2.27 (m, 1H), 2.27 (s, 3H), 2.18 (d, J = 9.8 Hz, 1H), 1.98-1.83 (m, 2H) )

1,80-1 , 46 (p m (8H), 1 , 43 (with, 3H), 1, 40 (s, 3H), 1.30 (d, J = 6, 1 Hz, 3H), 1.26 (s, 3H) , 1,2 3 (d, J = 7.1 Hz, 3H), 1.21 (d, J = 7.4 Hz, 3H), 1.15 (d, J = 7.1 Hz, 3H), 1.12 (d, J = 7.4 Hz , 3H), 1.02 (d, J = 7.2 Hz, 3H), 0 91 (t, J = 7.3 Hz, 3H) , 82 (t , J = 7.3 Hz, 3H) ; ¹³ C NMR (75 > MHz, CDCl 3) δ 216, 3 176,4, 158.8 , 157.2, 140.0 , 1 39,9, 130,3, 125.4 (2C) 118.8, 117,3, 117.0 , 102.9, 96.2, 82 , 8, 8 0.1, 78 9, 77 , 9 (20, 76.2, 72.6, 70, 6, 68.8, 65.8, 65 , 6, 60.3 , 55,0, 50.7, 49.5, 45.5, 45,3, 44,8, 39.1 (2C), 39, 0, 36,9, 34,8, 32,8, 29.5, 21.9,

• ·

21.5, 21.4, 23.2, 18.9, 18.7, 16.0, 14.2, 14.1, 11.6, 10.2,

9.9; MS (FAB) (M + H) ⁺ at m / z 957: analysis: calcd for C ₄₉ H ₇₈ ClFN ₂ O 13: C, 61.46; H, 8.21; N, 2.93. Found: C, 61.45;

H, 8.17; N, 3.10.

Example 17

3'-N-demethyl-3'-N-isopropropyl-11-deoxy-11- [carboxy- (4-chloro-3-fluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 10, substituting 4-chloro-3-fluorophenethylamine for α, α-cyclopropyl-3,4-dichlorophenethylamine;

MS (FAB) (M + H) &lt; + &gt; at m / z 957.

Example 18

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (4-chloro-3-fluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 1, substituting 4-chloro-3-fluorophenethylamine for 3,4-dichlorophenethylamine; MS (FAB) (M + H) &lt; + & gt ^; at m / z 983.

Example 19

3'-N-demethyl-3'-N-cyclobutylmethyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 1 except substituting 3,4-dichlorophenethylamine

use 4-chlorophenethylamine and cyclobentyl cararooxaldehyde in place of cyclopentanone; MS (FAB) (M + H) &lt; + & gt ^; m / z 965.

Example 20

3'-N-demethyl-2'-N-cyclobutylmethyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 1, substituting 4-chlorophenethylamine for 3,4-dichlorophenethylamine and cyclobutylcarboxaldehyde for cyclopentanone. The desired product is obtained by crystallization from CH ₃ CN / H ₂ O; R _f = 0.46 (8.5% MeOH / DCM + 0.1% NH ₄ OH); IR (KBr) 3440, 2970, 1760, 1740, 1715, 1490, 1455, 1420, 1375, 1345, 1320, 1280, 1165, 1100, 1090, 1060, 1005, 990 ^{'1; 3} H NMR (300 MHz, CDCl ₃ ) δ 7.26-7.25 (m, 4H series), 4,964.92 (m, 2H series), 4.45 (d, J = 67.5 Ήζ, 1H) 4.04-3.98 (m, 1H), 3.87-3.54 (m series, 6H), 3.50-3.43 (m / 1H), 3.33 (s, 3H), 3.19-3.11 (m, 2H), 3.07 (s, 3H), 3.05-2.84 (m, 5H series), 2.64-2.61 (m, 1H), 2 50-2.42 (m, 1H), 2.37 (d, J =

15.3 Hz, 1H), 2.12 (d, J = 10.5 Hz, 1H), 2.06 (s, 3H), 2.00 (s, 1H), 1.98-1.48 ( m series, 12H), 1.42 (s, 3H), 1.40 (s, 3H),

1.29 (d, J = 6.4 Hz, 3H), 1.25 (s, 3H), 1.25-1.24 (m, 1H),

1.23-1.20 (m, 6H), 1.15 (d, J = 7.5Hz, 3H), 1.12 (d, J = 57.4

Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 216, 2, 176, 3, 157.2, 137.4, 131.8, 130.3, 128.4, 103.0, 96.0, 82.7 , 80.3, 78.8, 77.9, 77.7, 76.2,

72.6, 70.0, 66.9, 65.7, 60.3, 60, 1, 56.8, 50, 6, 49,4, 45,5, 45,2, 45,0, 39.0, 34.8, 32,8, 31.0, 29.6, 28, 5, 28.1, 21,9, 21,4, 20,1, 16.8, 18.6, 15, 9, 14.2, 14.1, 14,0, 10.2, 9.0; MS (FAB) (M + H) ⁺ at 951: analysis: calculated for C50H79 ¹ C1N ₂ O ₁₃ • 0.6 H ₂ O: C, 62.40; Η, 8.40; N , 2.91. Found:

C, 62.22; H, 6.33: N, 3.28.

• ·

Example 21

3'-N-demethyl-2'-N-ethyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 20, substituting acetaldehyde for cyclobutylcarboxaldehyde; MS (FAB) (M + H) &lt; + & gt ^; at m / z 925.

Example 22

3'-N-demethyl-3 '-N-isopropyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared according to the procedure in Example 20, substituting acetone for cyclobutylcarboxaldehyde; MS (FAB) (M + H) &lt; + & gt ^; at m / z 939.

Example 23

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared according to the procedure in Example 20, substituting cyclopentanone for cyclobutylcarboxaldehyde; MS (FAB) (M + H) &lt; + & gt ^; at m / z 965.

Example 24

3'-N-demethyl-2'-N-cyclopentyl-11-deoxy-11- [carboxy- (3-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 1, substituting 3-chlorophenethylamine for 3,4-dichlorophenethylamine. The desired product is obtained by crystallization from CH ₃ CN / H ₂ O; R _f = 0.55 (8% MeOH / DCM + 0.1% NH ₄ OH); IR (KEr) ν 3440, 2965, 2940, 2870, 1750, 1730, 1710, 1595, 1570, 1455, 1420, 1375, 1360, 1310, 1280, 1235, 1165, 1125, 1100, 1075, 1050, 1010, 995 cm ¹ ; ¹ H NMR (300 MHz, CDCl 3) 67.34 (s, 1H), 7.23-7.15 (m series, 3H), 4.97-4.90 (m series, 2H), 4.46 ( d, J = 7.1 Hz (1H), 4.08-3.96 (m, 1H), 3.92-3.78 (m, 2H), 3.77-3.70 (m, 2H) 3.66 (d, J = 7.5 Hz, 1H), 3.543.42 (m, 1H), 3.33 (s, 3H), 3.17-3.11 (m, 2H), 3, 09 (s, 3H), 3.07-2.82 (m series, 5H), 2.70-2.56 (m, 2H), 2.38 (d, J = 15.6 Hz, 1H), 2.18 (s, 3H), 2.14 (d, J = 10.5 Hz, 1H), 2.02-1.48 (m series, 14H), 1.47-1.22 (m series, 3H), 1.43 (s, 3H), 1.40 (s, 3H), 1.30 (d, J = 6.1 Hz, 3H), 1.26 (s, 3H), 1.22 (s) d, J = 6.1 Hz, 3H), 1.22 (d, J = 6.1 Hz, 3H), 1.15 (d, J = 7.4 Hz, 3H), 1.12 (d, J = 7.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.84 (t, J = 7.1 Hz, 3H); ¹³ C NMR (75 MHz, CDCl 3) δ 216.2, 176.3,

157,2, 141, 1, 134, 1, 129 , 6, 129.2, 127.1, 126.4, 103.1 , 96,1, 82,8, 80,3, 78, 9, 78,0, 76, 3, 72.7, 70,4, 69.0, 65.8, 63, 6, 63, 1, 60,4, 5C, 7, 49,5, 45.5, 45.3, 45,0, 39.1, 39.0, 34,9, 33,2, 33.1, 31, 6, 31,0, 30.2, 23.8, 22,0, 21.5, 20.2, 18,9, 18,7, 16,0, 14,2, 14.1, 10.3, 9.0; MS (FAB) (M + H) &lt; + &^gt; m / z 965;

Analysis: vypočzeno for C ₅ H ₈ iC1N 0i _{2 3} · 0.4 H ₂ O: C, 62.96; H, 8.47; N, 2.88. Found: C, 62.97; H, 8.57; N, 2.68.

Example 25

3'-N-demethyl-z'-N-propyl-11-deoxy-11- [carboxy- (3-chlorophenethylsmino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbemat)

The title compound was prepared as described in Example 3, substituting 3-chlorophenethylamine for 3,4-dichlorophenethylamine; MS (FAB) (M + H) &lt; + & gt ^; at m / z 939.

Example 26

3'-N-demethyl-6'-N-cyclopentyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carzamat)

The title compound was prepared as described in Example 1, substituting 3-chloro-4-fluorophenethylamine for 3,4-dichlorophenethylamine. The crude product was purified on a silica gel column (MeOH: CHCl ₃ , 5:95) to obtain crystallization from CH 3 CN / H 2 O; R _f = 0.32 (MeOH: CHCl3, 5:95); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.39 (dd, J = 2.7 Hz, 1H), 7.22-7.19 (m, 1H), 7.04 (dd, J = 9 Hz) 1 H, 4.93-4.89 (m, 2H series), 4.45 (d, J = 7 Hz, 1H), 4.04-4.00 (m, 1H). 3.86-3.80 (m series, 2H), 3.74 (d, J = 10Hz, 1H), 3.70 (s, IH), 3.67 (d, J = 7Hz, 1H) ,

3.49 -3.47 (m, IH), 3, 3 3 (s, 3 H), 3.19 (dd, J = 3.7 Hz, 1H) ) 3, 13 (m, 1H) 3.07 (with, 3H), 3.0 -2.86 (m series, 5H), 2.66 -2, 61 (m, 2H), 2.37 íd, J = 15 Hz, IH) 2.18 (s, 3H); 2.15 (d, J = 10 H z, IH), 1, . 93-1 , 51 (m series, 13H), 1.43 (s, 3H), 1.40 (with, 3H), 1,38-1,3í : (m, 2H) , 1.30 (d, J = 6.3H), 1.25 (s, 3H) OF 1,22 (s, 3H) 1,21 (with, 3H), 1.15 (d, J = 7Hz, 3H), 1.12 (d,

J = 7Hz, 3H), 1.02 (d, J = 7Hz, 3H), 0.83 (t, J = 7Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 216, 3, 176, 4 157.7, 157.2, 155.8,

136.0, 136.0 , 131.0, 128.6, 128.5, 116,4, 116.2, 103.0, 96.1, 82,8, 80.2, 7E, 9, 77, 9, 77, 8, 76, 2 72, 6, 70.3, 69.0, 65.7, 63, 5, 63,0, 6C, 3, 50.6, 49.4, 45.5, 45,2, 45.0, 39.1, 39.0, 34,8, 33, 1, 32.5, 31.6, 31.0, 30, 1, 23.7, 23, 7, 21, 9, 21.5, 20, 1, 18,8, 1E, 6, 16.0, 14.2, 14.1, 10.2, 8.9: MS (APCI) (M + H) &lt; tb &gt; at m / z 983; analysis: calculated for C ₅₁ H _{8 O 2} 0i3 C1 FN: C, 62.27; H,

8.20; N, 2.85. Found: C, 62.03; H, 8.34; N, 2.76.

6 <ϊ

Example 27

3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) )

The title compound was prepared as described in Example 4, substituting 3-chloro-4-fluorophenethylamine for 3,4-dichlorophenethylamine. The crude product was purified on a silica gel column (MeOH: CHCl ₃ , 5:95) and was obtained by crystallization from CH ₃ CN / H ₂ O; R _f = 0.30 (CHC1 _3, 92: 8); HPLC R _t = (C-18), 19.6 min, 45-55 CH ₃ CN, gradient 1% / min; MS (APCI) (M + H) &lt; + & gt ^; at m / z 969.

Example 28

3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 1, substituting 3-chloro-4-fluorophenethylamine for 3,4-dichlorophenethylamine and acetone for cyclopentanone. The crude product was purified on a silica gel column (MeOH: CHCl ₃ , 5:95) and was obtained by crystallization from a mixture

acetoni tril / water ; ³ h nm: R (300MHz, CDCl 3) δ 7.40 (d i d, J = 2.7 Hz, IH) , 7,22-7, 19 Dec (m, 1H, 7.05 (dd, J = 9Hz, ÍH ), 4.93-4.90 (series m, 2H), 4 , 46 (d, J = 7Hz, 1 Η), 4.04-4. 01 (m, 1 Η) 3,87-3, 79 (series m, 2H) 3.75 (d, J = 10 Hz, 1H ) 3.70 (s, (H), 3, 67 (d. C = 7 Hz, 1H, 3.52 -3.49 (m, 1H), 3, 34 (s. 3H), 3,16-3, 11 (series m, 2H) , 3.08 (s, 3H), 3.05 -2, 86 (m series, 5H), 2, 65-2,63 (: m, ÍH), 2,58-2,56 (m, 1H), 2.37 (d J = 15 Hz

1 H), 2.21 (s, 3H), 2.17 (d, J = 10 Hz,

Η), 1.94-1.86 (m series, 2H), 1.78-1.75 (m series, 2H), 1.66 1.52 (m series, 3H), 1.44 (s, 3H), 1.40 (s, 3H), 1.31 (d, J ~ 6). ** 9 · * · «« · And »« «··» · <

·· «» a a a a a a a

Hz, 3H), 1.26 (s, 3H), 1.24-1.21 (m series, 6H), 1.15 (d, J =

Hz, 3H), 1.13 (d, J = 7Hz, 3H), 1.09 (d, J = 6Hz, 3H),

1.06 (d, J = 5 Hz, 3H), 1.03 (d, J) = 7 Hz , 3H), 0.83 (t, J = Hz, 3 H); ¹³ C 211R (75MHz, CDCl 3) δ 2 16, 3 OF 176,4, 157, ' 7, 157.2, 155.8 , 136, 0, 136, 0, 131 , 0, 12 8.6, 128, 5, 116, 4 , 116 , 2, 102.9 96.1, 82,8, 8 5,1, 78,9, 77, 76, 2, 72, 6, 70,4, 68.9 , 65,7, 62,8, 60.3, 52,5, 50.6, 49.5, 45.5, 45, 3, 45,0, 39, 1 , 39,0, 39,0, 34,8, 22,5, 30, 8, 21.9, 21.5, 20, 1, 18,8, 18.6 , 16,0, 14,2, 14.1, 12,2, 8.9: M [S (ESI) (M &lt; + &gt;) H) ⁺ at m / z 957; analysis:

Calcd for 349H78ClFN2O13: C, 61.46; H, 8.21; N, 2.93. Found: C, 61.69; H, 8.36; N, 3.07.

Example 29

3'-N-demethyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 1, substituting 3-chloro-4-fluorophenethylamine for 3,4-dichlorophenethylamine and cyclopropanecarboxaldehyde for cyclopentanone. The crude product was purified on a silica gel column (MeOH: CHCl ₃ , 5:95) to obtain crystallization from acetonitrile / water; ¹ H NMR (300 MHz, CDCl 3) δ 7.40 (dd, J = 2.7 Hz, 1H), 7.23-7.20 (m, 1H), 7.05 (dd, J = 9 Hz, 1 H), 4.53-4.91 (m series, 2H), 4.47 (d, J = 7 Hz, 1 Η),

4.04 -4.02 (m, 1H), 3.87-3.81 (series m, 2H), 3.75 (d, J = 10 Hz, 1 Η), 3.71 (s, 1 Η), 3.67 (d, J = = 7 Hz, 1 Η), 3.51-3.49 (m, 1H), 3.34 (s, 3H), 3.22-3, 19 (m, IH) , 3, 13 (q, J = 7Hz, 1 H) 3.08 (s, 3H), 3.04-2.84 (series m, 5H), 2, 64-2.61 (series

m, 2H), 2.44-1.42 (m, 1H), 2.39 (d, J = 15 Hz, 1H), 2.31 (s,

3H), 2.26-2.2- (m, 1H), 2.17 (d, J = 10Hz, 1H), 1.94-1.85 (m series, 2H), 1.78-1 , 76 (m series, 2H), 1.64-1.57 (m series,

H, 1.44 (s, 3H), 1.41 (s, 3H), 1.31 (d, J = 6, 3H), 1.26

9 9

9 · r 99 9 9 · · • • •

999 9 * 9 «· ϊ ·

(with, 3H), 1.23 (s, 3H), 1.22 (s, 3H), 1.16 (d, J = 7Hz, 3H) 1.13 (d, J = 7Hz, 3H), 1.03 (d, J = 7Hz) , 3H), 0.84 (t, J = 7) Hz, 3H), 0.55-0.51 (m, 2 H), 0.11 (d, J = 4 Hz, 2H); ¹³ C NMR (75 MHz, CDCl 3) δ 216, 3, 176, 4, 157, 8, 157.2, 155,8, 136.0, 136.0, 131, 0, 128, 6, 128, 5, 116, 4, 116, 4, 103.0, 96.1, 82.8, 80.2, 78.9 , 77, 9, 76.3, 72, 6, 70.6, 68, 9, 65.8, 60,4, 58.6, 50.7, 49.5 , 45.5, 45.3, 45.0, 39, 1, 39, 1, 39, 0, 36, 9, 34, 9, 32.5, 29.5, 21.9, 21.5, 20.2, 18.9, 18.7, 16.0, 14,2, 14.1, 10.2, 10.0 9.0, 4.4, 3.4; MS (ESI) (M + H) &lt; + & gt ^; at m / z 969 ; analysis:

Calcd for C ₅ OH ₇ 8C1FN ₂ oi ₃ · 0.25 (CH ₃ CN): C, 61.90; H, 8.10; N, 3.21. Found: C, 61.96; H, 8.27; N, 3.44.

Example 30

3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 4, substituting 3,4-difluorophenethylamine for 3,4-dichlorophenethylamine. The desired product is obtained by crystallization from CH ₃ CN / H ₂ O; mp = 222-224 ° C (CH ₃ CN / H ₂ O);

IR (FTIR / MIC) at 3494, 2969, 2943, 2879, 2832, 1746, 1735, 1712, 1608, 1519, 1457, 1449, 1429, 1378, 1327, 1279, 1234, 1167,

1111, 1104, 1071, 1059, 1012, 1002 cm -1 ¹ H NMR (300 MHz,

CDC1 ₃₎ δ 7.23-7.03 (series of m, 3H), 4.95-4.90 (series of m, 2H), 4.45 (d, J = 7.1 Hz, 1H), 4, 06-3.96 (m, 1 H), 3.92-3.76 (m, 2 H),

3.74 (d, J = 8.8 Hz, 1H), 3.70 (s, 1H), 3.67-3.62 (m, 1H),

3.66 (d, J = 7.4Hz, 1H), 3.53-3.42 (m, 1H), 3.33 (s, 3H),

3.19-3.07 (m, 2H), 3.07 (s, 3H), 3.06-2.80 (m series, 5H),

2.68-2.57 (m, 2H), 2.50-2.42 (m, 1H), 2.37 (d, J = 14.9 Hz,

1H), 2.13 (d, J = 10.2Hz, 1H), 2.05 (s, 3H), 2.05-1.47 (m series, 14H), 1.43, s, 3H) 1.40 (s, 3H), 1.30 (d, J = 6.1 Hz, 3H).

I ^{1 2 1}

• · «·

1.25 (s, 3H), 1.22 (d, J = 8.5Hz, 3H), 1.21 (d, J = 6.1Hz, 3H), 1.15 (d, J = 7) 4 Hz, 3H), 1.12 (d, J = 7.5Hz, 3H), 1.02 (d, J = 6.8Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H); ¹³ NMR (75 MHz, CDCl ₃ ) δ 216.23, 176, 39, 157, 19, 152.5-146, 5 (m, 2C), 136.5135.5 (m, IC), 125.0- 124.7 (m, IC), 117.9-116.8 (m, 2C),

103.08, 72.68, 45.58, 29.74, 16.00,

96.07, 70.14, 45.30, 28.56, 14.23,

82.78 68.99, 45.01, 28.16, 14, 12, 80.34, 78.93, 77.96, 77.86, 76.29,

65.76, 60.42, 60.20, 56, 84, 50.66, 49.46, 39.10, 39.02 (2C), 34.88, 32.71, 31.04, 21.97 , 21.50, 21.47, 20.14, 18.88, 18.65, (2C), 10.23, 9.00; MS (FAB) (M + H) &lt; + & gt ^; at m / z

953; Calcd for C 50 H 78 F 2 N 2 O 13 · 0.2 H 2 O: C, 62.77; H, 8.26; N, 2.93. Found: C, 62.75; H, 8.36; N, 2.91.

Example 31

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 1, substituting 3,4-difluorophenethylamine for 3,4-dichlorophenethylamine. The desired product is obtained by crystallization from CH 3 CN / H 2 O; mp = 166-168 ° C (CH ₃ CN / H ₂ O);

IR (FTIR / MIC) ν 3451, 2968, 2943, 2880, 2831, 1763, 1747, 1709, 1520, 1453, 1432, 1378, 1327, 1283, 1234, 1168, 1128, 1106, 1069, 1055, 1012, 1000 cm ⁴ ; ³ H NMR (300 MHz, CDCl ₃ ) δ 7.22-7.03 (m series, 3H), 4.95-4.89 (m series, 2H), 4.46 (d, J = 7.1 Hz, 1H), 4.07-3.97 (m, 1H), 3.91-3.75 (m, 2H), 3.74 (d, J = 9.5 Hz, 1H), 3.70 s, 1H), 3.66 (d, J = 7.5Hz, 1H), 3.55-3.43 (m, 1H), 3.33 (s, 3H), 3.24-3.11 (m, 2H), 3.11-2.80 (m series, 5H), 3.07 (s, 3H), 2.69-2.58 (m, 2H), 2.37 (d, J = 15.2 Hz, 1H)

2.18 (s, 3H), 2.14 (d, J = 10.2 Hz, 1H), 1.98-1.48 (m series,

14H), 1.43 (s, 3H), 1.40 (s, 3H), 1.35-1.31 (m, 2H), 1.30 (d,

J = 6.1 Hz, 3H, 1.18-1.21 (m, 1H), 1.26 (s, 3H), 1.22 (d, J = •)

6.1 Hz, 3H), 1.22 (d, J = 6.1 Hz, 3H), 1.15 (d, J = 7.1 Hz, 3H), 1.12 (d, J = 7, 8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.83 (t, J = 7.3 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 216, 35, 176, 42,

157,20, 152.5-146.5 (m, 2C), 136.5-135.5 (m, 1C), 125.0-124.7 (m, 1C) , 117.2-116.8 (m, 2C) , 103.04, 96, 07, 82.77, 80.23, 78,91, 77, 94, 77, 81 76, 24, 72,65, 70.29, 69,01, 65,74, 63,53, 63,06, 60.34, 50.67, 49, 49, 45,58, 45,27, 44,99, 39.07, 38.99 (2C), 34.85, 23.15, 32.69, 31, 67, 31,00, 30,10, 23,74, 23,71, 21,95, 21.51, 20.17, 18, 87, 18,66, 16,03, 14,23, 14,15, 10,25,

8.99; MS (FAB (M + H) ⁺ at m / z 967; Analysis calc'd for C ₅ H ₈ F ₂ N 20 ₁₃ 0 · _{{4 CH3} CN 0 · 4 H ₂ O: C, 62.79; H, 8 N, 3.39 Found: C, 52.78; H, 8.45; N, 3.46.

Example 32

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 3, substituting 3,4-difluorophenethylamine for 3,4-dichlorophenethylamine. The desired product is obtained by crystallization from CH ₃ CN / H ₂ O; mp = 228-229 ° C (CH ₃ CN / H ₂ O);

IR (FTIR / MIC) ν 3484, 2970, 2941, 2883, 1754, 1734, 1711, 1519,

1459, 1436, 1423, 1379, 1351, 1326, 1282, 1236, 1167, 1127, 1110, 1075, 1C55, 1044, 1014, 997 cm ^_1 ; ³ Η NMR (CDCl ₃ ) δ 7.22- 7.03 (series m, 3H) , 4.95 -4.89 (series m, 2H), 4.44 (d, J = 7.2)

Hz, 1H), 4.06-3.96 (m, 1H), 3.92-3.75 (m, 2H), 3.75 (d, J = 9.2 Hz, 1H), 2.69 (s, 1H), 3.67 (d, J = 7.8 Hz, 1H), 34.43-3.43

(m, IH) , 3.33. with, 3H), 3,23-3,11 (m, 2H), 3.10-2 , 80 (m series, 5H), 3, 07 (s, 3H) , 2.69 -2.58 (m, IH) , 2.54-2.40 (m, 2H), 2.37 (d, J = 14.9 Hz, 1 Η), 2,33-2,24 (m, 1 Η), 2.23 (with, 3H), 2.17 (d, J = 10.2 Hz, IH), 1 , 98-1.82 (m, 2H), 1.79-1. 75 (m, 2H) 1.71 -and, 44 (ser m, 6H) 1.43 (s , 3H 1.40 (s, 3H) , 1.30 (d,

• «

J = 6.4 Hz, 3 Η), 1.26 (s, 3H), 1.22 (d, J = 6.1 Hz, 3H), 1,21 (d, J = 7.8 H z, 3H), 1.15 (d, J = 7) (Hz, 3H), 1.12 (d, J = 7.4 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3 H), 0.90 (t, J = 7.5 Hz, 3H) 0.83 (t, J = 7.3 Hz, 3H); ¹³ C NMR (CDCl ₃ ) δ 216, 36, 176,45, 157 , 19, 152.5 -146.5 (m, 2C) :), 136,5- 135.5 (m, 1H) C, 125.0 - 124 .7 (m, IC) , 117,9-116, 8 (m 2C) , 102.94, 96 , 17, 82.7 6, 80, 09, 78.94, 77.91 (2C), 76.24, 72 , 62, 70, 64 68, 99, 65 <76, 65, 60, 60.31, 54.96, 50.67 , 49,47, 45.56, 45.28 , 44,96, 39.09

(2C), 38.98, 36.87, 34.84, 32.67, 29.39, 21.91, 21.48, 21.40, 20.17, 18.87, 18.68, 16, 03, 14.22, 14.13, 11.58, 10.24, 8.96: MS (FAB) (M + H) ⁺ at m / z 941; Calcd for C49H78F2N2O13: C, 62.53; H, 8.35; N, 2.98. Found: C, 62.69; H, 8.34; N, 3.12.

Example 33

3'-N-demethyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 1, substituting 3,4-difluorophenethylamine for 3,4-dichlorophenethylamine and cyclopropanecarboxaldehyde for cyclopentanone. The desired product is obtained by crystallization from CH ₃ CN / H ₂ O; mp = 220-222 ° C (CH ₃ CN / H ₂ O);

IR (FTIR / MIC) at 3446, 2977, 2938, 2883, 1745, 1734, 1713, 1607, 1518, 1459, 1425, 1378, 1327, 1284, 1236, 1168, 1103, 1094, 1070, 1055, 1013; 1 H NMR (300 MHz, CDCl ₃ ) δ 7.23-7.03 (m, 3H series), 4.94-4.89 (m, 2H series), 4.46 (d, J = 7.4) Hz, 1H), 4.07-3, 97 (m, 1H), 3.92-3.78 (m, 2H series), 3.75 (d, J = 9.1 Hz, 1H), 3, 70 (s, 1H), 3.6f (d, J = 7.8Hz, 1H), 3.54-3.44 (m, 1H), 3.33 (s, 3H), 3.24-3 11 (m, 2H), 3.10-2.80 (m series,

5H), 3.07 (s, 3H), 2.68-2.55 (m, 2H), 2.47-2.40 (m, 1H), 2.37 (d, J = 15.2 Hz) 1 H, 2.31 (s, 3H), 2.31-2.19 (m, 1H), 2.15 • ·

(d, J = 10.1 Hz, 1H), 1.98-1.72 (m series, 4H), 1.68 -1.46 (ser ie m , 4H), 1, 43 (s, 3 H), 1.40 (s, 3 H) , 1.30 (d, J = 6.1 Hz, 3H), 1.25 (s, 3H), 1.22 (d, J = 6.1 H) z, 3H) , i, 22 (d, J 6.1 Hz, 3H), 1.15 (d, J = 7.4Hz, 3H), 1, 13 (d, J = 7.5 Hz, 3H), 1.0 2 (d. J = 6.8 Hz, 3H), 0.89-0.78 (ra, 1 Η), 0.83 (t, = 7, 3 Hz , 3H), 0 58-0.46 (m, 2H), 0.15-0, 07 (m, 2H) ; ¹³ C NMR (75 MHz, CDC1J δ 216.35, 176.43, 157.20, 152,5- -146, , 5 (m, 2C), 136,5-13 5.5 (m, 1C), 125.0-124.7 (m, 1 C), 117,9-116 (ra, 2C), 103.32, 96.13, 82.77, 80.19, 78, 94, 77 , 92, 77,89,

76.26, 72.63, 70,55, 68,96, 65.78, 64.61, 60.34, 58.59, 50.67, 49.49, 45.56, 45,30, 44,99, 39.09 (2C), 39.09 , 01, 36.91 , 34,85, 32.69, 29.42, 21,93, 21,49, 20.18, 18.89, 18.68 16, 03, 14.23, 14.13, 10.25, 10,04, 9,01, 4.41, 3.36; MS (M + H) at m / z 953; analysis: calculated for C50H78F2N2O13: C, 63.01; H, 8.25; N,

2.94. Found: C, 63.08; H, 8.28; N, 2.89.

Example 34

3'-N-demethyl-3'-N- (4-pyridylmethyl) -1-deoxy-11- [carboxy- (4-chlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 20, substituting 4-pyridylcarboxaldehyde for cyclobutanone. MS (APCI) (M + H) &lt; + & gt ^; at m / z 988.

Example 35

3'-N-demethyl-3'-N- (2-butyl) -11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 20, substituting cyclobutanone instead

2-butanone. MS APCI) (M + H) &lt; + & gt ^; m / z 953.

Example 36

3'-N-demethyl-3'-N- (3-pentyl) -1-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 20, substituting cyclobutanone

3-pentanone. MS (APCI) (M + H) &lt; + & gt ^; at m / z 967.

Example 37

3'-N-demethyl-3'-N- (cyclopropylmethyl) -1-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 20, substituting cyclopropanecarboxaldehyde for cyclobutanone. MS (APCI) (M + H) &lt; + & gt ^; at m / z 951.

Example 38

3'-N-demethyl-3'-N- [2- (cyclopropyl) ethyl] -11-deoxy-11- [carboxy- (4-chlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 20, substituting cyclopropyl methyl ketone for cyclobutanone. MS (APCI) (M + H) &lt; + & gt ^; at m / z 965.

Example 39

3'-N-demethy 1-3'-N-propyl-11-deoxy-11- [carboxy- (4-methoxyphenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 2C, substituting 4-chlorophenethylamine

4-methoxyphenezhylamine and propanal are used instead of cyclobutanone. MS APCI) (M + H) &lt; + & gt ^; at m / z 935.

Example 40

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (4-methoxyphenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic caroamate)

The title compound was prepared as described in Example 20, substituting 4-methoxyphenethylamine for 4-chlorophenethylamine and cyclopentanone for cyclobutanone. MS (APCI) (M + H) &lt; + & gt ^; at m / z 961.

Example 41

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3,4-dimethylphenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 20, substituting 4-chlorophenethylamine

3,4-dimethylphenethylamine and propanal are used instead of cyclobutanone. MS APCI) (M + H) &lt; + & gt ^; at m / z 933.

Example 42

3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3-bromo-4-methoxyphenethylamino)] -6-O-methyl-erythromycin A,

11,12- (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 4-chlorophenethylamine

3-Bromo-4-methoxyphenethylamine and cyclopentanone were used in place of cyclobutanone. MS (APCI) (M + H) &lt; + & gt ^; at m / z 1039.

Example 43

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3-bromo-4-methoxyphenethylamino)] -6-O-methyl-erythromycin A,

11,12- (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 3-bromo-4-methoxyphenethylamine for 4-chlorophenethylamine and propanal instead of cyclobutanone. MS (APCI) (M + H) &lt; + & gt ^; at m / z 1013.

Example 44

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 3-chloro-4-fluorophenethylamine for 4-chlorophenethylamine and propanal instead of cyclobutanone. MS (APCI) (M + H) ⁺ at m / z 957.

Example 45

3'-N-demethyl-3'-N- (2-furyl) methyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A, 11, 12 (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 4-chlorophenethylamine

3-chloro-4-fluorophenethylamine was used instead of cyclobutanone

2-furalaldehyc. MS (APCI) (M + H) &lt; + & gt ^; at m / z 995.

• · «»

Example 46

3'-N-demethyl-3'-N- [2- (5-hydroxymethyl) furyl] methyl-11-deoxy-1- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-0-methyl -erythromycin A, 11,12- (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 3-chloro-4-fluorophenethylamine for 4-chlorophenethylamine and cyclobutanone for 4-chlorophenethylamine.

5-hydroxymethyl-2-furalaldehyde. MS (APCI) (M + H) &lt; + & gt ^; at m / z 1025.

Example 47

3'-N-demethyl-3'-N- (2-pyridyl) methyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A, 11, 12 (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 3-chloro-4-fluorophenethylamine for 4-chlorophenethylamine and cyclobutanone for 4-chlorophenethylamine.

2-pyridylcarbaldehyde. MS (APCI) (M + H) &lt; + & gt ^; at m / z 1006.

Example 48

3'-N-demethyl-3'-N- [2- (6-methyl) pyridyl] methyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl- erythromycin A, 11,12- (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 4-chlorophenethylamine

3-chloro-4-fluorophenethylamine was used instead of cyclobutanone

6-methyl-2-pyrrdylcarboxaldehyde. MS (APCI) (M + H) &lt; + & gt ^; at m / z 1020.

Example 49

3'-N-demethyl-3'-N- (4-hydroxyethoxybenzyl) -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A,

11,12- (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 4-chlorophenethylamine

3-chloro-4-fluorophenethylamine was used instead of cyclobutanone

4-hydroxyethoxybenzaldehyde. MS (APCI) (M + H) &lt; + & gt ^; at m / z 1065.

Example 50

3'-N-demethyl-3'-N- (3-methylthio) butyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A, 11, 12 (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 3-chloro-4-fluorophenethylamine for 4-chlorophenethylamine and 3-methylthiobutyraldehyde for cyclobutanone. MS (APCI) (M + H) &lt; + & gt ^; at m / z 1017.

Example 51

3'-N-demethyl-3'-N- (4,4,4-trifluorobutyl) -1-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin AND,

11,12- (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 3-chloro-4-fluorophenethylamine for 4-chlorophenethylamine and cyclobutanone for 4-chlorophenethylamine.

4,4,4-trifluoroutyraldehyde. MS (APCI) (M + H) &lt; + & gt ^; at m / z 1025.

Example 52

3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (4-chloro-3-fluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamat)

The title compound was prepared according to the procedure in Example 19, substituting 4-chloro-3-fluorophenethylamine for 4-chlorophenethylamine; MS (APCI) (M + H) &lt; + & gt ^; at m / z 969.

Example 53

3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamine) -6-O-methyl-erythromycin A, 11,12- (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 4-chlorophenethylamine

3,4-difluorophenethylamine and acetone is used instead of cyclobutanone. MS (APCI) (M + H) &lt; + & gt ^; at m / z 941.

Example 54

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- [3,4 (1,4-dioxano) phenezhylamino]] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 4-chlorophenethylamine

3,4- (1,4-dioxano) phenethylamine and propanal is used instead of cyclobutanone. MS APCI) (M + H) &lt; + & gt ^; at m / z 963.

Example 55

3'-N-demethyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 4-chlorophenethylamine

3,4-dichlorophenethylamine and cyclopropanecarboxaldehyde is used instead of cyclobutanone. MS (APCI) (M + H) &lt; + & gt ^; at m / z 985.

Example 56

3'-N-demethyl-3'-N- [3- (methylsulfoxy) propyl] -1,1-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A , 11,12- (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 4-chlorophenethylamine

3,4-dichlorophenethylamine and 3 (methylsulfoxy) propanal are used instead of cyclobutanone followed by oxidation to the sulfoxide. MS (APCI) (M + H) &lt; + & gt ^; at m / z 1035.

Example 57

3'-N-demethyl-3'-N-ethylthiourea-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12- (cyclic carbamate)

The 3-amino derivative of compound 11 (0.36 g, 0.39 mmol) was dissolved in 10 mL of CHCl 3, treated with 0.39 mmol of the ethylisothiocyanate derivative and the reaction mixture was stirred at room temperature. After 24 hours, the reaction mixture was partitioned with EtOAc (100 mL) and the organic phase was washed with NaHCO ₃ (saturated solution, 3 x 10 mL), brine (100 mL) and then dried (Na ₂ SO 4 and concentrated). MS (APCI) (M + H) ⁺ at m / z 1018.

Example 58

3'-N-demethyl-3'-N- [2- (5-hydroxymethyl) furyl] methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethyl amino)] -6-O-methyl -erythromycin

A, 11,12- (cyclic carbamate)

The title compound was prepared as described in Example 15, substituting 4-chlorophenethylamine

3,4-Dichloroperethylamine and instead of cyclobutanone were used

5-hydroxymethyl-2-furaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1041.

Example 59

3'-N-demethyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11, 12- (cyclic carbamate)

The title compound was prepared as described in Example 19 except that α, α-cyclopropyl-3,4-dichlorophenethylamine was used instead of 4-chlorophenethylamine and cyclopropanecarboxaldehyde was used instead of cyclobutanone. MS (APCI) (M + H) &lt; + & gt ^; at m / z 1011.

Example 60

3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (4-chloroanilinoethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic cartamate)

Step 1: Preparation of 4-chloroanilinoethylamine

4-Chloroaniline hydrochloride salt (6.2 g, 38 mmol) and 2-oxazolidone 3.29 g, 38 mmol) are suspended in a minimum amount of di (ethylene glycol) ethyl ether and the resulting suspension is heated at 16: C. After 4 hours at which CO ₂ evolution ceased, the mixture was cooled to room temperature. The solid obtained was recrystallized from EtOH / ether to give 4.6 g (58%) of 4-chloroanilinoethynylamine as its HCl salt. MS (CI) (M + H) ⁺ at m / z 171. The amine was prepared by partitioning the HCl salt between?

CH 2 Cl 2 and NaHCO 3 (saturated), drying the organic layer (Na 2 SO ₄ ), filtering and concentrating.

Step 2: 3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (4-chloroanilinoethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 4-chloro-phenethylamine for 4-chloroanilinoethylamine prepared in Step 1 and substituting propanal for cyclobutanone; MS (APCI) (M + H) &lt; + & gt ^; at m / z 954.

Example 61

3'-N-demethyl-3'-N-pentyl-11-deoxy-11- [carboxy- (4-chloroanilinoethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

Step 1: Preparation of 4-chloroanilinoethylamine

The 4-chloroaniline hydrochloride salt (6.2 g, 38 mmol) and 2-oxazolidone (3.29 g, 38 mmol) were suspended in a minimum amount of di (ethylene glycol) ethyl ether and the resulting suspension was heated at 160 ° C. After 4 hours at which CO 2 evolution ceased, the mixture was cooled to room temperature. The solid obtained is recrystallized from EtOH / ether to give 4.6 g (58%) of 4-chloroanilinoethylamine as its HCl salt. MS (Cl) (M + H) ⁺ at m / z 171. The free amine was prepared by partitioning the HCl salt between CH 2 Cl 2 and NaHCO 3 (saturated), drying the organic layer (Na ₂ SO ₄ ), filtering and concentrating.

Step 2: 3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (4-chloroanilinoethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carcinam)

The title compound was prepared as described in Example 15, substituting 4-chloro-phenethylamine for 4-chloroanilirethylamine prepared in Step 1 and substituting propanal for cyclobutanone; MS (APCI) (M + H) &lt; + & gt ^; at m / z 980.

Example 62

3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 19, substituting 4-chlorophenethylamine

3,4-difluorophenethylamine and acetone is used instead of cyclobutanone. MS (APCI) (M + H) &lt; + & gt ^; at m / z 941.

Example 63

3'-N-demethyl-3'-N- (2-imidazolyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorenethylamino)] -6-O-methyl-erythromycin A, 11, 12 (cyclic caramate)

The title compound was prepared as described in Example 1, substituting imidazole-2-carcoxaldehyde for cyclopentanone; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1013.

Example 64

3'-N-demethyl-2'-N- (3-pyridyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 ( cyclic carbamate)

·· ··

The title compound was prepared as described in Example 1, substituting pyridyl-3-carboxaldehyde for cyclopentanone; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1022.

Example 65

3'-N-demethyl-3'-N- (2-pyridyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 ( cyclic carbamate)

The title compound was prepared as described in Example 1, substituting pyridyl-2-carboxaldehyde for cyclopentanone; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1022.

Example 66

3'-N-demethyl-3'-N - [(5-nitro) -2-thienyl] methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12- (cyclic carbamate)

The title compound was prepared according to the procedure in Example 55, substituting 5-nitro-thiophene-2-carboxaldehyde for cyclopropanecarboxaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1072.

Example 67

3'-N-demethyl-3'-N- [5- (4-chlorophenyl) -2-furylmethyl] -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-0 -methyl-erythromycin A, 11,12- (cyclic carbamate)

The title compound was prepared according to the procedure in Example 55, substituting 5- (4-chloro-phenyl) -2-furalaldehyde instead of cyclopropanecarboxaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1123.

• «.

♦ »

Example 68

3'-N-demethyl-3'-N- [5-nitro-2-furylmethyl] -1,1-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12- (cyclic carbamate)

The title compound was prepared as described in Example 55, substituting cyclopropanecarboxaldehyde

2use 5-nitro-furaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1059.

Example 69

3'-N-demethyl-3'-N- [2,5-dimethoxy-3-tetrahydrofurylmethyl] -1-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methylerythromycin A, 11 , 12- (cyclic carbamate)

The title compound was prepared as described in Example 55, substituting 2,5-dimethoxy-3-tetrahydrofuraldehyde for cyclopropanecarboxaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1075.

Example 70

3'-N-dimethyl-3'-N- [6-methyl-2-pyridylmethyl] -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A , 11, 12- (cyclic carbamate)

The title compound was prepared according to the procedure in Example 55, substituting 6-methyl-pyridyl-2-carboxaldehyde for cyclopropanecarboxaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1036.

Example 71 * t * i * i * *** *** *** ·······

3'-N-demethyl-3'-N- (4,4,4-trifluorobutyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin

A, 11,12- (cyclic carbamate)

The title compound was prepared according to the procedure in Example 55, substituting 4,4,4-trifluorobutyraldehyde for cyclopropanecarboxaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1041.

Example 72

3'-N-demethyl-3'-N- (1-bromo-2-naphthylmethyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin

A, 11,12- (cyclic carbamate)

The title compound was prepared according to the procedure in Example 55, substituting 1-bron-2-naphthylcarboxaldehyde for cyclopropanecarboxaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1149.

Example 73

3'-N-demethyl-3'-N- (4-methyl-1-naphthylmethyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin

A, 11,12- (cyclic carbamate)

The title compound was prepared according to the procedure in Example 55, substituting 4-methyl-1-naphthylcarboxaldehyde for cyclopropanecarboxaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1085.

Example 74

3'-N-demethyl-3'-N- (4-dimethylamino-1-naphthylmethyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12- (cyclic carbamate) · · · · · · · · · · · · · · · · · · · · · · · ·

The title compound was prepared according to the procedure in Example 55, substituting 4-dimethylamino-1-naphthylcarboxaldehyde for cyclopropanecarboxaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1114.

Example 75

3'-N-demethyl-3'-N- (2-furylmethyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12- ( cyclic carbamate)

The title compound was prepared according to the procedure in Example 55, substituting 2-furaldehyde for cyclopropanecarboxaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1011.

Example 76

3'-N-demethyl-3'-N- [3- (4-pyridyl) propyl] -1-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11.12 (cyclic carbamate)

The title compound was prepared in a manner analogous to Example 1 except that 4-pyridylpropanal was used in place of cyclopentanone. The crude product was purified on silica gel column (CHCl ₃ - »MeOH: CHC1 ₃ 5: 95) to afford a crystalline solid; mp 144-5 ° C; IR (film) v

3315, 2968, 2937, 1754, 1733, 1603, 1457, 1417, 1168 1066 1011, 1000 cm * ¹ ; ¹³ C NMR (CDCl ₃ ) δ 216.27, 176,37, 157,16, 150.72 , 149, 6 *, 146.79, 139.25, 132.14, 130.99, 130,24, 130.10 , 128.3 *, 102.76, 96.15, 82.77, 80.20, 78.88, 77,89, 77.83, * 6.22, 72.67, 70.71, 68.77, 65,78, 65.58, 60.31, 52,69, 50, 64, 49.4 6, 45, 48, 45.24, 44.77, 39, 06, 39.01, 38.96, 36,76, 34, 80, 32.59, 29, 71, 28.63, 21.87, 21,44, 21.38, 20, 14, 18,86, 18, 66, 36.01, 14, 18, 14.10, 10.22, 9, 02. MS (APCI)

(M + H) ⁺ at m / z 1052; Anal Calcd for C ₅₄ H ₈ Cl ₂ N ₃ O 13: C, 61.70; H, 7.7-; N, 4.00. Found: C, 61.56; H, 7.78; N, 4.03.

Example 77

3'-N-demethyl-1'-N- [3- (2-pyridyl) propyl] -1-deoxy-11- [carboxy- (3,4-dichlorosenethylamino)] - 6-O-methyl-erythromycin A, 11.12 (cyclic carramat)

The title compound was prepared in a manner analogous to Example 1 except that 3- (2-pyridyl) propanal was used in place of cyclopentanone. The crude product was purified by silica gel column chromatography (CHC1 ₃ -> MeOH: CHC1 ₃ 5:95) to afford a crystalline solid; IR (film) at 3446, 2970, 2937, 1756,

1458, 1167, 1252, 1011, 998 cm ¹ ; ¹³ ( C NMR (CDCl 3) δ 216,29, 176.44 , 157.19, 149, 14, 139, 31, 136 , 42, 132.19, 131,04, 130.26 , 130.11, 128.45, 128, 40, 122 , 78, 121.05, 102.97, 96.22, 82,83, 80.17, 78.99, 78.00, 77,94, 76.27, 72.66, 70.67, 68.81, 65,83, 65.68, 60.41, 53.38, 52,83, 50, 66, 49, 48 45.53, 45.32, 44,83, 39.15, 39.02, 36.58, 35,57, 34.89, 32.64, 29.73, 28.15, 21,92, 21.47, 21.44, 20.18, 18.88, 18.70, 16.01, 14.22, 14.12,

10.23, 9.02. k '3 (APCI) (M + H) ⁺ at m / z 1052; ; Calcd for C ₅ H ₈₁ Cl ₂ N ₃ O ₁₃ : C, 61.70; H, 7.77; N, 4.00. Found: C, 61.69; H, 7.62; N, 3.87.

Example 78

3'-N-demethyl-1'-N- [4- (4-pyridyl) butyl] -1-deoxy-11- [carboxy- (3,4-dichloroenethylamino)] -6-O-methyl- erythromycin A, 11.12 (cyclic carramate)

The title compound was prepared in a manner analogous to Example 1 except that 4- (4-propyl) butanal was used instead of cyclopentanone. The crude product was purified on a silica gel column (CHCl ₃ → MeOH: CHCl ₃ 5: 9 5) to give a.

crystallization from acetonitrile; mp 192-3 ° C; IR (film) ν 3416, 2969, 2936, 1755, 1733, 1457, 1168, 1067, 1011, 1000 cm ^-1 ; ¹³ C NMR (CDCl ₃ ) δ 216.27, 176, 40, 157.15, 151.04, 149, 65, 139, 25,

132,13, 130.99, 130.24, 130.10, 128.37, 123.85, 102.76, 96, 25, 82,77, 80.22, 78.91, 78.00, 77, 87, 76.26, 72, 68, 70, 66, 68,74, 65,79, 65, 55, 60.31, 52, 93, 50, 64, 49, 44, 45.48, 45.27, 44,78, 39.07, 38.96, 36.86, 35.01, 34.92, 34.84, 32.60, 32.12, 29, 66, 27,62, 21.87, 21.44, 21.38, 20.15, 18.86, 18.66, 16.03, 14,20, 14,10, 10.22, 9.02. MS (APCI) (M + H) &lt; + & gt ^; at m / z 1066; analysis: Calcd for C 55 H 83 Cl 2 N 3 O 13: C, 62.02; H, 7.85; N, 3.94. Found: C, 62.31; H, 7.80; N, 3.77.

Example 79

3'-N-demethyl-3'-N- [3- (3-pyridyl) propyl] -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11.12 (cyclic carbamate)

The title compound was prepared in a manner analogous to Example 1 except substituting 3- (3-pyridyl) propanal for cyclopentanone. The crude product was purified by silica gel column chromatography (CHC1 ₃ -> MeOH: CHC1 ₃ 2: 98). IR (MIC) ν 2971, 2936, 1759, 1735, 1457, 1423, 1167, 1128, 1067, 1053, 1013 cm ^-1 . ¹³ C NMR (CDCl 3) δ 216, 32, 176, 43, 157.20, 149, 78, 147.38,

139,33, 137.14 , 135, 82, 132 , 16, 13 1.03, 13 0, 27, 130.12 t 128,42, 123.34 , 102, 90, 96, 23, 82, 83, 80.2 0, 78.95, 77 , 97, 77,93, 76,23, 72,72, 70,77, 68,86, 65,82, 65 , 33, 60.35 , 52 , 59, 50.67, 49,51, 45,53, 45.29, 44,81, 39,12, 39 , 07, 38.99 , 36 , 77, 34,91, 32,63, 30,48, 29, 66, 29,53, 21,91, 21 , 46, 21.43 , 20 , 18, 18,89, 18,71, 16.04, 14,20, 14,13, 10,25, 9, 04. MS (AP Cl) m / z 1038 (M &lt; + &gt;) Ή) ⁺ ; an slýza: calculate yes for 053879012 N ₃ ( D13: C 61 37; H, 7.69; N 4.05. Finding eno: C, 61.61; H, 7.81 r N, 3.98.

• ·

Example 80

3'-N-demethyl-3'-N- [3- (3-pyridyl) propyl] -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin AND,

11,12- (cyclic carbamate)

The title compound was prepared in a manner analogous to that in Example 79 except that 3-chloro-4-fluorophenethylamine was used in place of 3,4-dichlorophenethylamine. The crude produkz was purified by silica gel column chromatography (CHC1 ₃ -> MeOH: C (- (C 1 ₃ 2: 98). IR (MIC) 2971, 2937, 1759, 1735, 1502, 1458, 1423, 1168, 1105, 1055, 1012, 997 cm ^-1 . ¹³ C NMR (CDCl ₃ ) δ 216.31, 176.42, 157.22, 149.83, 147.45, 135.80,

131,07, 128.51, 123, 35, 102, 95, 96 25, 82 , 81, 80 28, 78 , 96, 78,00, 76.30, 72.74, 70, 80, 68,90, 65,86, 65,39, 60,39, 52, 66, 50.69, 49, 52, 45.56, 45 33, 45,04, 39,16, 39,11, 39,03, 36, 80, 34,92, 32.54, 30.52, 29, 71, 21,95, 21,48, 21, 43, 20,20, 18, 91, 18,71, 16.04, 14.25, 14, 15, 10.28, 9.07. MS (APCI ) m / z 1034 (M + H) ^&lt; ^{+ &gt};; analysis: calculates; no p ro C54H ₈ iC1FN ₃ O 13: C, 62.68; H, 7, 91; N, 4.06 . Found: C, 62 , 76; H, 7, 87; N, 3, 92.

Example 81

3'-N-demethyl-1'-N- [3- (4-pyridyl) propyl] -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin AND,

11,12- (cyclic carbamate)

The title compound was prepared in a manner analogous to that of Example 76 except that 3-chloro-4-fluorophenethylamine was used in place of 3,4-dichlorophenethyl / lamin. Give the crude product is purified by silica gel column chromatography (CHC1 ₃ -> MeOH: Chile ₃ 5:95) to afford crystallization from acetonitrile; mp 162-3 ° C; IR (film) at 3312, 2972, 2936, 1752, 1459, 1168, 1063, 1010 cm @ -1; ¹³ C NMR (CDCl ₃ ) δ 216.22, 176, 33, 157.10,

156.65 (d, J = 247Hz) , 150.82 r 149, 62, 146.69, 135 , 94 (d , J-3.7 Hz), 1 30.93, 128.47 (d, J = 6) 7 Hz), 126.09, 12 3, 69 , 120, 39 (d, J = 17.4 Hz), 116.22 ( d, J = 20 4 Hz), 102.75, 96 , 10, 82.70 r 80.06, 78.83, 77.81, 77,79, 76 , 14, 72.59 70 67, 68,75, 65.67, 65,50, 60.23, 52.50, 50.56, 49 , 39, 45.43 45 18, 44,90, 39,00, 38,97, 38.89, 36.66, 34,76, 32 , 53, 32.40, 29, 53, 28,77, 21,81, 21,35, 21.33, 20.07, 18,79, 18 , 61, 15.92 14 11, 14.02, 10, 16, 8.92. MS (APCI) at m / z 1034 ( M + H) ⁺ ; analysis: off očteno for

C18H11ClFNaOn: Z, 62.68; H, 7.89; N, 4.06. Found: C, 62.40; H, 7.53; N, 3.39.

Example 82

3'-N-demethyl-3'-N- [3- (2-pyridyl) propyl] -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl- erythromycin A,

11,12- (cyclic carbamate)

The title compound was prepared in a manner analogous to Example 77 except that 3-chloro-4-fluorophenethylamine was used in place of 3,4-dichlorophenethylamine. The crude product was purified on a silica gel column (CHCl 3 → MeOH: CHCl 3 5:95) to obtain crystallization from acetonitrile; mp 167-9 ° C; IR (film) ν 3266, 2971, 2937, 1754, 1459, 1167, 1064, 1010, cm ^-1 ; ¹³ C NMR (CDCl ₃ ) δ 216.22, 176, 33,

157,10, 156.8 (d, J = 247Hz), 149.15 , 136.4, 136.03, 131.04, 128.56 (d, J = 13Hz), 122.84. 121.08 120.40 (d, J = 17Hz), 116.34 (d, J = 23Hz), 102.84, 96.20, 82.79, 80.08, 78.96, 77,95, 77, 92, ^ 6.26, 72.65, 70.61, 68.80, 65.82, 65.68, 60.34, 52,56, 50.67, 19.49, 45.53, 45.30, 45.01, 39.11, 39.01, 36.62, 35,54, 34.87, 32.52, 29.65, 28.54, 21.93, 21.49, 21.43, 20, 18, 18,89, 18.71, 26.04, 14.25, 14.14, 10.27, 9.06. MS (APCI) at m / z 1034 (CI + H) ⁺ ; Anal. Calcd for C ₅₄ H ₈ ClFN ₃ O 13: C, 62.68; H, 7.89; N, 4.06. Found: C, 62.64; H, 7.81; N, 3.99.

«· I

Example 83

3'-N-demethyl-3'-N- [4- (4-pyridyl) butyl] -1-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl- erythromycin A,

11,12- (cyclic carbamate)

The title compound was prepared in a manner analogous to Example 78 except that 3-chloro-4-fluorophenethylamine was used in place of 3,4-dichlorophenethylamine. The crude product was purified on a silica gel column (CHCl 3 → MeOH: COCl 3 5:95) and was obtained by crystallization from acetonitrile; mp 118-120 ^c C; IR (film) at 3437, 2971, 2938, 1755, 1459,

1167, 1055, 1C11 cm ^-1 , ; ¹³ C NMR (CDCl 3) δ 216.23, 176, 40, 157.17 156, 78 (d, J = = 247 Hz), 151.07, 149.71, 136.03 (d, J = 5 Hz), 131.02, 128.52 ( d, J = 5 Hz), 123.82, 120.61 (d, J = 14 Hz), 116.31 (d, J = 28Hz) 102.89, 96.28, 82.76, 80.24, 78.98, 78,09, 77, 92, 76, 30 72.71, 70.75, 68.84, 65.80, 65.62, 60.39, 52,91, 50.64, 49.45, 45.50, 45.32, 45.01, 39.15, 39.12, 39.01, 36,85, 35.05, 34.89, 32.51, 29, 66, 29, 61, 27, 66, 21.92, 21.45, 21,41, 20.16, 18.86, 18.67, 16.02, 14.22, 14.09, 10.24, 9.01. MS (APCI) m / z 1048 (M + H) ^&lt; ^{+ &gt};; Analysis: Calculated for C54H81ClFN3O13: C, 62, 99; H, 7.98; N, 4.01. Found: C, 63.14; H, 7.95; N,

3, 80.

Example 84

3'-N-demethyl-3'-N- [4- (6-methyl) -2-pyridyl] butyl] -1-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methylerythromycin A, 11,12- (cyclic carbamate)

The title compound was prepared in a manner analogous to that in Example 80 except that [4- (6-methyl) -2-pyridyl] butanal was used in place of 3- (3-pyridyl) propanal.

The crude product was purified on a silica gel column # (CHCl ₃ → MeOH: CHCl 3 2:98) to yield a crystalline product; mp 68-78 ° C (acetonitrile); IR (MIC) ν 2971, 2938, 1758, 1734, 1457, 1168, 1135, 1054, 1013 cm ^-1 . ¹³ C NMR (CDCl ₃ ) δ 216.31, 176.45, 157.78, 157.20, 136.67, 136.54, 136.09 (d, J = 3.7 Hz),

131 , 07, , 128,5 · 5 (d , J = Hz, 3Hz) OF 120, 53, 119 62 (d, J = 20.8 Hz) OF 116 , 35 (d, j =; 13.8 Hz) , 102.9 '3, 96, 21, 82, 81, 80.15, 78, 99, 77, 95, 77,63, 77, 22, 76, 53, 76 , 49, 76,30, 72, 69, 70.70, 68, 92, 65, 84, 65,78, 62, 43, 60,40, 50 , 69, 49,51, 45.56, 45.33, 45, 04, 39, 16, 39,11, 39, 03, 38,34, 37 , 48, 36, 86, 34, 90, 32.54, 32, 15, 27, 70, 25,92, 24, 54, 21,95, 21 , 50, 21,47, 20.19, 18.89, 18, 71, 16, 03, 14,23, 14, 13, 10.26, 9, 00. MS (APC I) m / z 1062 (M &lt; + &gt;) + H) ⁺ OF

Analysis: Calculated for C56H85CIFN3O13.1,75 H ₂ O: C, 61.46; H, 8.15; N, 3.83. Found: C, 61.54; H, 7.86; N, 3.76.

Example 85

3'-N-demethyl-3'-N- (1-methyl) [3- (4-hydroxy) phenyl) propyl] -1-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6- O-methylerythromycin A, 11,12- (cyclic carbamate)

The title compound was prepared in a manner analogous to Example 1 except that 4- (4-hydroxyphenyl) -2-butanone was used in place of cyclopentanone. The crude product was purified by crystallization from acetonitrile; m.p. 133-4 ° C; IR (MIC)

3396, 2971, 2937, 1760, 1735, 1458, 1168, 1053, 1012, 997 cm ^-1 ; ¹³ C NMR (CDCl 3)? ₃ ) δ 216, 49, 176 50, 176,45, 157.33, 154.19, 139,20, 133.81 , 133, 63, 132, 14, 130 , 99, 130.30, 130,23, 130,10, 129.31 , 129, 21, 128, 37, 115.27, 115.22, 102.89, 102.75, 96,23, 96, 18 , 82,94, 80 , 01, 78,98, 78.02 , 77,94, 77,91, 76,21, “2,66, 72,58, 70, 80, 70,44, 68,86, 68,71, 65,73, 64,97, 63,34, 60,41, 58,50, 55, 95, 50.61, 49, 45 45, 46, 45,28, 44,78, 39,12, 6 8 95 37,69, 37, 30, 34,83, 34,78, 33,79, 33,73, 33,64, 32,58, Z-2.38, 32,28, 31, 83, 27,93, 23, 53, 21.88, 21,45, 21,41, 20,16, 18.80, 18,64, 17, 50, 16,00, 14,15, 14.06, 10,20,

• · · · ·

8.94 (the number of signals greater than the number of carbon atoms is due to a mixture of diastereomers). MS (APCI) (M + H) &lt; + & gt ^; at m / z 1079; Calcd for C56H84Cl2N2O4.4: C, 62.27; H, 7.84; N, 2.59. Found: C, 62.29; H, 7.67: N, 2.53.

Example 86

3'-N-demethyl-3'-N- (1-methyl) [3- (4-hydroxyphenyl) propyl] -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methylerythromycin A, 11,12- (cyclic carbamate)

The title compound was prepared in a manner analogous to that of Example 85 except that the title compound was prepared

3,4-Dichloro-ethylamine uses 3-chloro-4-phenethylamine. The crude product was purified by crystallization from acetonitrile; mp 131-2 ° C; IR (MIC) ν 3373, 2971, 2937, 1733, 1457, 1168, 1055, 1012 cm ^-1 ; ¹³ C NMR (CDCl ₃ ) δ 216, 42, 176.47, 158.42, 157.30,

155 , 15, 154.03 F 136, 01 135 96, 134 , 1, 133 , 9, 13 1.04 r 129,41, 129 , 37, 129.31 r 128, 60 128 50, 120 , 65 , 12 0,40, 116, 47 F 116 , 18, 115,30 r 115, 24, 102, 95, 102 , 82 , 96 , 28, 9 6.25 t 82.88, 80, 09, 79,01, 78 , 12, 78.07, 77, 99, 77, 94, 77,19, 76, 27 Mar: , 72,71, 72, 61, 70,85, 70 , 48, 68,89, 68,76, 65, 80, 65,04, 63, 53 , 60,42, 58, 45, 56,05, 50 , 64, 49,48, 45,51, 45, 35, 45,01, 39, 17 , 39,00, 37, 68, 37,34, 34 , 88, 34,81, 33,79, 33, 66, 32,51, 32, 40 , 32,33, 31, 70, 29,68, 27 Mar: , 96, 21,92, 21,54, 21, 50, 21,42, 20, 19 Dec , 18,85, 18, 67, 17,63, 17 , 55, 16,03, 14,20, 14, 09, 10,25, 8.9 9 (more

signals than the number of carbon atoms are caused by a mixture of diastereomers; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1063; Analysis: Calculated for C 5 ₆ H _{84 2} C1FN Oi _4: C, 63.23; H, 7.96; N, 2.63. Found: C, 63.45; H, 7.93; N, 2.48.

Example 87

3'-N-demethyl-3'-N- [3- (6-methyl-2-pyridyl) propyl] -1-; 1

-deoxy-11 - [carooxy- (3-chloro-4-fluorophenethylamino)] -6-O-methylerythromycin A, 11,12- (cyclic carbamate)

Preparation of 3- (6-methyl-2-pyridyl) propyn-1-ol

Stage la:

To a solution of 2-bromo-6-methylpyridine (3.0 g, 17.4 mmol) in triethylamine, 1 H ₂ O (30 mL / 6 mL), is added LiCl (65 mg), CuBr (65 mg), and propargyl alcohol (1.06 g, 19 mmol). Argon was then slowly bubbled through the reaction mixture for 15 minutes, then Pd (PPh ₃ ) ₄ (150 mg) was added. The reaction mixture was then heated at reflux for 3 hours. After cooling to room temperature, the solvents were evaporated in vacuo and the brown residue was treated with 2 N NaOH. The aqueous layer was extracted with CHCl ₃ (3 ×), the organic layer was dried over MgSO _4, and concentrated in vacuo. The obtained residue was purified by column chromatography (silica gel, ethyl acetate) to give a yellow solid (78%). MS (DCI) (M + H) &lt; + & gt ^; at m / z 148.

Step 1fc: 3- (6-methyl-2-pyridyl) propanol

3- (6-methyl-2-pyridyl) propin-1-ol was dissolved in MeOH (100 mL) and PtO ₂ (0.09 g) was added. The reaction mixture was then hydrogenated at 4 atm for 30 minutes. The catalyst was filtered off and the methanol was evaporated in vacuo. The orange oil residue (2 g) was purified by column chromatography (silica gel, ethyl acetate) to give a yellow oil (77%). MS (DCI) (M + H) &lt; + & gt ^; at m / z 152.

Step 1c: 3- (6-methyl-2-pyridyl) propanal

To a solution of oxalyl chloride (11.3 mmol) in dichloromethane (6 mL) cooled to -78 ° C and under nitrogen atmosphere was added a solution.

DMSO (1.78, 22.9 mmol) in dichloromethane (4 mL). Reaction mixture. :

After stirring for 5 min, 3- (6-methyl-2-pyridyl) -proppanol (1.57 g, 10.4 mmol) in dichloromethane (20 mL) was added over 5 min. Stirring at -78 ° C was continued for 20 minutes and triethylamine (8 mL) was added resulting in a dark slurry. The cooling bath was then removed and after 3 hours the reaction mixture was quenched with brine and then extracted with dichloromethane (3x). After removal of the solvent, the dark residue was purified by column chromatography (silica gel, ethyl acetate) to give a yellow oil (77%). MS DCI (M + H) &lt; + & gt ^; at m / z 150.

Step 2: 3'-N-demethyl-3'-N- [3- (6-methyl-2-pyridyl) propyl] -11-deoxy-11 - [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12- (cyclic carbamate)

The title compound was prepared in a manner analogous to that in Example 80, substituting 3- (6-methyl-2-pyridyl) propanal for 3- (3-pyridyl) propanal. The crude product was purified by silica gel column chromatography (CHC1 ₃ -> MeOH: CHC1 ₃ 2:98) to yield a crystalline product; mp 165-173 ° C; IR (MIC) ν 2970, 2936, 1756, 1731, 1501, 1458, 1170, 1104, 1092, 1061, 1012, 996 cm ^-1 . ¹³ C NMR (CDCl ₃ ) δ 215.02, 175.18, 159, 96, 156.43, 155.89, 155.45 (d, J = 247 Hz), 135.31, 134.73 (d, J = 3.8

Hz), 129.72, 127.26 (d, J = 6.8Hz) 119,20, 119.19 (d, J = 17) 4 Hz), 118.24, 115.02 (d, J = 21.2Hz) , 101.67 , 94.89, 81.49, 78,71, 77, 67, 6,61, 74.91, 71.31, 69, 26, 67.53, 64.49, 64, 45, 59.02, 50.88, 49,35, 48.17, 44.21, 43,98, 43.69, 37.86, 37, 68, 35,42, 34.17, 33,55, 31.20, 28.31, 27,26, 23.07, 20.60, 20, 15, 20,10, 18,87, 17,56, 17.40, 14.71, 12,90, 12.80, 8, 95, 7.69

MS (APCI) m / z 1D 48 (M + H) ^&lt; ^{+ &gt};; Calcd for C ₅₅ H ₈₃ ClFN ₃ O 13: C, 62.99; H, 7.98; N, 4.01. Found: C, 62.83; H,

8.09; N, 4.16.

Example 88

3'-N-demethyl-2'-N- [3- (5-methyl-2-pyridyl) propyl] -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-0 -methyl-erythromycin A, 11,12- (cyclic carbamate)

The title compound was prepared in a manner analogous to that in Example 80, substituting 3- (5-methyl-2-pyridyl) propanal for 3- (3-pyridyl) propanal. The crude product was purified by silica gel column chromatography (CHC1 ₃ -> MeOH: CHC1 ₃ 2:98) to yield a crystalline product; mp 196-202 ° C; IR (MIC) ν 2972, 2938, 1756, 1732, 1501, 1458, 1169, 1128, 1105,

106 8, 1060, 1) 12, 997 cm ^-1 . ¹³ C NMR (CDCl ₃ ) δ 2 16, 35, 176 , 49, 158 , 73 , 157.21, 156.7 7 (d, J = 247Hz), 149 44, 13 7.02, 1 36.07, 136 , 06 (d, J = 1.8Hz) 131.04, 130.22, 128, 59 (d, J = 6.9 Hz), 122 , 21 120.52 (d, J = 17.4 Hz), 116.34 (d, J = 2 1,2 Hz), 1 05,50, 103 , 01 , 96.21, 82.82, 80.08, 79.00, 77.94, 76 , 23 , 72.65 F 70, 67, 68.87, 65.78, 65.69, 60.35, 52.71, 50, 68, 49,47, 45, 55 45, 31, 45.01, 39, 16, 39.16, 39, 01, 36, 56, 35, 11, 34.88, 32,52, 29, 61, 28.47, 21.93, 21.47, 20.19, 18.90, 18, 72, 18,04, 16.04, 14, 22, 14.13, 10.28, 9.00. MS (APCI) m / z 1 .048 (M + H) ⁺ ; analysis: off ocht for C ₅₅ H ₈₃ C1 FN ₃ O ₁₃ : C, 62, 99; H, 7 , 98 ; N, , 4.01.

Found: C, 62.40; H, 8.06; N, 4.13.

Example 89

3'-N-demethyl-3'-N- (2-pyridyl) ethyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 ( cyclic cartamat)

A solution of compound 11 described in Example 1 (0.150 g, 0.161 mmol), 2-vinylcyridine (0.085 g, 0.805 mmol) and acetic acid (0.048 g, 0.041 mL, 0.805 mmol) in methanol (3 mL) was heated at reflux for days. flow. The residue was partitioned between chloroform and saturated NaHCO ₃ solution, the organic layer was dried over anhydrous magnesium sulfate, and the solvents were evaporated in vacuo.

100 ALIGN!

The crude product was purified on a silica gel column (CHCl 3 → MeOH: CHCl 3 5:95) to yield a crystalline product; m.p. 125-6 ° C (acetonitrile); IR (MIC) ν 3452, 2972, 2938, 1760,

1735, 1459, 1168, 1055, 1012, 1000 cm ^-1 ; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1036; ) ⁺ ; Calcd for C53H79Cl2N3O13: C, 61.38; H, 7.68; N, 4.05. Found: C, 61.25; H, 7.57; N, 4.05.

Example 90

3'-N-demethyl-2'-N- (2-pyridyl) ethyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A,

11,12- (cyclic carbamate)

The title compound was prepared in a manner analogous to that in Example 89 except that 3-chloro-4-fluorophenethylamine was used in place of 3,4-dichlorophenethylamine. The crude product was purified on a silica gel column (CHCl 3 → MeOH: CHCl 3 5: 95) to yield a crystalline product; mp 200-202 ° C (acetonitrile); IR (MIC) ν 3452, 2972, 2938, 1757, 1732, 1459, 1168, 1055, 1012, 1000 cm ^-1 ; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1020

Example 91

3'-N-demethyl-2'-N- (4-hydroxybenzyl) -1-deoxy-11- [carboxy- (3,4-dichloro-ethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic) carbamat)

The title compound was prepared as described in Example 55, substituting 4-hydroxybenzaldehyde for cyclopropanecarboxaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1037.

Example 92

ΙΟΙ

3'-N-demethyl-3'-N- (4-pyridylmethyl) -1-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic karcamat)

The title compound was prepared as described in Example 5 příkladu, substituting 4-pyridylcarboxaldehyde for cyclopropanecarboxaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1022.

Example 93

3'-N-demethyl-3'-N - [(3-methylthio) butyl] -1-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11, 12 (cyclic caramate)

The title compound was prepared according to the procedure in Example 55, substituting 3- (mechylthio) butyraldehyde for cyclopropanecarboxaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 1033.

Example 94

3'-N-demethyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12- (cyclic carbamate)

The title compound was prepared as described in Example 1, substituting 2-methyl-cyclopropanecarboxaldehyde for cyclopropanecarboxaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 999.

Example 95

3'-N-demethyl-2'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A , 11,12- (cyclic carbamate) • · · ·

102

The title compound was prepared according to the procedure in Example 29, substituting 2-methyl-cyclopropanecarboxaldehyde for cyclopropanecarboxaldehyde; MS (APCI) (M + H) &lt; + & gt ^; at m / z 983.

Example 96

3'-N-demethyl-3'-N-oxiranylmethyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] -6-O-methyl-erythromycin A,

11,12- (cyclic carbamate)

The title compound was prepared as described in Example 57, substituting epibromohydrin and triethylamine for ethyl isothiocyanate and 4-chlorophenethylamine for 3,4-dichlorophenethylamine; MS (APCI) (M + H) &lt; + & gt ^; at m / z 981.

Example 97

3'-N-demethyl-3'-guanidino-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate)

The title compound was prepared as described in Example 96, substituting epibromohydrin

3,5-dimethylpyrazolecarboxamidine; MS (APCI) (M + H) &lt; + & gt ^; at m / z 939.

Example 98

3'-N-demethyl-3'-N-2- (4,5-dihydroimidazolyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11 , 12- (cyclic carbamate)

The title compound was prepared as described in Example 97, substituting epibromohydrin

3,5-dimethylpyrazolyl-4,5-dihydroimidazole; MS (APCI) (M + H) &lt; + & gt ^; at m / z 965.

Claims (15)

PATENT CLAIMS A compound of the formula at or a pharmaceutically acceptable salt or ester thereof wherein A represents a group selected from the group consisting of: a) -C, b) -N, and c) -O; X and Y independently and at each occurrence are z groups including and) hydrogen, (b) halocenid, C) trifluoromethyl, (d) alkoxy, E) alkyl, F) aryl, and • · 104 g) substituted aryl; R is selected from the group consisting of: (a) alkyl; b) cycloalkyl, c) heterocycle, d) substituted heterocycle, (e) alkylcycloalkyl; f) substituted alkylcycloalkyl, (g) alkylaryl; (h) alkyl heterocycle; (i) alkenyl; j) alkynyl, k) -C (S) -NHR ₄ , C (NR ₄ ) -NHR ₄ , wherein R ₄ is hydrogen, alkyl or aryl; and l) - _{(CH2) n} ^_ C (CH ₂₎ m ^- R5, wherein m is 2, 3, 4, or 5, and R5 is a radical from the group comprising alkyl, alkoxy, aryl or substituted aryl; R ₂ and R ₃ are independently at each occurrence (a) hydrogen, (b) a methyl group; or R ₂ and R _3, when A is C, together form a cyclic group; R ₃ , when A is N, has no meaning; and n = 1, 2 or 3. A compound according to claim 1, wherein R is alkyl, alkenyl, cycloalkyl, heterocycle, (heterocycle, alkyl and alkylcycloalkyl; X and Y independently at each occurrence are chloro, fluoro, dioxolano, hydrogen or alkoxy A is -C or N; R ₂ and R ₃ are independently at each occurrence hydrogen or together form a cyclopropyl group; and n is 1. 3. A compound of claim 1 selected from the group consisting of: 3'-N-demethyl-2'-N-cyclopentyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N-cyclopropyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N-n-propyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A ,. 11.12 (cyclic carbamate); 3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N-cyclohexyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N-isovaleryl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 106 3'-N-demethyl-3'-N- (3-methylthiopropyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N- (3-tetrahydrothienyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12- ( cyclic carbamate); 3'-N-demethyl-3'-N- (3,4-dimethylcyclopentyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 - (cyclic carbamate); 3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 - (cyclic carbamate); 3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 - (cyclic carbamate); 3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethylamino)) - 6-O-methyl-erythromycin A, 11, 12 - (cyclic carbamate); 3'-N-demethyl-3'-N-cyclohexyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 - (cyclic carbamate); 3'-N-demethyl-3'-N-n-propyl-11-deoxy-11- [carboxy- (3,4-dioxolanophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 108 • · «« 3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3,4-dioxolanophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ; 3'-N-demethyl-3'-Nn-propyl-11-deoxy-11- [carboxy- (4-chloro-3-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) : 3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (4-chloro-3-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ; 3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (4-chloro-3-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12, (cyclic carbamate) ); 3'-N-demethyl-3'-N-cyclobutylmethyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N-cyclobutylmethyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N-ethyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 108 3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3-chlorophenethylamino)) - β-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N-n-propyl-11-deoxy-11- [carboxy- (3-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ; 3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ; 3´-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N-cyclopropylmethyl-11-deoxy-11- (carboxy- (3-chloro-4-fluorophenethylamino)) -6-O-methyl-erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); • · 999 109 3'-N-demethyl-2'-N-cyclopentyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic cartamate) ; 3'-N-demethyl-1'-N-n-propyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-2'-N-cyclopropylmethyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-2'-N- (4-pyridylmethyl) -11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ; 3'-N-demethyl-2'-N- (2-butyl) -11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ; 3'-N-demethyl-2'-N- (3-pentyl) -11-deoxy-11- [carboxy- (4-chlorophenethylamino)) - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ; 3'-N-demethyl-3'-N- (cyclopropylmethyl) -11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N- (2-cyclopropylethyl) -11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ; I · · · · 3'-N-demethyl-2'-N-propyl-11-deoxy-11- [carboxy- (4-methoxyphenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-2'-N-cyclopentyl-11-deoxy-11- [carboxy- (4-methoxyphenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-2'-N-propyl-11-deoxy-11- [carboxy- (3,4-dimethylphenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3-bromo-4-methoxyphenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ; 3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3-bromo-4-methoxyphenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ; 3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ; 3'-N-demethyl-2'-N- (2-furyl) methyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N- [2- (5-hydroxymethyl) furyl) methyl-11-deoxy-11- (carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl -erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N- (2-pyridyl) methyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N- [2- (6-methyl) pyridyl] methyl-11-deoxy-11- (carboxy- (3-chloro-4-fluorophenethylamino)) -6-O-methyl -erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N- (4-hydroxyethoxybenzyl) -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N- (3-methylthio) butyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A ,. 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N- (4,4,4-trifluorobutyl) -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin AND, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (4-chloro-3-fluorophenethylamino)] -6-O-methyl-erythromycin, 11 11,12 (cyclic carbamate) ; 3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- [3,4- (1,4-dioxano) phenethylamino)] - 6-O-methyl-erythromycin A, 11, 12 (cyclic carbamate); • · · · 112 3'-N-demethyl-ζ'-N-cyclopropylmethyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carramate) ; 3'-N-demethyl-3'-N- [3- (methylsulfoxy) propyl] -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N-ethylthiourea-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carramate) ; 3'-N-demethyl-3'-N- [2- (5-hydroxymethyl) furyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12- (cyclic carbamate): 3'-N-demethyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy- (α, α-cyclopropyl-3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11, 12 - (cyclic carbamate); 3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (4-chloroanilinoethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-2'-N-cyclopentyl-11-deoxy-11- [carboxy- (4-chloroanilinoerhylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (3,4- (difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-2'-N- (2-imidazolo) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-2'-N- (3-pyridyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 ( cyclic carbamate); 3'-N-demethyl-3'-N- (2-pyridyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N - [(5-nitro) -2-thienyl] methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N- [5- (4-chlorophenyl) -2-furyl] methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methylerythromycin 1111,12- (cyclic carbamate); 3'-N-demethyl-3'-N- [5-nitro-2-furyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A 11.12 (cyclic carbamate); 3'-N-demethyl-3'-N- [2,5-dimethoxy-3-tetrahydrofuryl] methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methylerythromycin A 11,12- (cyclic carbamate); 3'-N-demethyl-2'-N- [6-methyl-2-pyridyl] methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12- (cyclic carbamate); • · · 114 3'-N-demethyl-3'-N- (4,4,4-trifluorobutyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)) - 6-O-methyl-erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-2'-N- (1-bromo-2-napthyl) methyl-11-deoxy-11- [carboxy- (3'-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-2'-N- (4-methyl-1-napthyl) methyl-11-deoxy-11- [carboxy- (3'-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-2'-N- (4-dimethylamino-1-napthyl) methyl-11-deoxy-11- [carboxy-3,4-dichlorophenethylamino]] - 6-O-methylerythromycin A, 11, 12- (cyclic carbamate); 3'-N-demethyl-2'-N- (2-furyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 ( cyclic carbamate); 3'-N-demethyl-2'-N- [3- (4-pyridyl) propyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11.12 (cyclic carbamate); 3'-N-demethyl-2'-N- [3- (2-pyridyl) propyl] -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11.12 (cyclic carbamate); 3'-N-demethyl-2-N-3- [4- (4-pyridyl) butyl] -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A 11.12 (cyclic carbamate); 115 3'-N-demethyl-3'-N- [3- (3-pyridyl) propyl] -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11.12 (cyclic carbamate); 3'-N-demethyl-3'-N - [(3- (3-pyridyl) propyl] -11-deoxy-11- (carboxy- (3-chloro-4-fluorophenethylamino)) - 6-O-methyl- erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N- [3- (4-pyridyl) propyl] -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin AND, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N- [3- (2-pyridyl) propyl] -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin AND, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N- [4- (4-pyridyl) butyl] -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin AND, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N- [4- (6-methyl-2-pyridyl)] butyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] -6- O-methyl-erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N- [1-methyl-3- (4-hydroxyphenyl) propyl] -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] -β-O-methyl -erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N - [(1-methyl) -3- (4-hydroxyphenyl) propyl] -1-deoxy-11- [carbuxyl- (3-chloro-4-fluorophenethylamino)] - 6-0 -methyl-erythromycin A, 11,12- (cyclic carbamate); • • • 116 3'-N-demethyl-3'-N- [3- (6-methyl-2-pyridyl) propyl] -11-deoxy-11 [carboxy- (3-chloro-4-fluorophenethylamino)] - 6- O-methyl-erythromycin A 11,12- (cyclic carbamate); 3'-N-demethyl-2'-N- [3- (5-methyl-2-pyridyl) propyl] -11-deoxy-l- [carboxy- (3-chloro-4-fluorophenethylamino)] -6- O-methyl-erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N- (2-pyridylethyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3´-N-demethyl-3'-N- (2-pyridylethyl) -11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N- (4-hydroxybenzyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic) carbamate); 3'-N-demethyl-3'-N- (4-pyridyl) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)) - 6-O-methyl-erythromycin A, 11, 12- (cyclic carbamate); 3'-N-demethyl-3'-N - [(3-methylthio) butyl] -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - β-O-methyl-erythromycin A, 11, 12 (cyclic carbamate); 3'-N-demethyl-3'-N- (1-methylcyclopropane) methyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin- A, 11,12- (cyclic carbamate); • · · · 117 3'-N-demethyl-3'-N- (1-methylcyclopropyl) methyl 1-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl- erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N-oxiranylmethyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-guanidino-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); and 3'-N-demethyl-3'-N-2- (4,5-dihydroimidazolyl) -11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11 12- (cyclic carbamate). A compound according to claim 3 selected from the group consisting of: 3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); 3'-N-demethyl-3'-N-cyclopropyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 [cyclic carbamate]; 3'-N-demethyl-3'-N-propyl-11-deoxy-11- [carboxy- (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); • · 118 3'-N-demethyl-3'-N-isopropyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ; 3'-N-demethyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy- (3-chloro-4-fluorophenethylamino)) -6-O-methyl-erythromycin A, 11,12- (cyclic carbamate); 3'-N-demethyl-3'-N-cyclobutyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate) ); 3'-N-demethyl-3'-N-cyclopentyl-11-deoxy-11- [carboxy- {3,4- (difluorophenethylamino)] -6-O-methyl-erythromycin A, 11,12 (cyclic carbamate): 3'-N-demethyl-3'-N-n-propyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate); and 3'-N-demethyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy- (3,4-difluorophenethylamino)] - 6-O-methyl-erythromycin A, 11,12 (cyclic carbamate). A pharmaceutical composition that inhibits LH release comprising a therapeutically effective amount of a compound of claim 1 in association with a pharmaceutically acceptable carrier. 6. A method of inhibiting LH release in a mammal in need of treatment comprising administering to said mammal a therapeutically effective amount of a compound of claim 1. 7. A method for adding a compound of the formula: 119 or a pharmaceutically acceptable salt or ester thereof, wherein A is a group selected from the group consisting of: a) -C, b) -N, and c) -0; X and Y independently and at each occurrence are z ny including and) guided · :, (b) halooenid, C) trifluoromethyl, (d) Alcohol: ·: v, E) alkyl, F) aryl, and G) substituted aryl; 120 R is selected from the group consisting of: (a) alkyl; b) cycloalkyl, c) heterocycle, d) substituted heterocycle, (e) alkylcycloalkyl; f) substituted alkylcycloalkyl, (g) alkylaryl; (h) alkyl heterocycle; (i) alkenyl; j) alkynyl, k) -C (S) -NHR ₄ , C (NR ₄ ) -NHR ₄ , wherein R ₄ is hydrogen, alkyl or aryl; and l) - (CH ₂ ) _n -C (CH 2) _m -R 5 where m is 2, 3, 4, or 5 and R 5 is alkyl, alkoxy, aryl or substituted aryl; R2 and R3 are independently at each occurrence (a) hydrogen, (b) a methyl group; or R ₂ and R _3, when A is C, together form a cyclic group; R ₃ , when A is N, has no meaning; and n = 1, 2 or 3; characterized by the following steps: (a) reacting a compound of the formula: 121 with sodium hexamethyldisilazide and carbonydiimidazole to form a compound of formula: b) reacting the compound prepared in step (a) with an amino compound of the general formula: to ₂ - A - R 3 / (CH ₂ ) _n -NH ₂ followed by deprotection of the 2 ', 4 protected hydroxyl groups to give a compound of formula: • · »» 122 c) demethylating the 3'-amino group comprising treating the compound prepared in step (b) to a compound of the formula: d) alkylating the 3'-N-demethylated compound prepared in step (c) with an alkylating agent. 8. The method according to claim 7, characterized _f in that the reaction stage (a) is performed in an aprotic solvent at 0 to 25 ° C. Process according to claim 7, characterized in that reaction step (b) is carried out in the absence of solvent or in the presence of acetonitrile at 25 to 80 ° C. * ·· * The process according to claim 1, wherein the demethylation is carried out by reacting the compound prepared in step (b) with iodine in the presence of a base and a light or heat source. 11. The process of claim 7 wherein the demethylation is carried out by reacting the compound prepared in step (b) with a chloroformate selected from the group consisting of benzyl chloroformate, allyl chloroformate and vinyl formate. The process according to claim 7, wherein the alkylation step (d) is carried out by reacting the compound prepared in step (c) with an aldehyde or ketone in the presence of a metal hydride or in the presence of a Pd / C catalyst in a protic or non-protic solvent in the atmosphere. hydrogen. The process according to claim 7, wherein the alkylation step (d) is carried out by reacting the compound prepared in step (c) with an alkyl halide in the presence of a base. 14. The method of claim 7 wherein R is selected from the group consisting of alkyl, alkenyl, cycloalkyl, heterocycle, (heterocycle) alkyl and alkylcycloalkyl; X and Y independently at each occurrence are selected from the group consisting of chloro, fluoro, dioxolano, hydrogen or alkoxy; A is -C; R ₂ and R ₃ are independently at each occurrence hydrogen or together form a cyclopropyl group, and _n is 1. * ··· 123 «· ··« · u « 9 9 · · · 15. The process of claim 7 wherein the alkylating agent is cyclopentanone and the alkylation is carried out in the presence of sodium cyanoborohydride in methanol.