Indian Patents
Title of Invention

14 AND 15 MEMBERED-RING COMPOUNDS AND COMPOSITIONS COMPRISING THEM.
Abstract This invention discloses a compound of formula (I) wherein A, R1, R2, R3, R4,R5 ,R6 are described in the specification. The invention is also for composition comprising said compound.
Full Text The present invention relates to novel semi-synthetic macrolides having antimicrobial
activity, in particular antibacterial activity. More particularly, the invention relates to 15-
membered macrolides substituted at the 4" position, to processes for their preparation, to
compositions containing them and to their use in medicine.
Macrolide antibacterial agents are known to be useful in the treatment or prevention of
bacterial infections. However, the emergence of macrolide-resistant bacterial strains has
resulted in the need to develop new macrolide compounds.
According to the present invention, we have now found novel 15-membered macrolides
substituted at the 4" position which have antimicrobial activity.
Thus, the present invention provides compounds of general formula (I)
wherein
A is a bivalent radical selected from -C(O)NH-, -NHC(O)-, -N(R7)-CH2- and -CH2-N(R7)-;
R1 is -NHC(O)(CH2)dXR8;
R2 is hydrogen;
R3 is hydrogen, C1-4alkyl, or C3-6alkenyl optionally substituted by 9 to 10 membered
fused bicyclic heteroaryl;
R4 is hydroxy, C3-6alkenyloxy optionally substituted by 9 to 10 membered fused bicyclic
heteroaryl, or C1-6alkoxy optionally substituted by C1-6alkoxy or -O(CH2)eNR7R9,
R5 is hydroxy, or
R4 and R5 taken together with the intervening atoms form a cyclic group having the
following structure:
wherein Y is a bivalent radical selected from -CH2-. -CH(CN)-, -O-, -N(R10)- and -
CH(SR10) with proviso that when A is -NHC(O)-, -N(R7)-CH2- or -CH2-N(R7)-, Y is -O-;
R6 is hydrogen or fluorine;
R7 is hydrogen or C1-6alky I;
R8 is a heterocyclic group having the following structure:
R9 is hydrogen or C1-6alkyl;
R10 is hydrogen or C1-4alkyl optionally substituted by a group selected from optionally
substituted phenyl, optionally substituted 5 or 6 membered heteroaryl and optionally
substituted 9 to 10 membered fused bicyclic heteroaryl;
R11 is hydrogen, -C(O)OR14, -C(O)NHR14, -C(O)CH2NO2 or -C(O)CH2SO2R7;
R12 is hydrogen, C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy, C3.
7cycloalkyl, or optionally substituted phenyl or benzyl;
R13 is halogen, C1-4alkyl, C1-4hioalkyl, C1-4alkoxy, -NH2, -Nh(C1-4alkyl) or -N(C1-4
alkyl)2;
R14 is hydrogen,
C1-4alkyl optionally substituted by up to three groups independently selected from
halogen, cyano, C1-4alkoocy optionally substituted by phenyl or C1-4alkoxy, -
C(O)C1-6alkyl, -(O)C1-6alkyl, -OC(O)C1-6alkyl, -OC(O)OC1-6alkyl,
C(O)NR17r18, -NR17R18and phenyl optionally substituted by nitro or -C(O)OC1-6
alkyl,
-(CH2)wC3-7cycloalkyl,
-(CH2)wheterocyclyl,
-(CH2)wheteroaryl.
-(CH2)waryl,
C3-6alkenyl, or
C3-6alkyny';
r15 is hydrogen, C1-4alkyl, C3-7cycloalkyl, optionally substituted phenyl or benzyl, acetyl
or benzoyl;
r16 is hydrogen or R13 or R16 and R12 are linked to form the bivalent radical -O(CH2)2-
or-(CH2)t
R17 and R18 are each independently hydrogen or C1-6alky I optionally substituted by
phenyl or -C(O)OC1-6alkyl, or
R17 and R18, together with the nitrogen atom to which they are bound, form a 5 or 6
membered heterocyclic group optionally containing one additional heteroatom selected
from oxygen, nitrogen and sulfur;
X is -U(CH2)vB-. -U(CH2) or a group selected from:
U and B are independently a divalent radical selected from -N(R15)-, -O-, -5(0)z-, -
N(R15)C(OK -C(O)N(R15)- and -HC(O)R15]-;
W is -C(R16)- or a nitrogen atom;
d is 0 or an integer from 1 to 5;
e is an integer from 2 to 4;
j and z are each independently integers from 0 to 2;
w is an integer from 0 to 4;
t is 2 or 3;
v is an integer from 1 to 8;
and pharmaceutically acceptable derivatives thereof.
According to a further embodiment the present invention provides compounds of general
formula (IA)
wherein
A is a bivalent radical selected from -C(O)NH-, -NHC(O)-, -N(R7)-CH2- and -CH2-N(R7)-;
R1 is -NHC(O)(CH2)dXR8;
R2 is hydrogen;
R3 is hydrogen, C1-4alkyl, or C3-6alkenyl optionally substituted by 9 to 10 membered
fused bicyclic heteroaryl;
R4 is hydroxy, C3-6alkenyloxy opionally substituted by 9 to 10 membered fused bicyclic
heteroaryl, or C1-4alkoxy optionaly substituted by C1-4alkoxy or -O(CH2)eNR7R9,
R5 is hydroxy, or
R4 and R5 taken together with fie intervening atoms form a cyclic group having the
following structure:
wherein Y is a bivalent radical selected from -CH2-. -CH(CN)-, -O-, -N(R10)- and -
CH(SR10)-, with proviso that when A is -NHC(O)-, -N(R7)-CH2- or -CH2-N(R7)-, Y is -O-;
R6 is hydrogen or fluorine;
R7 is hydrogen or C1-6alkyl;
R8 is a heterocyclic group having the following structure:
R9 is hydrogen or C1-6alky!;
R10 is hydrogen or C1-4alkyl substituted by a group selected from optionally substituted
phenyl, optionally substituted 5 or 6 membered heteroaryl and optionally substituted 9 to
10 membered fused bicyclic heteroaryl;
R11 is hydrogen, -C(O)OR14, -C(O)NHR14 or -C(O)CH2NO2;
R12 is hydrogen, C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy, C3-7
cycloalkyl, or optionally substituted phenyl or benzyl;
R13 is halogen, C1-6alkyl, C1-4thioalkyl, C1-4alkoxy, -NH2, -NH(C1-4alkyl) or -N(C1-6.
alkyl)2;
R14 is hydrogen or C1-6alkyl optionally substituted by up to three groups independently
selected from halogen, C-|^alkoxy, -OC(O)C1-4alkyl and -OC(O)OC-|^alkyl;
R15 jS hydrogen, C1-6alkyl, C3_7cycloalkyl, optionally substituted phenyl or benzyl, acetyl
or benzoyt;
R16 is hydrogen or R13, or R16 and R12 are linked to form the bivalent radical -O(CH2>2-
or-(CH2H-:
X is -U(CH2)vB-, -U(CH2)v- or a group selected from:
U and B are independently a divalent radical selected from -N(R15)-, -O-, -S(O)Z-, -
N(R15)C(O)-. -C(O)N(R15)- and -N[C(O)R15]-;
W is -C(R16)- or a nitrogen atom;
d is 0 or an integer from 1 to 5;
e is an integer from 2 to 4;
j and z are each independently integers from 0 to 2;
t is 2 or 3;
v is an integer from 2 to 8;
and pharmaceutically acceptable derivatives thereof.
The term "pharmaceutically acceptable" as used herein means a compound which is
suitable for pharmaceutical use. Salts and solvates of compounds of the invention which
are suitable for use in medicine are those wherein the counterion or associated solvent
is pharmaceutically acceptable. However, salts and solvates having non-
pharmaceutically acceptable counterions or associated solvents are within the scope of
the present invention, for example, for use as intermediates in the preparation of other
compounds of the invention and their pharmaceutically acceptable salts and solvates.
The term "pharmaceutically acceptable derivative" as used herein means any
pharmaceutically acceptable salt, solvate or prodrug, e.g. ester, of a compound of the
invention, which upon administrates to the recipient is capable of providing (directly or
indirectly) a compound of the invention, or an active metabolite or residue thereof. Such
derivatives are recognizable to those skilled in the art, without undue experimentation.
Nevertheless, reference is made to the teaching of Burger's Medicinal Chemistry and
Drug Discovery, 5th Edition, Vol 1: Principles and Practice, which is incorporated herein
by reference to the extent of teaching such derivatives. Preferred pharmaceutically
acceptable derivatives are salts, solvates, esters, carbamates and phosphate esters.
Particularly preferred pharmacetically acceptable derivatives are salts, solvates and
esters. Most preferred pharmacetically acceptable derivatives are salts and esters, in
particular salts.
The compounds of the present invention may be in the form of and/or may be
administered as a pharmaceutical/ acceptable salt. For a review on suitable salts see
Berge et a/., J. Pharm. Sci., 1977.66,1-19.
Typically, a pharmaceutical acceptable salt may be readily prepared by using a desired
acid or base as appropriate. The salt may precipitate from solution and be collected by
filtration or may be recovered by evaporation of the solvent. For example, an aqueous
solution of an acid such as hydrodhloric acid may be added to an aqueous suspension of
a compound of formula (I) and the resulting mixture evaporated to dryness (lyophilised)
to obtain the acid addition salt as a solid. Alternatively, a compound of formula (I) may
be dissolved in a suitable solvent for example an alcohol such as isopropanol, and the
acid may be added in the same solvent or another suitable solvent. The resulting acid
addition salt may then be precipitated directly, or by addition of a less polar solvent such
as diisopropyl ether or hexane, and isolated by filtration.
Suitable addition salts are formed from inorganic or organic acids which form non-toxic
salts and examples are hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate,
nitrate, phosphate, hydrogen phosphate, acetate, trifluoroacetate, maleate, malate,
fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate,
oxaloacetate, trifluoroacetate, saccharate, benzoate, alky! or aryl sulphonates (eg
methanesulphonate, ethanesulphonate, benzenesulphonate or p-toluenesulphonate)
and isethionate. Typical examples include trifluoroacetate and formate salts, for example
the bis or tris trifluoroacetate salts and the mono or diformate salts.
Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such
as those of sodium and potassium, alkaline earth metal salts such as those of calcium
and magnesium and salts with organic bases, including salts of primary, secondary and
tertiary amines, such as isopropytamine, diethylamine, ethanolamine, trimethylamine,
dicyclohexyl amine and N-methyl-D-glucamine.
Compounds of the invention may have both a basic and an acidic centre may therefore
be in the form of zwitterions.
Those skilled in the art of organic chemistry will appreciate that many organic
compounds can form complexes win solvents in which they are reacted or from which
they are precipitated or crystallized. These complexes are known as "solvates". For
example, a complex with water is tnown as a "hydrate". Solvates of the compound of
the invention are within the scope of the invention. The salts of the compound of formula
(I) may form solvates (e.g. hydrates) and the invention also includes all such solvates.
The term "prodrug" as used herea means a compound which is converted within the
body, e.g. by hydrolysis in the thood, into its active form that has medical effects.
Pharmaceutically acceptable produgs are described in T. Higuchi and V. Stella,
"Prodrugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series, Edward
B. Roche, ed., "Bioreversible Carters in Drug Design", American Pharmaceutical
Association and Pergamon Press. 1987, and in D. Fleisher, S. Ramon and H. Barbra
"Improved oral drug delivery: soliblity limitations overcome by the use of prodrugs",
Advanced Drug Delivery Reviews (696) 19(2) 115-130, each of which are incorporated
herein by reference.
Prodrugs are any covalently bondat carriers that release a compound of structure (\) in
vivo when such prodrug is admintstaed to a patient. Prodrugs are generally prepared by
modifying functional groups in a my such that the modification is cleaved, either by
routine manipulation or in vivo, yielding the parent compound. Prodrugs include, for
example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are
bonded to any group that, when administered to a patient, cleaves to form the hydroxy,
amine or sulfhydryl groups. Thus, representative examples of prodrugs include (but are
not limited to) acetate, formate and benzoate derivatives of alcohol, sulfhydryl and amine
functional groups of the compounds of structure (I). Further, in the case of a carboxylic
acid (-COOH), esters may be employed, such as methyl esters, ethyl esters, and the
like. Esters may be active in their own right and/or be hydrolysable under in vivo
conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable
ester groups include those which break down readily in the human body to leave the
parent acid or its salt.
References hereinafter to a compound according to the invention include both compounds
of formula (I) and their pharmaceutically acceptable derivatives.
With regard to stereoisomers, the compounds of structure (I) have more than one
asymmetric carbon atom. In the general formula (I) as drawn, the solid wedge shaped
bond indicates that the bond is above the plane of the paper. The broken bond indicates
that the bond is below the plane of the paper. The wavy bond ( ) indicates that the
bond can be either above or below the plane of the paper. Thus, the present invention
includes both epimers at the 4"-carton.
It will be appreciated that the substituents on the macrolide may also have one or more
asymmetric carbon atoms. Thus, tie compounds of structure (I) may occur as individual
enantiomers or diastereomers. Al such isomeric forms are included within the present
invention, including mixtures thereof.
Where a compound of the inventk» contains an alkenyl group, cis (Z) and trans (E)
isomerism may also occur. The present invention includes the individual stereoisomers
of the compound of the invention and, where appropriate, the individual tautomeric forms
thereof, together with mixtures thaeof.
Separation of diastereoisomers ores and trans isomers may be achieved by
conventional techniques, e.g. by factional crystallisation, chromatography or H.P.L.C. A
stereoisomeric mixture of the aged may also be prepared from a corresponding optically
pure intermediate or by resolutiort,such as H.P.L.C, of the corresponding mixture using
a suitable chiral support or by fratifcnal crystallisation of the diastereoisomeric salts
formed by reaction of the corresponding mixture with a suitable optically active acid or
base, as appropriate.
The compounds of structure (I) maf be in crystalline or amorphous form. Furthermore,
some of the crystalline forms of thecompounds of structure (I) may exist as polymorphs,
which are included in the present wention.
R6 is hydrogen or fluorine. However, it will be appreciated that when A is -C(O)NH- or -
CH2-N(R7)-, R6 is hydrogen.
When R8 is a heterocyclic group having the following structure:
said heterocyclic is linked in the 5, 6, 7 or 8 position to the X group as above defined. In
one embodiment, the heterocyclic is linked in the 6 or 7 position. In another embodiment,
the heterocyclic is linked in the 5 or 8 position. When present, the R13 group or groups
may be attached at any position on the ring. In one embodiment, an R13 group is
attached at the 7 position.
When R8 is a heterocyclic group having the following structure:
wherein W is -C(R16)- where R16 is R13 or R16 and R12 are linked to form the bivalent
radical -O(CH2)2~ or -(CH2)t-. said heterocyclic is linked in the (i), (ii) or (iii) position to the
X group as above defined. In one embodiment, the heterocyclic is linked in the (i)
position. In another embodiment, the heterocyclic is linked in the (ii) or (iii) position.
When R8 is a heterocyclic group having the following structure:
said heterocyclic is linked in the 5, 6 or 7 position to the X group as defined above. In one
embodiment, the heterocyclic is linked in the 6 or 7 position. In another embodiment, the
heterocyclic is linked in the 5 position.
When R8 is a heterocyclic group having the following structure:
said heterocyclic is linked in the 6. 7, 8 or 9 position to the X group as above defined. In
one embodiment, the heterocyclic is linked in the 7 or 8 position. In another embodiment,
the heterocyclic is linked in the 6 or 9 position.
When R8 is a heterocyclic group having the following structure:
wherein W is -C(R16)- where R18 is R13 or R16 and R12 are linked to form the bivalent
radical -O(CH2)2- or -(CH2H-. sail heterocyclic is linked in the (i), (ii) or (iii) position to the
X group as above defined. In one embodiment, the heterocyclic is linked in the (i)
position. In another embodiment, tie heterocyclic is linked in the (ii) or (iii) position.
When R8 is a heterocyclic group laving the following structure:
said heterocyclic is linked in the Z. 3 or 4 position to the X group as above defined. In one
embodiment, the heterocyclic is irted in the 2 or 3 position. In another embodiment, the
heterocyclic is linked in the 4 possiton.
The term "alky!" as used herein as a group or a part of a group refers to a straight or
branched hydrocarbon chain containing the specified number of carbon atoms. For
example, C1-10alkyl means a straight or branched alkyl containing at least 1, and at most
10, carbon atoms. Examples of "alky!" as used herein include, but are not limited to,
methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, t-butyl, hexyl, heptyl, octyl,
nonyl and decyl. A C1-4alkyl group is preferred, for example methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl or t-butyl.
The term "C3-7cycloalkyl" group as used herein refers to a non-aromatic monocyclic
hydrocarbon ring of 3 to 7 carbon atoms such as, for example, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl.
The term "alkoxy" as used herein refers to a straight or branched chain alkoxy group
containing the specified number of carbon atoms. For example, C1-6alkoxy means a
straight or branched alkoxy containing at least 1, and at most 6, carbon atoms. Examples
of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-
2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy and hexyloxy.
A C1-4alkoxy group is preferred, for example methoxy, ethoxy, propoxy, prop-2-oxy,
butoxy, but-2-oxy or 2-methylprop-2-oxy.
The term "alkenyl" as used herein as a group or a part of a group refers to a straight or
branched hydrocarbon chain containing the specified number of carbon atoms and
containing at least one double bond. For example, the term "C2-6alkenyl" means a
straight or branched alkenyl containing at least 2, and at most 6, carbon atoms and
containing at least one double bond. Similarly, the term "C3-6alkenyl" means a straight or
branched alkenyl containing at least 3, and at most 6, carbon atoms and containing at
least one double bond. Examples of "alkenyl" as used herein include, but are not limited
to, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl,
3-methylbut-2-enyl, 3-hexenyl and 1,1-dimethylbut-2-enyl. It will be appreciated that in
groups of the form -O-C2-6alkenyl, the double bond is preferably not adjacent to the
oxygen.
The term "alkynyl" as used herein as a group or a part of a group refers to a straight or
branched hydrocarbon chain containing the specified number of carbon atoms and
containing at least one triple bond. For example, the term C3-6alkenyr means a straight
or branched alkynyl containing at least 3, and at most 6, carbon atoms containing at least
one triple bond. Examples of "alkynyl" as used herein include, but are not limited to,
propynyl, 1-butynyl, 2-butynyl, 1-pentynyl and 3-methyl-1-butynyl.
The term "aryl" as used herein refers to an aromatic carbocyclic moiety such as phenyl,
biphenyl or naphthyl.
The term "heteroaryl" as used herein, unless otherwise defined, refers to an aromatic
heterocycle of 5 to 10 members, having at least one heteroatom selected from nitrogen,
oxygen and sulfur, and containing at least 1 carbon atom, including both mono and
bicyclic ring systems. Examples of heteroaryl rings include, but are not limited to, furanyl,
thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
triazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl,
triazinyl, quinolinyl, isoquinoSnyl, 1,2,3,4-tetrahydroisoquinolinyl, benzofuranyl,
benzimidazolyl, benzothienyl, benzoxazolyl, 1,3-benzodioxazolyl, indolyl, benzothiazolyl,
furylpyridine, oxazolopyridyl and benzothiophenyl.
The term "5 or 6 membered heteroaryl" as used herein as a group or a part of a group
refers to a monocyclic 5 or 6 membered aromatic heterocycle containing at least one
heteroatom independently selected from oxygen, nitrogen and sulfur. Examples include,
but are not limited to, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl,
pyrazinyl, pyrimidinyl and triazinyl.
The term "9 to 10 membered fused bicyclic heteroaryl" as used herein as a group or a part
of a group refers to quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, benzofuranyl,
benzimidazolyl, benzothienyl, benzoxazolyl, 1,3-benzodioxazolyl, indolyl, benzothiazolyl,
furylpyridine, oxazolopyridyl or benzothiophenyl.
The term "heterocyclyi" as used herein, unless otherwise defined, refers to a monocyclic
or bicyclic three- to ten-membered saturated or non-aromatic, unsaturated hydrocarbon
ring containing at least one heteroatom selected from oxygen, nitrogen and sulfur.
Preferably, the heterocyclyi ring Ibs five or six ring atoms. Examples of heterocyclyi
groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothbphenyl,
imidazolidinyl, pyrazolidinyl, pipokdyl, piperazinyl, morpholino, tetrahydropyranyl and
thiomorpholino.
The term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.
The terms "optionally substituted phenyl", "optionally substituted phenyl or benzyl",
"optionally substituted 5 or 6 manbered heteroaryl" or "optionally substituted 9 to 10
membered fused bicyclic heteroajl" as used herein refer to a group which is substituted
by 1 to 3 groups selected from ialogen, C1-4alkyl, C1-4alkoxy, hydroxy, nitro, cyano,
amino, C1-4alkylamino or diC1-4atylamino, phenyl and 5 or 6 membered heteroaryl.
In one embodiment, A is -N(R7)-GH2- or -CH2-N(R7)-. A representative example of A is -
N(R7)-CH2-.
A representative example of R2 is hydrogen.
In one embodiment, R3 is hydrogen or C1-4alkyl. A representative example of R3 is
hydrogen.
In one embodiment, R4 and R5 are hydroxy, or R4 and R5 taken together with the
intervening atoms form a cyclic group having the following structure:
wherein Y is the bivalent radical -O-. A representative example of R4 and R5 is hydroxy.
Alternatively, R4 and R5 taken together with the intervening atoms form a cyclic group
having the following structure:
wherein Y is a bivalent radical selected from -O-.
A representative example of R6 is hydrogen.
A representative example of R7 isC1-6galkyl, for example C1-4alkyl, in particular methyl.
Representative examples of R8 include heterocyclic groups having the following structure:
wherein the heterocyclic is linked in the 6 or 7 position to the X group as above defined.
In particular, the heterocyclic is Meed in the 6 position.
In one embodiment, R10 is hydmgen or C1-4alkyl substituted by a group selected from
optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl and
optionally substituted 9 to 10 mertered fused bicyclic heteroaryl.
In one embodiment, R11 is hydrogen, -C(O)0R14, -C(O)NHR14 or -C(O)CH2NO2. In
another embodiment, R11 is -C(O)OR14, -C(O)NHR14 or -C(O)CH2NO2. In a further
embodiment, R11 is -C(O)OR14. A representative example of R11 is -C(O)OR14,
wherein R14 is hydrogen. A further representative example of R11 is -C(O)OR14,
wherein R14 is C1-6alkyl.
A representative example of R12 is C3-7cycloalkyl, in particular cyclopropyl.
A representative example of R13 is halogen, in particular chlorine.
In one embodiment, R14 is hydrogen or C1-6alky! optionally substituted by up to three
groups independently selected from halogen, C1-4alkoxy, -OC(O)C1-6alkyl and -
OC(O)OC1-6alkyl. Representative examples of R14 include hydrogen and C1-6alkyl, in
particular hydrogen and methyl.
In one embodiment, R15 is hydrogen or C1-4alkyl. A representative example of R15 is
hydrogen. A further representative example of R15 is methyl.
A representative example of R16 is hydrogen.
In one embodiment, X is -U(CH2),B-. -U(CH2) or a group selected from:
A representative example of X is -U(CH2)vB-.
Representative examples of U anT B include the divalent radicals -N(R15)- and -O-. In
particular, U is -O- and B is a divalent radical selected from -N(R15)- and -O-.
Alternatively, U and B are each independently the divalent radical -N(R15)-.
A representative example of Y is He bivalent radical -O-.
A representative example of d is 1 Id 3, for example 2.
In one embodiment, v is an integer from 2 to 8. A representative example of v is 2 to 4,
for example 2.
In one embodiment, j is 0 or 1. A representative example of j is 1. A further
representative example of j is 0.
It is to be understood that the present invention covers all combinations of particular and
preferred groups described hereinabove. It is also to be understood that the present
invention encompasses compounds of formula (I) in which a particular group or
parameter, for example R7, R13. R15, R17, R18 and z may occur more than once. In
such compounds it will be appreciated that each group or parameter is independently
selected from the values listed.
Particularly preferred compounds of the invention are:
4"-(S)-{3-[2-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)-
ethoxy]-propionylamino}-4"-deoxyazithromycin;
4"-(R)-{3-[2-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)-
ethoxy]-propionylamino}-4"-deoxyazithromycin;
4"-(SH3-[2-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-yloxy)-ethoxy]-
propionylamino}-4"-deoxyazithrowycin;
and pharmaceutically acceptable derivatives thereof.
Further particularly preferred compounds of the invention are:
4"-(S)-{3-[2-(3-carboxy-1-cycloprapyl-4-oxo-1,4-dihydro-quinolin-6-yloxy)-ethoxy]-
propionylamino}-4"-deoxyazithronycin 11,12-cyclic carbonate;
4"-(3-{l2-(7-chloro-1-cyclopropyl-3-methoxycarbonyl-4-oxo-1,4-dihydro-quinolin-6-
ylamino)-ethyl]-methyl-amino}-pM|Honylamino)-4,'-deoxyazithromycin;
and pharmaceutically acceptable derivatives thereof.
Compounds according to the invention also exhibit a broad spectrum of antimicrobial
activity, in particular antibacterial activity, against a wide range of clinical pathogenic
microorganisms. Using a standad microtiter broth serial dilution test, compounds of the
invention have been found to ahibit useful levels of activity against a wide range of
pathogenic microorganisims. In particular, the compounds of the invention may be active
against strains of Staphylococnus aureus, Streptopococcus pneumoniae, Moraxella
catarrhalis, Streptococcus pyoganes, Haemophilus influenzae, Enterococcus faecalis,
Chlamydia pneumoniae, Mycoptema pneumoniae and Legionella pneumophila. The
compounds of the invention mat also be active against resistant strains, for example
erythromycin resistant strains, h particular, the compounds of the invention may be
active against erythromycin resistant strains of Streptococcus pneumoniae, Streptococcus
pyogenes and Staphylococcus aneus.
The compounds of the invention may therefore be used for treating a variety of diseases
caused by pathogenic microorganisms, in particular bacteria, in human beings and
animals. It will be appreciated that reference to treatment includes acute treatment or
prophylaxis as well as the alleviation of established symptoms.
Thus, according to another aspect of the present invention we provide a compound of
formula (I) or a pharmaceuticaliy acceptable derivative thereof for use in therapy.
According to a further aspect of the invention we provide a compound of formula (I) or a
pharmaceuticaliy acceptable derivative thereof for use in the therapy or prophylaxis of
systemic or topical microbial infections in a human or animal subject.
According to a further aspect of the invention we provide the use of a compound of
formula (I) or a pharmaceuticaliy acceptable derivative thereof in the manufacture of a
medicament for use in the treatment or prophylaxis of systemic or topical microbial
infections in a human or animal body.
According to a yet further aspect of the invention we provide a method of treatment of the
human or non-human animal body to combat microbial infections comprising
administration to a body in need of such treatment of an effective amount of a compound
of formula (I) or a pharmaceuticaly acceptable derivative thereof.
While it is possible that, for use in therapy, a compound of the invention may be
administered as the raw chemical it is preferable to present the active ingredient as a
pharmaceutical formulation eg when the agent is in admixture with a suitable
pharmaceutical excipient, diluent or carrier selected with regard to the intended route of
administration and standard pharmaceutical practice.
Accordingly, in one aspect, the present invention provides a pharmaceutical composition
or formulation comprising at least one compound of the invention or a pharmaceuticaliy
acceptable derivative thereof in association with a pharmaceuticaliy acceptable
excipient, diluent and/or carrier. The excipient, diluent and/or carrier must be
"acceptable" in the sense of being compatible with the other ingredients of the
formulation and not deleterious to the recipient thereof.
In another aspect, the invention provides a pharmaceutical composition comprising, as
active ingredient, at least one compound of the invention or a pharmaceuticaliy
acceptable derivative thereof m association with a pharmaceuticaliy acceptable
excipient, diluent and/or carrier far use in therapy, and in particular, in the treatment of
human or animal subjects suffering from a condition susceptible to amelioration by an
antimicrobial compound.
In another aspect, the invention provides a pharmaceutical composition comprising a
therapeutically effective amount of the compounds of the present invention and a
pharmaceutically acceptable excipient, diluent and/or carrier (including combinations
thereof).
There is further provided by the present invention a process of preparing a
pharmaceutical composition, which process comprises mixing at least one compound of
the invention or a pharmaceutically acceptable derivative thereof, together with a
pharmaceutically acceptable excipient, diluent and/or carrier.
The compounds of the invention may be formulated for administration in any convenient
way for use in human or veterinary medicine and the invention therefore includes within
its scope pharmaceutical compositions comprising a compound of the invention adapted
for use in human or veterinary medicine. Such compositions may be presented for use in
a conventional manner with the aid of one or more suitable excipients, diluents and/or
carriers. Acceptable excipients, diluents and carriers for therapetic use are well known
in the pharmaceutical art, and are described, for example, in Remington's
Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice
of pharmaceutical excipient, diluent and/or carrier can be selected with regard to the
intended route of administration and standard pharmaceutical practice. The
pharmaceutical compositions may comprise as - or in addition to - the excipient, diluent
and/or carrier any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s),
solubilising agent(s).
Preservatives, stabilisers, dyes and even flavouring agents may be provided in the
pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic
acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be
also used.
For some embodiments, the agents of the present invention may also be used in
combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-
inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may
modify the solubility, dissolution rate, bioavailability and/or stability property of a drug
molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and
administration routes. As an alternative to direct complexation with the drug the
cyclodextrin may be used as an auxiliary additive, e. g. as a carrier, diluent or solubiliser.
Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples
are described in WO 91/11172. WO 94/02518 and WO 98/55148.
The compounds of the invention may be milled using known milling procedures such as
wet milling to obtain a particle size appropriate for tablet formation and for other
formulation types. Finely divided (nanoparticulate) preparations of the compounds of the
invention may be prepared by processes known in the art, for example see International
Patent Application No. WO 02/00196 (SmithKline Beecham).
The routes for administration (delivery) include, but are not limited to, one or more of:
oral (e. g. as a tablet, capsule, or as an ingestable solution), topical, mucosal (e. g. as a
nasal spray or aerosol for inhalation), nasal, parenteral (e. g. by an injectable form),
gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine,
intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular,
intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral),
transdermal, rectal, buccal, epidural and sublingual.
There may be different composition/formulation requirements depending on the different
delivery systems. By way of example, the pharmaceutical composition of the present
invention may be formulated to be delivered using a mini-pump or by a mucosal route,
for example, as a nasal spray or aerosol for inhalation or ingestable solution, or
parenterally in which the composition is formulated by an injectable form, for delivery, by,
for example, an intravenous, intramuscular or subcutaneous route. Alternatively, the
formulation may be designed to be delivered by both routes.
Where the agent is to be delivered mucosally through the gastrointestinal mucosa, it
should be able to remain stable during transit though the gastrointestinal tract; for
example, it should be resistant to proteolytic degradation, stable at acid pH and resistant
to the detergent effects of bile.
Where appropriate, the pharmaceutical compositions can be administered by inhalation,
in the form of a suppository or pessary, topically in the form of a lotion, solution, cream,
ointment or dusting powder, by use of a skin patch, orally in the form of tablets
containing excipients such as starch or lactose, or in capsules or ovules either alone or
in admixture with excipients, or in the form of elixirs, solutions or suspensions containing
flavouring or colouring agents, or they can be injected parenterally, for example
intravenously, intramuscularly or subcutaneously. For parenteral administration, the
compositions may be best used in the form of a sterile aqueous solution which may
contain other substances, for e»mple enough salts or monosaccharides to make the
solution isotonic with blood. For buccal or sublingual administration the compositions
may be administered in the fora of tablets or lozenges which can be formulated in a
conventional manner.
It is to be understood that not alof the compounds need be administered by the same
route. Likewise, if the compos^an comprises more than one active component, then
those components may be administered by different routes.
The compositions of the invention include those in a form especially formulated for
parenteral, oral, buccal, rectal, topical, implant, ophthalmic, nasal or genito-urinary use.
For some applications, the agents of the present invention are delivered systemically
(such as orally, buccally, sublingually), more preferably orally. Hence, preferably the
agent is in a form that is suitable for oral delivery.
If the compound of the present invention is administered parenterally, then examples of
such administration include one or more of: intravenously, intraarterially,
intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally,
intracranially, intramuscularly or subcutaneously administering the agent; and/or by
using infusion techniques.
For parenteral administration, the compound is best used in the form of a sterile
aqueous solution which may contain other substances, for example, enough salts or
glucose to make the solution isotonic with blood. The aqueous solutions should be
suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of
suitable parenteral formulations under sterile conditions is readily accomplished by
standard pharmaceutical techniques well-known to those skilled in the art.
The compounds according to the invention may be formulated for use in human or
veterinary medicine by injection (e.g. by intravenous bolus injection or infusion or via
intramuscular, subcutaneous or intrathecal routes) and may be presented in unit dose
form, in ampoules, or other unit-dose containers, or in multi-dose containers, if
necessary with an added preservative. The compositions for injection may be in the form
of suspensions, solutions, or emulsions, in oily or aqueous vehicles, and may contain
formulatory agents such as suspending, stabilising, solubilising and/or dispersing
agents. Alternatively the active ingredient may be in sterile powder form for
reconstitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
The compounds of the invention can be administered (e. g. orally or topically) in the form
of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain
flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed-
or controlled-release applications.
The compounds of the invention may also be presented for human or veterinary use in a
form suitable for oral or buccal administration, for example in the form of solutions, gels,
syrups, mouth washes or suspensions, or a dry powder for constitution with water or other
suitable vehicle before use, optionally with flavouring and colouring agents. Solid
compositions such as tablets, capsules, lozenges, pastilles, pills, boluses, powder, pastes,
granules, bullets or premix preparations may also be used. Solid and liquid compositions
for oral use may be prepared according to methods well known in the art. Such
compositions may also contain one or more pharmaceutically acceptable carriers and
excipients which may be in solid or liquid form.
The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium
citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as
starch (preferably com, potato or tapioca starch), sodium starch glycollate,
croscarmellose sodium and certain complex silicates, and granulation binders such as
polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose
(HPC), sucrose, gelatin and acacia.
Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl
behenate and talc may be included.
Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high
molecular weight polyethylene gJycols. For aqueous suspensions and/or elixirs, the agent
may be combined with various sweetening or flavouring agents, colouring matter or dyes,
with emulsifying and/or suspendng agents and with diluents such as water, ethanol,
propylene glycol and glycerin, and combinations thereof.
The compounds of the invention may also be administered orally in veterinary medicine in
the form of a liquid drench such as a solution, suspension or dispersion of the active
ingredient together with a pharmaceutically acceptable carrier or excipient.
The compounds of the invention may also, for example, be formulated as suppositories
e.g. containing conventional suppository bases for use in human or veterinary medicine or
as pessaries e.g. containing conventional pessary bases.
The compounds according to the invention may be formulated for topical administration,
for use in human and veterirwy medicine, in the form of ointments, creams, gels,
hydrogels, lotions, solutions, shampoos, powders (including spray or dusting powders),
pessaries, tampons, sprays, dips^ aerosols, drops (e.g. eye ear or nose drops) or pour-
ons.
For application topically to the skin, the agent of the present invention can be formulated
as a suitable ointment containing the active compound suspended or dissolved in, for
example, a mixture with one or nore of the following: mineral oil, liquid petrolatum, white
petrolatum, propylene glycol, pofcoxyethylene polyoxypropylene compound, emulsifying
wax and water.
Alternatively, it can be formulatei as a suitable lotion or cream, suspended or dissolved
in, for example, a mixture of one or more of the following: mineral oil, sorbitan
monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax,
cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds may also be dermally or transdermally administered, for example, by use
of a skin patch.
For ophthalmic use, the compounds can be formulated as micronised suspensions in
isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted,
sterile saline, optionally in combination with a preservative such as a benzylalkonium
chloride. Alternatively, they may be formulated in an ointment such as petrolatum.
As indicated, the compound of the present invention can be administered intranasally or
by inhalation and is conveniently delivered in the form of a dry powder inhaler or an
aerosol spray presentation from a pressurised container, pump, spray or nebuliser with
the use of a suitable propellant. e. g. dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA
134AT"") or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide or other
suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined
by providing a valve to deliver a metered amount. The pressurised container, pump,
spray or nebuliser may contain a solution or suspension of the active compound, e. g.
using a mixture of ethanol and the propellant as the solvent, which may additionally
contain a lubricant, e. g. sorbitan trioleate.
Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or
insufflator may be formulated to contain a powder mix of the compound and a suitable
powder base such as lactose or starch.
For topical administration by inhalation the compounds according to the invention may be
delivered for use in human or veterinary medicine via a nebuliser.
The compounds of the invention may also be used in combination with other therapeutic
agents. The invention thus provides, in a further aspect, a combination comprising a
compound of the invention or a pharmaceutically acceptable derivative thereof together
with a further therapeutic agent.
When a compound of the invenfon or a pharmaceutically acceptable derivative thereof
is used in combination with a second therapeutic agent active against the same disease
state the dose of each compotad may differ from that when the compound is used
alone. Appropriate doses will beieadily appreciated by those skilled in the art. It will be
appreciated that the amount of a compound of the invention required for use in treatment
will vary with the nature of the condition being treated and the age and the condition of
the patient and will be ultimately at the discretion of the attendant physician or
veterinarian. The compounds of the present invention may for example be used for
topical administration with other active ingredients such as corticosteroids or antifungals
as appropriate.
The combinations referred to above may conveniently be presented for use in the form
of a pharmaceutical formulation and thus pharmaceutical formulations comprising a
combination as defined above together with a pharmaceuticaliy acceptable carrier or
excipient comprise a further aspect of the invention. The individual components of such
combinations may be administered either sequentially or simultaneously in separate or
combined pharmaceutical formulations by any convenient route.
When administration is sequential, either the compound of the invention or the second
therapeutic agent may be administered first. When administration is simultaneous, the
combination may be administered either in the same or different pharmaceutical
composition.
When combined in the same formulation it will be appreciated that the two compounds
must be stable and compatible with each other and the other components of the
formulation. When formulated separately they may be provided in any convenient
formulation, conveniently in such manner as are known for such compounds in the art.
The compositions may contain from 0.01-99% of the active material. For topical
administration, for example, the composition will generally contain from 0.01-10%, more
preferably 0.01-1% of the active material.
Typically, a physician will determine the actual dosage which will be most suitable for an
individual subject. The specific dose level and frequency of dosage for any particular
individual may be varied and will depend upon a variety of factors including the activity of
the specific compound employed, the metabolic stability and length of action of that
compound, the age, body weight, general health, sex, diet, mode and time of
administration, rate of excretion, drug combination, the severity of the particular condition,
and the individual undergoing therapy.
For oral and parenteral administration to humans, the daily dosage level of the agent may
be in single or divided doses.
For systemic administration the daily dose as employed for adult human treatment it will
range from 2-100mg/kg body weight, preferably 5-60mg/kg body weight, which may be
administered in 1 to 4 daily doses, for example, depending on the route of administration
i and the condition of the patient. When the composition comprises dosage units, each unit
will preferably contain 200mg to 1g of active ingredient. The duration of treatment will be
dictated by the rate of response rather than by arbitrary numbers of days.
Compounds of general formula (I) and salts thereof may be prepared by the general
methods outlined hereinafter, said methods constituting a further aspect of the invention.
In the following description, the groups R1 to R18. A, B, X, Y, U, W, d, e, j, t, v, w and z
have the meaning defined for the compounds of formula (I) unless otherwise stated.
The group XaR8a is XR8 as defined for formula (I) or a group convertible to XR8.
Similarly, the group BaR8a is BR8 as defined for formula (I) or a group convertible to BR8.
Conversion of a group XaR8a or BaR8a to a XR8 or BR8 group typically arises if a
protecting group is needed during the reactions described below. A comprehensive
discussion of the ways in which such groups may be protected and methods for cleaving
the resulting protected derivatives is given by for example T.W. Greene and P.G.M Wuts
in Protective Groups in Organic Synthesis 2nd ed., John Wiley & Son, Inc 1991 and by P.J.
Kocienski in Protecting Groups, Georg Thieme Veriag 1994 which are incorporated herein
by reference. Examples of suitable amino protecting groups include acyl type protecting
groups (e.g. formyl, trifluoroacetyl and acetyl), aromatic urethane type protecting groups
(e.g. benzyloxycarbonyl (Cbz) and substituted Cbz, and 9-fluorenylmethoxycarbonyl
(Fmoc)), aliphatic urethane protecting groups (e.g. t-butyloxycarbonyl (Boc),
isopropyioxycarbonyl and cyclohexyloxycarbonyl) and alkyl type protecting groups (e.g.
benzyl, trityl and chlorotrityl). Examples of suitable oxygen protecting groups may include
for example alkyl silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers
such as tetrahydropyranyl or tert-butyl; or esters such as acetate. Hydroxy groups may be
protected by reaction of for example acetic anhydride, benzoic anhydride or a trialkylsilyl
chloride in an aprotic solvent. Examples of aprotic solvents are dichloromethane, N.N-
dimethylformamide, dimethylsulfoxide, tetrahydrofuran and the like.
Compounds of formula (I) wherein d is an integer from 1 to 5 may be prepared by reaction
of a 4" amine compound of formula (II) with a carboxylic acid compound of formula (III), or
a suitable activated and protected derivative thereof, followed where necessary by
subsequent conversion of the XaR8a group to XR8.
Suitable activated derivatives of the carboxyl group include the corresponding acyl halide,
mixed anhydride or activated ester such as a thioester. The reaction is preferably carried
out in a suitable aprotic solvent such as a halohydrocarbon (e.g. dichloromethane) or N,N-
dimethylformamide optionally in the presence of a tertiary organic base such as
dimethylaminopyridine or triethylamine or in the presence of inorganic base (eg sodium
hydroxide) and at a temperature within the range of 0s to 120'C. The compounds of
formula (II) and (III) may also be reacted in the presence of a carbodiimide such as
dicyclohexylcarbodiimide (DCC).
Compounds of formula (I) wherein d is 0 and U is -C(O)N(R15)- may be prepared by
reaction of the 4" amine of formula (II) with a suitable activated derivative of the carboxylic
acid HOC(O)C(O)N(R15)(CH2)vBaR8a (IV) followed where necessary by subsequent
removal of the hydroxyl protecting group R2 and conversion of the BaR8a group to BR8.
Compounds of formula (I) wherein d is 0 and U is -NH- may be prepared by reaction of the
4" amine of formula (II) with a suitable activated derivative such as the isocyanate
OCN(CH2)vBaR8a.
Compounds of formula (I) wherein d is 0 and U is -N(R15)- may be prepared by reaction
of the 4" amine of formula (II) with a suitable activated derivative such as the carbamoyl
chloride CIC(O)N(R15)(CH2)vBaR8a.
Compounds of formula (I) wherein d is 0 and U is -O- may be prepared by reaction of the
4" amine of formula (II) with a suitable activated derivative such as the chloroformate
CIOC(O)O(CH2)vBaR15a.
In a further embodiment of the invention, compounds of formula (I) wherein d is an integer
from 1 to 5 and U is a group selected from -N(R15)- and -S-, may be prepared by reaction
of compounds of formula (V)
wherein d is an integer from 1 to 5 and L is a suitable leaving group, with XaR8a (VI) in
which U is a group selected from -N(R15)- and -S-. The reaction is preferably carried out
in a solvent such as a halohydrocarbon (e.g. dichloromethane), an ether (e.g.
tetrahydrofuran or dimethoxyethane), acetonitrile or ethyl acetate and the like,
dimethylsulfoxide, N.N-dirnethylformamide or 1-methyl-pyrrolidone and in the presence of
a base, followed, if desired, by conversion of the XaR8a group to XR8. Examples of the
bases which may be used include organic bases such as diisopropylethylamine,
triethylamine and 1,8-diazabicydo[5.4.0]undec-7-ene, and inorganic bases such as
potassium hydroxide, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride,
potassium hydride and the like. Suitable leaving groups for this reaction include halide
(e.g. chloride, bromide or iodide) or a sulfonyloxy group (e.g. tosyloxy or
methanesulfonyloxy).
Compounds of formula (V) may be prepared by reaction of a compound of formula (II) with
a carboxylic acid HOC(O)(CH2^jL (VII), wherein L is a suitable leaving group as above
defined, or a suitable activated thereof. Suitable activated derivatives of the carboxyl
group are those defined above for carboxylic acid (III). The reaction is carried out using
the conditions described above for the reaction of a compound of formula (II) with
carboxylic acid (III).
Compounds of formula (I) may be converted into other compounds of formula (I). Thus
compounds of formula (I) wherein U or B is -S(O)z and z is 1 or 2 may be prepared by
oxidation of the corresponding compound of formula (I) wherein z is 0. The oxidation is
preferably carried out using a peracid, e.g. peroxybenzoic acid, followed by treatment with
a phosphine, such as triphenylphosphine. The reaction is suitably carried out in an organic
solvent such as methylene chloride. Compounds of formula (I) wherein U or B is -N(R15)-
and R15 is C1-4alkyl can be prepared from compounds wherein R15 is hydrogen by
reductive alkylation.
Compounds of formula (II) wherein A is -C(O)NH- or -NHC(O)-, R4 or R5 are hydroxy, R3
is hydrogen and R6 is hydrogen are known compounds or they may be prepared by
analogous methods to those known in the art. Thus they can be prepared according to the
procedures described in EP 507595 and EP 503932.
Compounds of formula (II), wherein A is -C(O)NH- or -NHC(O)-, R4 or R5 are hydroxy and
R3 is C-1-4alkyl or C3-6alkenyl optionally substituted by 9 to 10 membered fused bicyclic
heteroaryl and R6 is hydrogen are known compounds or they may be prepared by
analogous methods to those known in the art. Thus they can be prepared according to the
procedures described in WO 9951616 and WO 0063223.
Compounds of formula (II). wherein A is -C(O)NH-, R4 and R5 taken together with the
intervening atoms form a cyclic group having the following structure:
R3 is C1-6alkyl, or C3-6alkenyl optionally substituted by 9 to 10 membered fused bicyclic
heteroaryl and R6 is hydrogen are known compounds or they may be prepared by
analogous methods to those known in the art. Thus they can be prepared according to the
procedures described in US 6262030.
Compounds of formula (II), wherein A is -C(O)NH-, -NHC(O)-, -N(CH3)-CH2- or -CH2-
N(CH3)-, R4 or R5 are hydroxy or R4 and R5 taken together with the intervening atoms
form a cyclic group having the following structure:
and R6 is hydrogen are known compounds or they may be prepared by analogous
methods to those known in the art. Thus they can be prepared according to the
procedures described in EP 508699 and J.Chem. Res.Synop (1988 pages 152-153), US
6262030.
Compounds of formula (II), wherein A is -C(O)NH-, R4 and R5 taken together with the
intervening atoms form a cyclic group having the following structure:
R6 is hydrogen and R3 is C1-4 alkyl may be prepared by decarboxylation of a compound
of formula (VIII), wherein R19 is amino protecting group followed, if required, by removal
of the protecting group R19.
The decarboxylation may be carried out in the presence of a lithium salt such as lithium
chloride, preferably in an organic solvent such as dimethylsulfoxide.
Compounds of formula (II), wherein A is -C(O)NH-, R4 and R5 taken together with the
intervening atoms form a cyclic group having the following structure:
uc.
and R3 is C-|_4 alkyl may be prepared according to the procedures described in WO
02/50091 and WO 02/50092.
Compounds of formula (III) wherein X is -U(CH2)v or -U(CH2)vN(R15)-, in which U is -
N(R15)-, -O- or -S-, or X is a group selected from:
may be prepared by reaction of XaR8a (VI), wherein X has the meaning defined above
with R20OC(O)(CH2)dL (IX) wherein R2n is carboxyl protecting group and L is a suitable
leaving group, followed by removal of R20. Suitable R20 carboxyl protecting group include
t-butyl, allyl or benzyl.
Compounds of formula (III) may also be prepared by reaction of XaR8a (VI) with
acrylonitrile followed by hydrolysis of the nitrile to the acid, or by reaction of XaR8a (VI)
with t-butyl acrylate followed by removal of the t-butyl group.
Compounds of formula (VI) wherein X is -U(CH2)vB- in which B is -N(R15)-, -O- or-S- or
X is a group selected from:
may be prepared by reaction of a compound of formula R8aL (X), wherein L is a suitable
leaving group such as chlorine; fluorine or bromine, with a compound of formula -
U(CH2)vB- (X) in which B is -N(R15) -O- or -S-, or with piperazine or with 1H-
pyrrolo[3,4-b]pyridine, octahydro.
In order that the invention may be more fully understood the following examples are given
by way of illustration only.
The following abbreviations are used in the text: DBU for 1,8-diazabicyclo[5.4.0]undec-7-
ene, DCC for dicyclohexylcabodiimide, DCM for dichloromethane, DMAP for 4-
dimethylaminopyridine, DMF for N,N-dimethylformarnide, DMS for dimethylsulfide, DMSO
for dimethyl sulfoxida, EtOAc far ethyl acetate. EtOH for ethanol, KOteu for-potassium
fert-butoxide, MeOH for methaneiand i-PrOH for isopropanol.
Examples
4"-(S) and 4"-(R)-Amino-9a-azithromycin may be prepared by the procedure described ir.
EP 508 699. 4"-Keto-9a-azithromycin may be prepared using the Pfitzner-Moffati
procedure (J. Am.Chem.Soc.,87, 5670-5678, 1965) at room temperature for 4 hours anc
deprotecting in MeOH.
Intermediate 1
7-Chloro-1-cvclopropvl-6-(2-hvdroxy-ethvlamlno)-4-oxo-1.4-dihvdro-aulnoline-3-
carbaoxvlic acid (A)
and
1-Cvclopropvl-6-fluoro»7-(2-hvdroxv-ethvlamtno>-4-oxo-1.4-dihvdro-auinoHne-3-
carboxvllc acid (B)
To a solution of ethanolamine (55.5 mL) in N-methyl pyrrolidinone (500 mL) at 95 °C, 7-
chloro-1-cyclopropyl-6-fIuoro-4-owo-1,4-dihydro-quinoline-3-carboxylic acid (50.0 g) was
slowly added under vigorous stirring. The temperature was increased to 105 °C and the
reaction mixture was stirred at this temperature for 22 hours. The reaction mixture was
cooled to about 60 °C and poured into MeOH (800 mL). This mixture was stirred in an ice
bath and the precipitate was filtered off and dried affording a mixture of Intermediate 1A
and Intermediate 1B (49 g ) in a 1:1 ratio.
Intermediate 1A: MS; m/z (ES): 322.99 [MH]*
Intermediate 1B: MS; m/z (ES); 307.02 [MH]+
Intermediate 2
7-Chloro-6-r2- quinoline-3-carboxvlic acid (Ai
and
7-f2-(2-Cvano-ethoxv)-ethv>arninoM-cvc>opropvi-6-fluoro-4-oxo-1.4-dihvdro-
quinoline-3-carboxvlic acid (Bl
A solution of a mixture of Intermediate 1A and Intermediate 1B (14 g) in acrylonitrile
(140 mL) and DBU (14 mL) was stirred at 70 °C for 16 hours. The solvent was evaporated
and the residue dissolved in i-PiOH (50 mL). Water (50 mL) was added and the pH value
adjusted to 4. The precipitate was filtered and then triturated with methanol. After filtration,
5.35 g of pure Intermediate 2A*as obtained. The mother liquor was left overnight at 4 °C
and 4.4 g of Intermediate 2B precipitated.
Intermediate 2A: 1H-NMR (500 MHz, DMSO-d6) d: 8.56 (s, 1H), 8.23 (s, 1H), 7.40 (s,
1H), 5.93 (t, NH), 3.83 (qv, 1H),3.72 (t, 2H), 3.67 (t, 2H), 3.46 (q, 2H), 2.79 (t, 2H), 1.30
(q, 2H), 1.18 (q, 2H). 13C-NMR(75 MHz, DMSO-d6) 6: 176.52, 166.09, 145.72, 142.72,
132.17, 126.37, 125.38, 119.15, 118.99, 106.14, 102.76, 67.93, 65.05, 42.40, 35.77
18.01, 7.32. MS; m/z (ES): 376.02 [MH]+
Intermediate 2B: 1H-NMR (500 MHz, DMSO-d6) d: 8.55 (s, 1H), 7.76 (d, 1H), 7.22 (d
1H), 3.74 (t, 2H+1H), 3.67 (t, 2H), 3.52 (q, 2H), 2.78 (t, 2H), 1.31 (m, 2H), 1.18 (m, 2H).
"C-NMR (75 MHz, DMSO-d6)d:175.80,166.20, 148.12,146.89, 142.55.140.30, 119.22,
108.79, 106.10, 96.68, 68.29, 65.17, 42.06, 35.70, 17.99, 7.48. MS; m/z (ES): 360.04
[MH]+
Intermediate 3
6-[2-(2-Carboxv-ethoxv)-ethvlamino1-7-chioro-1-cvciopropvl-4-oxo-1.4-dihvdro-
quinoline-3-carboxylic acid
A solution of Intermediate 2A (4.7 g) in 60 mL cone. H2SO4 and 60 mL H2O was stirred
for 20 hours at 75 °C. The reaction mixture was poured into water (150 mL) and the pH
value was adjusted to 2. Filtration of the precipitate obtained yielded pure Intermediate 3
(3.07 g); 1H-NMR (500 MHz, DMSO-d6) d: 8.56 (s, 1H), 8.23 (s, 1H), 7.39 (s, 1H). 3.82
(m, 1H), 3.66 (q, 2H+2H), 3.42 (L 2H), 2.49 (t, 2H), 1.30 (q, 2H), 1.17 (m, 2H). 13C-NMR
(75 MHz, DMSO-d6) d: 178.70,174.73, 168.28, 147.89, 144.93, 134.34, 128.55, 127.56,
121.15, 118.99, 108.32, 104.90,69.98, 68.16, 44.59, 37.95, 36.74, 9.50. MS; m/z (ES):
395.05 [MH]*.
Intermediate 4
7-Chloro-1-cvclopropyl-6-(2-hyroxv-ethoxy)-oxo-1.4-dihydro-quinoline-3-
carfaoxvlic acid (A)
and
1-Cyclopropyl-6-fluoro-7-(2-hyroxv-ethoxy)-4-oxo-1.4-dihvdro-quinoline-3-
carboxylic acid (B)
To a mixture of DMSO (5 mL) and ethyleneglycol (6 ml), KOteu (1.6 g, 14.23 mmol) was
added portionwise over 10 min,and then heated to 90 °C. To the mixture, 7-chloro-1-
cyclopropyl-6-fluoro-4-oxo-1,4-dlydro-quinoline-3-carboxylic acid (1.0 g) was added
portionwise over 20 min, the teaperature was increased to 105 °C and the mixture was
stirred for 6 h. Water (30 mL) was added to the reaction solution and the pH of the
solution was adjusted to pH=5. He resulting solution was left in the refrigerator overnight.
The precipitate obtained was filtered, washed with cold water, and dried affording a 2:1
mixture of Intermediate 4A and Mermediate 4B (1.0 g).
Part of the crude product (700 mg) was dissolved in EtOH (15 mL) by heating to the
reflux. The resulting solution was cooled to 30°C and a first precipitation occurred. The
precipitate was filtered, washed with cold EtOH and dried under reduced pressure.
Intermediate 4A (204 mg) was dtained as a white solid.
1H-NMR (500 MHz, DMSO-d6) d: 15.06 (s, 1H), 8.71 (s, 1H), 8.40 (s. 1H), 7.86 (s, 1H),
4.97 (t, 1H), 4.25 (t, 2H), 3.87 (m, 1H), 3.82 (q, 2H), 1.32 (m, 2H), 1.20 (m, 2H). 13C-NMR
(75 MHz, DMSO-d6) d: 176.61, 165.67, 152.47, 147.54, 135.34, 129.48, 124.95, 120.02,
106.90,106.66, 71.22, 59.15, 35.99, 7.46. MS; m/z (ES): [MH]+
Intermediate 5: 7-Chloro-6-[2-(2-cvano-ethoxv)-ethoxvl-1-cyclopropyl-4-oxo.1.4-
dihydro-quinoline-3-carboxylic acid
To a suspension of Intermediate 4A (2 g) in acrylonitrile (40 mL) was added DBU (2.3
ml). The reaction mixture was stirred at 80°C for 24 h. The acrylonitrile was evaporated
under reduced pressure. Isopropanol (30 mL) was added to the residue and the pH of
the solution was adjusted to pH=5 by adding 2M HCI, during which the product
precipitated. The precipitate was filtered, washed with water, and dried affording
Intermediate 5(1.7 g) as a white solid.
1H-NMR (500 MHz, DMSO-d6) d: 8.68 (s, 1H), 8.38 (s, 1H), 7.84 (s, 1H), 4.38 (t, 2H), 3.91
(t, 2H), 3.86 (m, 1H), 3.75 (t, 2H), 2.79 (t, 2H), 1.32 (m, 2H), 1.20 (m, 2H). 13C-NMR (75
MHz, DMSO-d6) d: 176.63, 165.65, 152.18. 147.61, 135.50, 129.44, 124.97, 120.04,
119.11, 106.96. 106.80, 69.02. 68.30, 65.49. 35.99, 18.06, 7.46. MS; m/z (ES): 377.03
[MH]+
Intermediate 6: 6-[2-(2-Carboxy-ethoxy)-ethoxy1-7-chloro-1-cvclopropyl-4-oxo-1.4-
dlhvdro-quinoline-3-carboxvlic add
A solution of Intermediate 5 (1.10 g) in a mixture of cone. H2SO4 (10 mL) and H2O (20
mL) was stirred at 75 °C for 24 h. The pH of the reaction mixture was adjusted to 0.2 with
40% NaOH. during which the product precipitated. The precipitate was filtered, washed
with water, and dried affording Intermediate 6 (0.8 g) as a white solid.
1H-NMR (300 MHz, DMSO-d6) d: 15.0 (s, 1H), 11.8 (s, 1H), 8.69 (s, 1H), 8.38 (s, 1H),
7.85 (s, 1H), 4.35 (m, 2H), 3.91-3.82 (m, 3H), 3.74 (dt, 2H), 2.49 (m, 2H), 1.31 (m, 2H),
1.19 (m, 2H). MS; m/z (ES): 396.02 [MH]+.
Intermediate 7: 4"-Hvdroxvimlno-9a-azithromvcin
4"-Keto-9a-azithromycin (5.2 g, 0.007 mol) was treated with hydroxylamine hydrochloride
(2.4 g) in MeOH (260 mL) for 3.5 hours at room temperature. The methanol was
evaporated and the residue dissolved in EtOAc (200 mL). Water was then added (200
mL) and extracted at pH 9.8. Solvent was removed affording crude product (5.39 g). After
purification by flash chromatography (DCM-MeOH-NH4OH = 90:9: 0.5) the title compound
(2.4 g) was obtained; MS (ES+) m/z: [MH] = 762.33.
Intermediates 8 and 9: 4"-(S) and 4"-(R)-Amino-9a-azithromvcin
Intermediate 7 (2.0 g, 0.0026 mol) was dissolved in acetic acid (100 mL) and
hydrogenated over 2.0 g platinum oxide at 1150 psi for 48 hours at room temperature.
This was followed by a fresh addition of 0.8 g of platinum oxide and the reaction was
continued for another 24 hours under 1150 psi. Since TLC shown some starting
compound a further 0.8 g platinum oxide was added and reduction continued for a further
24 hours at the same pressure. The reaction mixture was filtered and acetic acid was
removed under vacuum. The residue was dissolved in 100 mL of CHCL3 and 50 mL of
water and extracted at pH 5 and 10. Evaporation of extract at pH 10 afforded a mixture of
4"-(S) and 4"-(R) amines (1.96 g).
After purification by column chromatography (DCM-MeOH-NH4OH = 90:9: 1.5) two
separate isomers were isolated: Intermediate 8 with Rf=0.67, 6 4.10, dq, H-5", 4"-(S)-
amine and Intermediate 9 with Rf=0.63, 6 4.57, dq, H-5", 4"-(f?)-amine.
MS (ES+) m/z: [MH]+ = 748.36.
Intermediate 10: 4MS)-Amino-8a-azithromvcin 11.12-cvclic carbonate
Intermediate 8 (0.1 g, 0.13 mmoi) was dissolved in benzene (4 mL) and then ethylene
carbonate (0.09 g) and K2CO3 (q11g) were added to the reaction mixture. The reaction
mixture was heating at 80*C overnight. After filtration, the filtrate was rinsed twice with
H2O and then evaporated giving q.097 mg of the title product. MS m/z = 774.4 (MH+).
Intermediate 11: 4"-(R)-Amino-8a-azithromvcin 11.12-cvclic carbonate
Starting from Intermediate 9 (0060 g), the title compound was prepared according the
procedure described for Intermeflate 10. MS m/z = 774.4 (MH+).
Intermediate 12 and Inter—diate 13: 6-[(2-Amino-ethvnamlno1-7-chloro-1-
cvclopropvl-1.4-dlhvdro-4-oxe ailnollne-3-carboxvltc acid hydrochlorlde (12) and 7-
r(2-amlno-ethvl)amino1-1-cvclqropyl-1.4-dihydro-6-fluoro-4-oxo-quinoline-3-
carboxvlic acid hvdrochloride[13]
7-Chloro-1-cyclopropyl-1,4-dihyde-6-fluoro-4-oxo-quinoline-3-carboxylic acid (56.3 g) and
ethylenediamine (36 g) were dissolved in N,N-dimethylacetarnide (650 mL) at 100°C and
stirred for 8.5 h at 115°C. Water (700 mL) was added to the reaction mixture cooled at
room temperature. The reaction mixture was stirred at room temperature for 2 h, cooled at
0-5°C and stirred for 1 h. The pncipitate obtained was filtered, washed with cold water,
cold EtOH, and dried at 110°C under reduced pressure for 1 h. The crude product was
treated with HCI (6% aqueous situation) heating for 1 h in the presence of charcoal. After
filtration, the solution was cooled to 35-40°C and a first precipitation occurred. The
precipitate was filtered, washed with water and dried at 110°C for 1 h. intermediate 12
(6.4 g) was obtained as a hydrochloride salt. The mother liquors, after first precipitation,
were cooled at room temperature and stirred overnight. The precipitate was filtered,
washed with water and dried at 110°C for 1 h to give a mixture containing Intermediates
12 and 13 (14.18 g). Intermediate 12: 1H-NMR (300 MHz, CF3COOD) d: 8.94 (s, 1H),
8.40 (s, 1H), 7.40 (s, 1H), 3.85 (m. 1H), 3.76 (m, 2H), 5.45 (m, 2H), 1.42 (m, 2H), 1.77 (m,
2H).
Intermediate 14: 6424(2-Carboxy-ethyl)-methyl-amino1-ethvlamino)-7-chloro-1-
cyclopropyl-4-oxo-1.4-dihvdro-ouinotlne-3-carboxvlic acid methyl ester
a) 6-{2-Amino-ethylamino)-7-chloro-1 -cyclopropyl-4-oxo-1 ,4-dihydro-quinoline-3-
carboxylic acid methyl ester.
A suspension of Intermediate 12 (120 mg) in a solution of HCI in MeOH (3%, 30 mL) was
sonicated in an ultrasonic water bath at 60°C for 3 h and then at room temperature for 48
h. The solvent was evaporated under reduced pressure and the crude product was
purified by flash chromatography (eluent: MeOH/DCM/NfyOH 9/5/0.5) affording the title
compound (80 mg). 1H-NMR (300 MHz, DMSO-d6) d: 8.37 (s, 1H), 8.04 (s. 1H), 7.36 (s,
1H), 5,77 (t, 1H), 3,37 (s, 3H, O-Me), 3.64 (m, 1H), 3,20 (q, 2H), 2,85 (t, 2H), 1.23 (m, 2H),
1.08 (m,2H).
b) 6-l2-(2-Carboxy-ethyhmino)-ethylarnino]-7-chloro-1 -cyclopropyl-4-oxo-1,4-
dihydro-quinoline-3-carboxylicacid methyl ester.
To a solution of acrylic acid (0.5 ml, 7.44 mmol) in 2-propanol (120 ml) was added Et3N (2
ml), H2O (20 ml) and Intermediate 14a (2.5 g), and the mixture was heated at 60°C for
24 h. Et3N (3 ml) was added to the reaction mixture and the mixture was heated at 60 °C
for an additional 24 h. The solvents were concentrated under reduced pressure, H2O (70
ml) was added to the residue, the pH was adjusted with 2 M NaOH to 9.5, and the mixture
was extracted with EtOAc (2 x 3D ml). The EtOAc was discharged, the pH of the aqueous
solution was adjusted with 2 M HCI to 3 and the solution was extracted with EtOAc (2 x 30
ml). The product was in the aqueous solution. Thus, the aqueous solution was
concentrated under reduced pressure, methanol was added to the residue and the
mixture was stirred for 15 min, filtered and the filtrate was concentrated under reduced
pressure, affording the crude product. Part of the crude product (1.0 g) was purified on an
SPE-column to afford the title compound.
c) 6-{2-[(2-Carboxy-ethyl)-methyl-amino]-ethylamlno}-7-chloro-1-cyclopropyl-4-oxo-
1,4-dihydro-quinoline-3-carbaqtic acid methyl ester.
To the rest of the crude Intermediate 14b were added acetone (60 mL), formaldehyde
(0.60 mL, 36 % solution) and fomic acid (0.60 mL). This mixture was heated at 55°C for
24 hours. The aqueous solution was concentrated under reduced pressure, methanol was
added to the residue and the mixture was stirred for 15 min, filtered and the filtrate was
concentrated under reduced pressure. The residue was purified on an SPE-cofumn to
afford the title compound (0.84 g ). 13C NMR (75 MHz, DMSO) d ppm: 174.3, 172.0,
165.1. 146.6, 141.9, 131.4.128.0. 124.6. 118.1. 107.8, 104.5. 57.7, 54.4, 53.1, 51.1, 41.3,
34.6, 33.2, 7.3.
Example 1: 4"-(S)-[3-[2-[3-Carboxv-7-chloro-1 -cvclopropyl-4-oxo-1.4-dihvdro-
- quinolin-6-ylamino)-ethoxv1-propionvlamino)-4"-deoxva2lthromvcln
To a DMF (3 mL) solution of Intermediate 3 (0.106 g, 0.268 mmol), DCC (0.110 g, 0.53
mmol), Intermediate 8 (0.100 g, 0.134 mmol) and DMAP (10 mg) were added and the
reaction mixture was stirred for 20 hours at room temperature. Water and EtOAc were
added and the layers were separated. The water layer was extracted with EtOAc and the
combined organic layers were dried over K2CO3 and then evaporated. The residue was
precipitated from EtOAc/n-hexane yielding 80 mg of crude product which was purified by
column chromatography (SPE-column, gradient polarity: 100 % DCM to
DCM:MeOH:NH3 = 90:9:0.5) yielding 50 mg of product which was precipitated from
EtOAc:n-hexane yielding 30 mg of pure Example 1; MS; m/z (ES): 1124.20 [MH]*.
Example 2: 4"-(R)-[ 3-[2-(3-Carboxv-7-chloro-1 -cvclopropyl-4-oxo-1.4-dihvdro-
quinolin-6-vlamlno)-ethoxvl-Droplonv1amino)-4"-deoxvazlthromvcln
To a DMF (3 mL) solution of Intermediate 3 (0.106 g, 0.268 mmol), DCC (0.110 g, 0.53
mmol), Intermediate 9 (0.100 g, 0.134 mmol) and DMAP (10 mg) were added and the
reaction mixture was stirred for 20 hours at room temperature. Water and EtOAc were
added and the layers were separated. The water layer was extracted with EtOAc and the
combined organic layers were dried over K2CO3 and then evaporated. The residue was
precipitated from EtOAc/n-hexane yielding 80 mg of crude product which was purified by
column chromatography (SPE-column, gradient polarity: 100 % DCM to DCM.MeOH.NH3
= 90:9:0.5) yielding of pure Example 2 (60 mg); MS; m/z (ES): 1124.30 fMH]*.
Example 3: 4"-(S)-[3-[2-(3-Carboxv-7-chloro-1 -cvclopropyl-4-oxo-1.4-dihvdro-
quinolin-6-vloxv)-ethoxv1-propionviamino)4"-deoxvazithromvcin
To a solution of Intermediate 8 (75 mg, 0.01 mmol) in DCM (3 mL) was added 1,3-
dicyclohexylcarbodiimide (0.082 g, 0.082 mmol). Intermediate 6 was added (64 mg)
followed by DMAP (10 mg). The reaction mixture was stirred at room temperature for 24
h. H2O (25 mL) was added to the reaction mixture. The aqueous phase was washed with
DCM (2x30 mL). The combined organic layers were concentrated under reduced pressure
and the residue was purified on silica gel using DCM/MeOH/NH4OH 90/10/0.5 affording
Example 3 (37 mg) as a white solid; MS; m/z (ES): 1125.46 [MH]+.
Example 4: 4"-(R){43-[2-(3-Carboxy-7-chloro-1-cvclopropyl-4-oxo-1.4-dihvdro-
autnotin-6-yloxyl)-ethoxvl-propionylamino)-4"-deoxvazithromvcln
To a solution of Intermediate 9 (0.20 g) in DCM (6 mL). Intermediate 6 (0.141 g), DMAP
(0.013 g) and DCC (0.111 g) were added and the reaction mixture was stirred at room
temperature for 48 hours. The solvent was evaporated yielding 0.480 g of crude product.
After purification by column chromatography (DCM-MeOH-NH4OH = 90:9: 1.5) the title
compound was isolated.
Example 5: 4'(R)-{3-[2-(3-Carpoxv-1-cvclopropvl-oxo-1.4-dlhvdro-qulnolin-6-
yloxv)-ethoxy1-proplonvlamlno)-4"'deoxvazthromvcln
Example 4 (80 mg) was dissolved in methanol (11 mL) and 10 % Pd/C (55 mg) was
added. Hydrogenolysis was performed at 4 x 105 Pa for 4 h. The reaction mixture was
filtered and the filtrate evaporated yielded 0.09 g of the title product. MS m/z = 1091.6
(MH)*
Example 6: 4'-(R)-{3-[2-(3-Carboxy-1-cvclopropyl-4-oxo-1.4-dlhvdro-quinolin-6-
vloxv)-ethoxv1-propionvlaminoV4"-deoxvazithromvcln 11.12-cvcllc carbonate
Intermediate 11 (0.073 g, 0.094 mmol) was dissolved in DMS (2.6 mL). To the reaction
solution, DCC (0.052 g), DMAP (0.0065 g) and Intermediate 6 (0.0.065 g) were added
and the reaction mixture was stirred at room temperature overnight. Filtration and
evaporation of solvent yielded a crude product. The crude product was dissolved in
EtOAc, H2O was added and extracted 3xEtOAc at pH 9.3. The combined organic layers
were evaporated under reduced pressure to a solid (0.099 g). Purification by column
chromatography (DCM-MeOH-NHi = 90:9:1.5) yielded 0.047 g of the title product. (M +
2H)2+m/z = 577.51.
Example 7: 4"-(S)-{3-[2-(3-Carboxv-1-cyclopropyl-4-oxo-1.4-dihvdro-quinolin-6-
v1oxy)-ethoxv1-propionylamino}-4"-deoxvazithromvcin 11,12-cvcllc carbonate
Intermediate 10 (0.097 g, 0.12 mmol) was dissolved in DMS (4 mL). To the reaction
solution, DCC (0.069 g), DMAP (0.0086 g) and Intermediate 6 (0.0.087 g) were added
and the reaction mixture was stirred at room temperature overnight. Filtration and
evaporation of solvent yielded a crude product. The crude product was dissolved in
EtOAc, H2O was added and extracted 3xEtOAc at pH 9.05. The combined organic layers
were evaporated under reduced pressure to a solid (0.114 g). Purification by column
chromatography (DCM-MeOH-NH3 = 90:9:1.5) yielded 0.041 g of the title product. (M +
2H)2+ m/2 = 577.52.
Example 8: 4'{3-[2-(7-Chloro-1-cvclopropvl-3-methoxvcarbonvl-4-oxo-1.4-dihvdro-
quinolin-6-vlamino)-ethvn-methyl-aminoVpropionvlamino)-4"-deoxvazlthromvcin
To a solution of 4"-amino-4"-deoxoazithromycin (0.11 mg, 0.26 mmol, mixture of
Intermediates 8 and 9) in DCM (2 mL) was added 1,3-dicyciohexylcarbodiimide (0.108 g,
0.052 mmol). Intermediate 14c (80 mg) was then added, followed by 4-dimethylamino
pyridine (10 mg). The reaction mixture was stirred at room temperature for 24 hours. H2O
(25 mL) was added to the reaction mixture and the aqueous phase was washed with DCM
(2x30 mL). The combined organic layers were concentrated under reduced pressure and
the residue was purified on silica gel using: DCM/MeOH/NHOH 90/10/0.5 affording the
title compound (12 mg). TLC (DCM-MeOH-NH4OH = 90:9: 1.5): Rf = 0.616. MS m/z =
1152.2 (MH)+.
Biological Data
Using a standard broth dilution method in microtitre, compounds were tested for
antibacterial activity. The compounds in the above examples gave minimum inhibitory
concentrations (MICs) less than 1 microgram per millilitre against erythromycin-sensitive
and erythromycin-resistant strains of Streptococcus pneumoniae and Streptococcus
pyogenes.
In addition, the MIC mg/mL) of test compounds against various organisms was
determined including:
S. aureus Smith ATCC 13709, S. pneumoniae SP030, S. pyogenes 3565, E. faecalis
ATCC 29212, H. influenzae ATCC 49247, M. catarrhalis ATCC 23246.
Examples 1 to 3 have an MIC pneumoniae SP030, S. pyogenes 3565 and E. faecalis ATCC 29212.
Examples 1 to 3 have an MIC catarrhalis ATCC 23246.
The application of which this description and claims forms part may be used as a basis for
priority in respect of any subsequent application. The claims of such subsequent
application may be directed to any feature or combination of features described herein.
They may take the form of product, composition, process, or use claims and may include,
by way of example and without limitaion, the following claims:
We Claim:
1. A compound of formula (I)
wherein
A is a bivalent radical selected from -C(O)NH-, -NHC(O)-, -N(R7)-CH2- and -CH2-N
(R7)-;
R1 is -NHC(O)(CH2)c|XR8;
R2 is hydrogen;
R3 is hydrogenor C1-4alkyl,;
R4 is hydroxy,
R5 is hydroxy, or
R4 and R5 taken together with the intervening atoms form a cyclic group having the
following structure:
wherein Y is the bivalent radical -O-; R° is hydrogen or fluorine;
R7 is hydrogen or C1-6galkyl;
R8 is a heterocyclic group having the following structure:
R9 is hydrogen or C-|_galkyl;
R11 is hydrogen, -C(O)OR14, -C(O)NHR14, -C(O)CH2NO2 or-C(O)CH2SO2R7;
R12 is hydrogen, C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy, C3.
7cycloalkyl, or optionally substituted phenyl or benzyl;
R13 is halogen, C1-4alkyl, C1-4thioalkyl, C1-4alkoxy, -NH2, -NH(C1-4alkyl) or -N
(C1-6alkylte;
R14 is hydrogen,
C1-6alkyl optionally substituted by up to three groups independently selected
from halogen, cyano, C1-4alkoxy optionally substituted by phenyl or C1-4.
alkoxy, -0(0)C1-6alkyl, -C(O)OC1-6alkyl, -OC(C)C1-6alkyl, -00(0)0C1-6
alkyl, -C(O)NR17R18, -NR17R18 and phenyl optionally substituted by nitro
or-C(0)OC1-6alkyl,
-(CH2)wC3_7cycloalkyl,
-(CH2)wheterocyclyl,
-(CH2)wheteroaryl,
-(CH2)waryl1
C3_6alkenyl, or
C3.6alkynyl;
R^5 is hydrogen, C1-4alkyl, C3_7cycloalkyl, optionally substituted phenyl or benzyl,
acetyl or benzoyl;
R16 is hydrogen or R13, or R1^ and R12 are linked to form the bivalent radical -O
(CH2)2-or-(CH2)t-;
R17 and R18 are each independently hydrogen or C-|_6alkyl optionally substituted by
phenyl or-C(0)OC-|_5alkyl, or
R17 and R18, together with the nitrogen atom to which they are bound, form a 5 or 6
membered heterocyclic group optionally containing one additional heteroatom
selected from oxygen, nitrogen and sulfur;
X is -U(CH2)VB-, -U(CH2V or a Qroup selected from:
U and B are independently a divalent radical selected from -N(R15)-, -O-, -S(O)2-, -N
(R15)C(O)-, -C(O)N(R15)- and -N[C(O)R15]-;
W is -C1-6R16)- or a nitrogen atom;
d is 0 or an integer from 1 to 5;
e is an integer from 2 to 4;
j and z are each independently integers from 0 to 2;
w is an integer from 0 to 4;
t is 2 or 3;
v is an integer from 1 to 8;
or a pharmaceutically acceptable salt, hydrate or ester thereof.
2. A compound as claimed in claim 1 wherein A is -N(R7)-CH2-.
3. A compound as claimed in claim 1 or claim 2 wherein X is -O(CH2)2H- or
-O(CH2)2O-.
4. A compound as claimed in any one of the preceding claims wherein d is 2.
5. A compound as claimed in any one of the preceding claims wherein R8 is a
heterocyclic group of the following formula:
wherein the heterocyclic is linked in the 6 or 7 position and j, R11, R12 and R13 are
as defined in claim 1.
6. A compound as claimed in claim 1 as defined in any one of Examples 1 to 8,
or a pharmaceutically acceptable salt, hydrate or ester thereof.
7. A compound selected from:
4"-(S)-{3-[2-(3-carboxy-7-chloro-1 -cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)-
ethoxy]-propionylamino}-4"-deoxyazithromycin;
4"-(R)-{3-[2-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)-
ethoxy]-propionylamino}-4"-deoxyazithromycin;
4"-(S)-{3-[2-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-yloxy)-
ethoxy]-propionylamino}-4"-deoxyazithrornycin;
4"-(S)-{3-[2-(3-carboxy-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-yloxy)-ethoxy]-
propionylamino}-4"-deoxyazithromycin 11,12-cyclic carbonate; and
4"-(3-{[2-(7-chloro-1 -cyclopropyl-3-methoxycarbonyl-4-oxo-1,4-dihydro-quinolin-6-
ylamino)-ethyl]-methyl-amino}-propionylamino)-4"-deoxyazithromycin;
or a pharmaceutically acceptable salt, hydrate or ester thereof.
8. A compound as claimed in any one of claims 1 to 7 for use in therapy.
9. A pharmaceutical composition comprising at least one compound as claimed
in any one of claims 1 to 7 in association with a pharmaceutically acceptable
excipient, diluent and/or carrier.
A is a bivalent radical selected from -C(O)NH-, -NHC(O)-, -N(R7)-CH2- and -CH2-N
(R7)-;
R1 is -NHC(O)(CH2)dXR8;
R2 is hydrogen;
R3 is hydrogen or C1-4alkyl,
R4 is hydroxy, R5 is hydroxy, or
R4 and R5 taken together with the intervening atoms form a cyclic group having the
following structure:
wherein Y is the bivalent radical, -O-, Rb is hydrogen or fluorine;
f7 is hydrogen or C1-6galkyl;
R8 is a heterocyclic group having the following structure:
R9 is hydrogen or C1-6alkyl;
R11 is hydrogen, -C(O)OR14, -C(O)NHR14 or-C(O)CH2NO2;
R12 is hydrogen, C1-6alkyl optionally substituted by hydroxy or C1-4alkoxy, C3.
7cycloalkyl, or optionally substituted phenyl or benzyl;
R13 is halogen, C1-4alkyl, C1-4thioalkyl, C1-4alkoxy, -NH2, -NH(C1-4alkyl) or -N
(C1-4alkyl)2;
R14 is hydrogen or C1-6alkyl optionally substituted by up to three groups
independently selected from halogen, C1-4alkoxy, -OC(O)C1-6alkyl and -OC(O)
OC1-6alkyl;
R15 is hydrogen, C1-4alkyl, C3-7cycloalkyl, optionally substituted phenyl or benzyl,
acetyl or benzoyl;
R16 is hydrogen or R13, or R16 and R12 are linked to form the bivalent radical -O
(CH2)2-or-(CH2)t-;
X is -U(CH2)VB-, -U(CH2)w- or a group selected from:
U and B are independently a divalent radical selected from -N(R15)-, -O-, -S(O)2-, -N
(R15)C(O)-, -C(O)N(R15)- and -N[C(O)R15]-;
W is -C(R16)- or a nitrogen atom;
d is 0 or an integer from 1 to 5;
e is an integer from 2 to 4;
j and z are each independently integers from 0 to 2;
t is 2 or 3;
v is an integer from 2 to 8;
or a pharmaceutically acceptable salt, hydrate or ester thereof.
This invention discloses a compound of formula (I)
wherein
A, R1, R2, R3, R4,R5 ,R6 are described in the specification.
The invention is also for composition comprising said compound.

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Patent Number 224148
Indian Patent Application Number 02188/KOLNP/2005
PG Journal Number 40/2008
Publication Date 03-Oct-2008
Grant Date 01-Oct-2008
Date of Filing 07-Nov-2005
Name of Patentee GLAXO GROUP LIMITED.
Applicant Address GLAXO WELLCOME HOUSE, BERKELEY AVENUE, GREENFORD, MIDDLESEX, UB6 0NN
Inventors:
# Inventor's Name Inventor's Address
1 BERDIK ANDREA PLIVA-ISTRAZIVACKI INSTITUT D.O.O. PRILAZ BARUNA FILIPOVICA 29, 10000 ZAGREB
2 JARVEST RICHARD LEWIS GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE SG1 2NY
3 LAZAREVSKI GORJANA PLIVA-ISTRAZIVACKI INSTITUT D.O.O. PRILAZ BARUNA FILIPOVICA 29, 10000 ZAGREB
4 ALIHODZIC SULEJMAN PLIVA-ISTRAZIVACKI INSTITUT D.O.O. PRILAZ BARUNA FILIPOVICA 29, 10000 ZAGREB
PCT International Classification Number C07H 17/08
PCT International Application Number PCT/EP2004/005086
PCT International Filing date 2004-05-11
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0310992.3 2003-05-13 U.K.