ZA200608516B - Ester linked macrolides useful for the treatment of microbial infections - Google Patents
Ester linked macrolides useful for the treatment of microbial infections Download PDFInfo
- Publication number
- ZA200608516B ZA200608516B ZA200608516A ZA200608516A ZA200608516B ZA 200608516 B ZA200608516 B ZA 200608516B ZA 200608516 A ZA200608516 A ZA 200608516A ZA 200608516 A ZA200608516 A ZA 200608516A ZA 200608516 B ZA200608516 B ZA 200608516B
- Authority
- ZA
- South Africa
- Prior art keywords
- ethoxy
- carboxy
- quinolin
- propionyl
- oxo
- Prior art date
Links
- 208000015181 infectious disease Diseases 0.000 title claims description 7
- 238000011282 treatment Methods 0.000 title claims description 7
- 230000000813 microbial effect Effects 0.000 title claims description 6
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- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229940044170 formate Drugs 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 229940028444 muse Drugs 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 208000030773 pneumonia caused by chlamydia Diseases 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229930195735 unsaturated hydrocarbon Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Description
ESTEMR LINKED MACROLIDES USEFUIL FOR THE TREATMENT OF MICROBIAL
INFECTIONS
The present invention relates to novel semni-synthetic macrolides hav=ing antimicrobial activity, in particular antibacterial activity. More particularly, the inventiomm relates to 14- and 15-memWbered macrolides substituted at thes 4” position, to processes for their preparation, to compositions containing them and to their muse in medicine.
1S Macrolisde antibacterial agents are knowm to be useful in the treatmemt or prevention of bacterial infections. However, the emergence of macrolide-resistant bacterial strains has resulted. in the need to develop new mamcrolide compounds. For exampole, EP 0 895 999 describes derivatives modified at the 4” gposition of the macrolide ring Inaving antibacterial
I. activity
Accord-ing to the present invention, wes have now found novel 14- and 15-membered macrolides substituted at the 4” position which also have antimicrobial activity. -SUMM_ARY OF THE INVENTION
Thus, the present invention provides compoumds of general formula (I)
CONFIRMATION COPY
RE
HC A | WwCH, HG CH,
Rhu, 10 ° 8 OR’ \/ 11 R20
R 7 2 or 12 s\"" CH, k TF
H,C’ di HC sp. z 4
CH,CH," 14 4 “rin a o 5 CH, 1 ., 0 “One Tn 0 5 CH,
CH, 2" 4" 3= “tty, 1 =, R
H,C OCH, @ wherein
Ais a bivalent rad_ical selected from -C(O)-, -C(O)NH—, -NHC(O)~, N®RN-CHy-, -CHp-NRT)-, -CHNRSRY)- and -C(=NR10)-;
Rl is -OC(O}CHo)gXR 11;
R2 is hydrogen or a hydroxyl protecting group;
R3 is hydrogen, C_4alkyl, or C3_galkenyl optionally substituted by 9 to 10 menmbered fused bicyclic heteroary 1;
R4 is hydroxy, C=9.galkenyloxy optionally substitutead by 9 to 10 membered fu sed bicyclic heteroaryl, or Cj. galkoxy optionally substituted by Cg _galkoxy or -O(CHp)eNR7 R12, }
RS is hydroxy, or
R4 and RS takem together with the intervening atoms form a cyclic group baving the following structumce: . Yeo,,,
T11 = 12 : of
H,C wherein Y is a bivalent radical selected from -C=Hp-, -CH(CN)-, -O-, -N(R!3)- and -
CH(SR13)-;
R6 is hydrogen o-r fluorine;
R7 is hydrogesn or C1_galkyl;
R® and RY ame each independently hydrogen, C).galkyl, -C(E=NRIONRI4R 15 or -C(O)R14, or
R8 and RY together form =CH(CR14R 15) gary, =CH(CR14R15)sheterocycls/, =CRI4R15 or =CRI14C(O)0R!4, wherein the alkyl, amyl and heterocyclyl groups. are optionally substituted bey up to three groups independently selected from R16;
R10 is -OR17, C}.galkyl, -(CHp)garyl, -(CHp)gheterocyclyl or -(CH),O(CH,);0R7, wherein each R10 group is optionally sub stituted by up to three grougos independently selected frorm R16;
R11 js a heterocyclic group having the follow ing structure: 20 . (R™), Q R'8
XX
Be
Ww N R32
R' or 20
SSN ]
Sw R* 18
R
R12 js hydrogen or Cy_galkyl;
R13 is hydrogen or Cj.4alkyl substituted by a group selected from optionally substituted phenyl, optionally substituted 5 or 6 membe=red heteroaryl and optionally substituted 9 to 10 membered fused bicyclic heteroaryl;
R14 and R®5 are each independently hydrogen or Cy_galkyl;
R16 is halogen, cyano, nitro, trifluoromethyl, azido, -C(O)R21, -C(0)OR_21, -OC(O)R2], -
OC(O)ORZ21, -NR22C(0)R23, -C(O)NRZ2ER23, -NR22R23, hydroxy, C1 ¢alkyl, -S(O)KC1.-
6alkyl, Cj_galkoxy, -(CHp)paryl or -(CHp)mheteroaryl, wherein the alkoxy group is optionally substituted by up to three groups independently selecte=d from -NR14R15, halogen- and -OR 14, and the aryl and heteroaryl groups are optionally sub stituted by up to five groups independently selected from halogen, cyano, mitro, trifluorormethyl, azido, -C(O)R%4, —
C(O)OR24, -OC(0)OR24, NRZSC(O)R2S, -C(O)NR25R26, -NER25R26, hydroxy, C1-galkyl and Cj_galkoxy;
R17 is hydrogen, Cj.galkyl, C3_7cycloalkyl, Cs.galkenylora 5 or 6 membered heterocyclic group, wherein the alkyl, cycloalkyl, alkenyl and heterocyclic groups are optionally substituted by up to three substituents independently selected fromm optionally substituted 5 Or 6 membered heterocyclic group, optionally substituted 5 or 6 me=mbered heteroaryl, -OR27, -
S(0)gR27, -NR27R28, -CONRZ7R28 halogen and cyano;
R18 is hydrogen, -C(O)OR29, -C(O)NHR2 -C(O)CHpNO2, or -C(0)CH2S0,R’;
R19 is hydrogen, Cj_4alkyl optionally substituted by hydroxy, cyano, NH», -NH(C1-4alkyl) or -N(C1.4alkyl); Cp.4alkenyl optionally substituted by hydrox=y, cyano, NHp, -NH(Cj.- 4alkyl) or -N(Cj.4alkyl)z; C1_g alkoxy, C3_7cycloalkyl, -NHjy, —NH(C1-4alkyl) or -N(C1. 4alkyD2; (C1-4atkyl) OC(O)N(C14alkyl) or optionally substitute=d phenyl or benzyl;
R20 js halogen, Cj_galkyl, Cy 4thivalkyl, C1_4alkoxy, -NHome, -NH(Cj4alky]) or -N(C3. 4alkyl)z;
R21 js hydrogen, Cj.1palkyl, -(CHy)paryl or -(CHp)pheteroary_l,
R22 and R23 are each independently hydrogen, -OR14, €Cp galkyl, -(CHp)qaryl or - (CHp)gheterocyclyl;
R24 is hydrogen, C1-10alkyl, ~(CH2)aryl or (CH) heteroaryl ;
R25 and R26 are each independently hydrogen, -OR14, -Cj_galkyl, (CHp)saryl or - {CHp)sheterocyclyl; 95 R27 and R28 are each independently hydrogen, C1_4alkyl or Cg 4alkoxyCj.4alkyl;
R29 is hydrogen or Cj. galkyl optionally substituted by up t=o three groups independently selected from halogen, Cj alkoxy, -OC(O)Cj_galkyl and -0C(0)OCy_galkyl, - (CHz)gheterocyclyl, (CHy)sheteroaryl, -(CH)qaryl, or -(CH2){C cycloalkyl;
S
R30 is hydrogen, C1_4alkyl, C3_7cycloalkyl, optionally substituted phenyl or benz=yl, acetyl or benzoyl;
R31is hydrogen or” R20, or R31 and R19 are linked to form the bivalent radical -O(®CH?)2-, 7 -(CH)i~;-NR(CH)r, -OCH,NR’-, -SCH,NR’-, -CH2 NR CHa, -CH,0CHj3-, -CE3,SCH)-, (CHR -;
R* is hydrogen, or~ R32 and R19 are linked to form thes bivalent radical selected fro-mu the group, ~S(CHo), and NR)CHo)e-, -O(CHa)p;
R*? is Cy _galkyl, C)._galkenyl or Cp.galkynyl;
X is -U(CHp)yB(CHp),D-, U(CHy)yB(CHp),D(CHIg)E-, -U(CH2){B-R* or U(CHz),B(CH),ID-R*~; or X is a group selected from: /N\ ST —N N—R33 \ / —N — N—R33 and lw
N
N—R3
H
U, B, D and E are independently divalent radicals selected from NR30)., -O-, -S(0)g -
NR30)C(0)-, -COINR30)- and -N[C(O)R30];
W is -C(R31)- omr a nitrogen atom; © aislor2 b is an integer fr-om 1 to 3; d is an integer from 1to 5; e is an integer fr-om 2 to 4; f,g, h,m,p, q,r ands are each independently intege=rs from 0-to 4; iis an integer froom 1to 6;
j,k, nand z are each independently integers from 0 to 2; tis 2 or 3; v is an integer from 1 to 8 independantly selected feor each occurance; and pharmaceutically acceptable derivatives thereof.
The term “pharmmaceutically acceptable” as used In erein 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 thee counterion or associa ted solvent is pharmaceutical ly acceptable. However, salts amd solvates having non-p~harmaceutically acceptable counterions or associated solvents are= within the scope of the present invention, for example, for use as intermediates in the prepaaration of other compounds of the invention . "15 and their pharmmaceutically acceptable salts and solvates.
The term “apharmaceutically acceptable derivative” as used here=in means any pharmaceuticamlly acceptable salt, solvate or prodrug, e.g. ester, of a c-ompound of the invention, which upon administration to the recipient is capable of provizding (directly or indirectly) 8 compound of the invention, or an active metabolite or residliue 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 Cheemistry and Drug
Discovery, 5 Edition, Vol 1: Principles and Practice, which is incorporated herein by reference to tThe extent of teaching such derivatives. Preferred pharmaceutically acceptable derivatives ar-e salts, solvates, esters, carbamate = and phosphate esters. Particularly preferred pharmaceutic-ally acceptable derivatives are salts, solvates and esters.. Most preferred pharmaceuticzally acceptable derivatives are sal®&s and esters.
The compoumds of the present invention may be in the form of and/or meay be administered as a pharma ceutically acceptable salt. For a Teview on suitable salts seze Berge ef al., J.
Pharm. Sci., 1977, 66, 1-19.
Typically, a pharmaceutical acceptable salt may be readily prepared by u_sing a desired acid or base as agppropriate. The salt may precipitate from solution and be collected by filtration or may be recovere=d by evaporation of the solvent. For example, an aqueous ssolution of an acid such as hydro chloric acid may be added to an aqueous suspension of a -compound of formula (I) and thes resulting mixture evaporated to diryness (iyophilised) to obtain the acid addition salt as a =solid. Alternatively, a compound of formula (I) may be dissolved in a suitable solvent, foor example an alcohol such as isopropanol, and the acid mamy be added in the same solvent cor another suitable solvent. The resulting acid addition sal t may then be precipitated directly, or by addition of a less polax solvent such as diisopxopyl ether or hexane, and isolat-ed by filtration.
Suitable addition salts are formed from inorganic <r organic acids which form non-toxic salts and exampRes are hydrochloride, hydrobronxide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, trifluoroacetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succsinate, pyruvate, oxalates, oxaloacetate, trifluoroacetate, saccharate, benzoate, alkyl or aryl sulphonates (eg metinanesulphonate, ethanesulphonate=, benzenesulphonate or p-toluenesulphonate) ancl isethionate.
Representative e=xamples include trifluoroacetate amd formate salts, for example the bis or tris trifluoroacet=ate salts and the mono or diforxmate salts, in particular the tris or bis trifluoroacetate ssalt and the monoformate salt.
Pharmaceuticall-y acceptable base salts include ammonium salts, alkali me=tal salts such as those of sodiunm and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, seconedary and tertiary amines, such as. isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-meethyl-D-glucamine.
Compounds of the invention may have both a pas c and an acidic centre maay therefore be in the form of zwi_tierions.
Those skilled in the art of organic chemistry will. appreciate that many or-ganic compounds - 30 can form com-plexes with solvents in which they are reacted or fromm which they are precipitated or= crystallized. These complexes aare known as “solvates”. For example, a complex with water is known as a “hydrate”. SoLvates of the compound of the invention are within the scope of the invention. The salts of the compound of form ula (I) may form solvates (e.g. kaydrates) and the invention also includes all such solvates.
© W © 2005/108412 PCT/IB2005/001186
Thae term “prodrug” as used herein means a compound which is con verted within the body, e.g by hydrolysis in the blood, into its active form that has medical effects.
Phharmaceutically acceptable prodrugss are described in T. Higuchi aend V. Stella, “Prodrugs ass Novel Delivery Systems”, Vol. 1 4 of the A.C.S. Symposium Se=ries, Edward B. Roche, ead, “Bioreversible Carriers in Drug Design”, American Pharmac eutical Association and
Pergamon Press, 1987, and in D. Fleisher, S. Ramon and H. Bartora “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs”, Advanced Drug Delivery
Reviews (1996) 19(2) 115-130, each of which are incorporated here=in by reference.
Prodrugs are any covalently bonded carriers that release a compourd of structure (1) in vivo wvhen such prodrug is administered to a patient. Prodrugs ares generally prepared by modifying functional groups in a way such that the modificatieon is cleaved, either by moutine manipulation or in vivo, yielding the parent compounci. Prodrugs include, for eexample, compounds of this invertion wherein hydroxy, amine or sulfhydryl groups are “bonded to any group that, when axdministered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of procinugs 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 thes 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 hydroly=sable ester groups include those which break down readily in_ the human body to leave the pa_rent 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) haves more than one asymmetric carbon atom. In the general formula (I) as drawn, the solid wedgee shaped bond indicates that the bond is above the plane of tine paper. The broken bond indicates that the bond is below the plane of the paper.
It will be appreciated that the substituents on the macrolide rmay also have one or more asymmetric carbon atoms. Thus , the compounds of structure «(I) may occur. as individual enantiomers or diastereomers. All such isomeric forms are included within the present inveention, including mixtures thereof.
Where a compound of the invention contains an alkenyl group, cis (Z) anc trans (E) isomerism may also occur. The present invention includes the individual =stereoisomers of thex compound of the invention and, where appropriate, the individual taustomeric forms thereof, together with mixtures thereof.
Sexparation of diastereoisomers or cis and trans isomers may be achieved by conventional te-chniques, e.g. by fractional crystallisation, chromatography or HPLC. A stereoisomeric nm jxture of the agent may also be prepared from a corresponding optically pure intermediate ox by resolution, such as HPLC of the corresponding mixture using a sum table chiral support osx by fractional crystallisation of the diastereoisomeric salts formed by reaction of the ceorresponding mixture with a suitable optically active acid or base, as appropriate. 15 .
T he compounds of structure (I) may be in crystalline or amorphous forma. Furthermore, some ofthe crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention.
Compounds wherein R? represents a hydroxyl protecting group are ir general intermediates
For the preparation of other compounds of formula (J). “When the group OR2 is a protected hydroxyl group this is convemuiently an ether or an -acyloxy group. Examples of particularly suitable ether groups include those in which R2isa trialkylsilyl (i.e. trimethylsilyl). When the group OR? represents a_n acyloxy group, then examples of suitable groups R2 include acetyl or benzoyl.
R6 is hydrogen or fluorine. However, it will be appreciated that winen A is -C(O)NH- or - } CHy-NR7)-, RS is hydrogen.
When R11 is a heterocyclic group baving the following structure:
(R ) Q R'8
C1)
K% N 2 R®
RE® said heterocyclic is linked in the 6 or 7 position to the X group as above efined. When present, the R270 group or groups may be attacked at any position on the ring. In one embodiment, an_ R20 group is attached at the 6 or 7 position.
When R11 is a lxeterocyclic group having the following structure: : 20 . (R ) ® T 18
R
CAEN
=" wherein W is -CC(R31)- where R31 is R20 or R31 znd R19 are linked to form tine bivalent radical -O(CHp=))-, -(CHp)¢-3-NR(CHz)a-, -OCH, INR -, -SCH;NR-, -CH,NR ~ CHy-, -
CH,0CHj-, -CCH»SCH3-, (CH2),NR -, said hetexocyclic is linked in the (ii) cr (iii) position to the X group =as above defined. i5
When R11 isa heterocyclic group having the following structure:
R) - —_ T RN as 7 7 8. —- 2
N N R% =" 20 said heterocyclic is linked in the 6 or 7 position toe the X group as defined abowve.
When R1-1 is a heterocyclic group having the following structure: (R™) Q R'
Rs NH :
SEPP R%
R® said hetesrocyclic is linked in the 7 or 8 position to the X group as abo- ve defined.
When R211 is a heterocyclic group having the following structure: 20
Ra § go
LORY ENS R%2
R" whereimn W is -C(R31)- where R31 is R20 or R31 and R19 are linked to form the bivalent radical -O(CH»)>-, ~(CHp)5-NR"(CHL),-, -OCH,NR’-, -SCH,NR’-, -CH,NRCHy-, -
CH,OCCH;-, -CH2SCH3-, (CH,),NR ’-, said heterocyclic is linked im the (i), (ii) or (iii) position to the X group as above defined. In one embodiment, the he—terocyclic is linked to the 15. (i) position. In another embodiment, the heterocyclic is linked in the (ii) or (iii) position. ’
When “R11 is a heterocyclic group having the following structure:
R ) ? 18 3 5 7 i i SN) aE
R'® said heterocwyclic is linked in the 2 or 3 position to the X group as abovee defined. In one embodiment, the heterocyclic is linked in the 2 or 3 position. In another embodiment, the heterocyclic is linked in the 4 position.
The term “alkyl” as used herein as a group or a gpart of a group refers to a strwaight or branched hydrocarbora chain containing the specified mumber of carbon atoms. Moor example, Ci- 10alkyl mezans a straight or branched alkyl containing at least 1, and a® most 10, carbon atoms. Examples of “alkyl” as used herein include, but are not limited tow, methyl, ethyl, n- propyl, n-buatyl, n-pentyl, isobutyl, isopropyl, t-Toutyl, hexyl, heptyl, octyl, mmonyl and decyl. A Cj_galkyl group is preferred, for example methyl, ethyl, n-propyl, isopropy=1, n-butyl, isobutyl or t-butyl.
The term <‘C3_jcycloalkyl” group as used Ferein refers to a non-arcomatic 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 chhain alkoxy group ‘containing the specified number of carbon atoms. For example, Cj.galko=xy means a straight or branchecd alkoxy containing at least 1, and a-t most 6, carbon atoms. Ex_amples of “alkoxy” as used herein include, but are not limited to, rmethoxy, ethoxy, propoxy, orop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop—2-oxy, pentoxy and hexyloxy. A Cj_galkoxy group is preferred, for example methoxy, etho-Xy, propoxy, prop-2-oxy, butoxy, but-2-0xy or 2-methylpr-op-2-oxy.
The term =‘alkenyl” as used herein as a grovap or a part of a group refers to a straight or branched Iaydrocarbon chain containing the sp ecified number of carbon aftoms and containing at least onee double bond. For example, the texm “Cs _galkenyl” means a =straight or branched alkenyl co ntaining at least 2, and at most 6, carbon atorus 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-bute=nyl, 3-methylbut-2- enyl, 3-he=xenyl and 1,1-dimethyibut-2-enyl. Ie will be appreciated that in groups of the form -
O-Cy_gall<enyl, the double bond is preferably not adjacent to the oxygen.
WO» 2005/108412 PCT/1B2005/0011886
The term “alkynyl” as used herein ass a group or a part of a group reefers to a straight or branched hydrocarbon chain containing the specified number of camrbon atoms and containisng at 1 east one triple bond. For examples, the term “Cy_galkynyl” mea=ns a straight or branched alk—ynyl containing at least 2, and at most 6, carbon atoms and containing at least one triple bomad. Examples of “alkynyl” as used herein include, but are not 1—imited to, ethynyl, 2-poropynyl, 3-butynyl, 2-butynyyl, 2-pentynyl, 3-pentynyl , 3-methyl-2-butynyl, 3- mesthylbut-2-ynyl, 3-hexynyl and 1,1-dimethylbut-2-ynyl. It wwill be appreciated that in greoups of the form -O-Cp_galkymyl, the triple bond is prefSerably not adjacent to the oxxygen.
Thhe term “aryl” as used herein refers to an aromatic carbocyclic moiety such as phenyl, biphenyl or naphthyl.
The term “heteroaryl” as used Therein, unless otherwise defSined, refers to an arommaatic heterocycle of 5 to 10 members, having at least one heteroatom selected from nitrogen, o-xygen and sulfur, and containing at least 1 carbon atom, inchamding both mono and bicyclic ring systems. Examples of heteroaryl rings include, but are not 1=imited to, furanyl, thioph _enyl, peyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tria=olyl, oxadiazolyl, tetrazolyl, thiadiazoXyl, pyridyl, pyridazinyl, pyr=xzinyl, pyrimidinyl, tria=inyl, yuinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, beenzofuranyl, benzimida=zolyl, toenzothienyl, benzoxazolyl, 1,3 -benzodioxazolyl, indolyl, ‘Oenzothiazolyl, furylpyrsdine,
Oxazolopyridyl and benzothiophenyl. “The term “5 or 6 membered hetexoaryl” as used herein as a greoup or a part of a group refers ao a monocyclic 5 or 6 membered aromatic heterocycle containing at least one heteroatom ~independently selected from oxygen, nitrogen and sulfur. Examples include, but amre not “limited to, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imida zolyl, oxazolyl, isoxamzolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, tetrazolyl, py=ridyl, pyridazinyl, pyreazinyl, pyrimidinyl and triazinyl.
The term “9 to 10 membered fussed bicyclic heteroaryl” as use=d herein as a group or a gpart of a group refers to quinolinyl, isoquinolinyl, 1,2,3 4-tetrahyroisoquinolinyl, benzofiaranyl, benzimidazolyl, benzothienyl, benzoxazolyl, 1,3-benzodioxamzolyl, indolyl, benzothizazolyl, furylpyridine, oxazolopyridyl or benzothiophenyl.
The term “heterocyclyl” ass used herein, unless otherwise defined _, refers to a monocyclic or bicyclic three- to ten-memmbered saturated or non-aromatic, unsaturated hydrocarbon ring containing at least one heteroatom selected from oxygen, nitrogen. and sulfur. Preferably, €he heterocyclyl ring has five or six ring atoms. Examples of heterecyclyl groups include, Bout are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrogthiophenyl, imidazolidirmyl, pyrazolidinyl, piperidyl, piperazinyl, morpholino, tetrahydropyran.yl and thiomorpholino.
The term “5 or 6 membereed heterocyclic group” as used herein a_s a group or part of a group refers to a monocyclic 5 -or 6 membered saturated hydrocarbon ring containing at least one heteroatom independently selected from oxygen, nitrogen and sulfur. Examples of s-uch heterocyclyl groups inc=lude, but are not limited to, pyrr-olidinyl, tetrahydrofura-uyl, tetrahydrothiophenyl, immidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morphol ino, tetrahydropyrany! and thisomorpholino.
The term “halogen” refers to a fluorine, chlorine, bromine or iodine atom.
The terms “optionally substituted phenyl”, “optionally substituted phenyl or ben=zyl”, " “optionally substituted 5 or 6 membered heteroaryl”, “optionally substituted 9 to 10 membered fused bicyclic= heteroaryl” or “optionally substituted 5 or 6 membered heterocyclic : group” as used herein refer to a group which is substituted by- 1 to 3 groups selected —from halogen, Cj_4alkyl, C1.~alkoxy, hydroxy, nitro, cyano, amino, Cj.4alkylamino or diCy_4alkylamino, phen=yl and 5 or 6 membered heteroaryl. 95 In one embodiment, A is -C(O)-, -C(O)NH-, -NHC(O)-, -N(R")-CHp-, -CHp-NR7)— or -
CH(NRSRY)-. In anoth_er embodiment, A is -C(O)-, -C(O)NHL-, -NHC(O)-, -CHy-NR_7)-, -
CH(NRSRY)- or -C(=NIR10)-. In a further embodiment, A is -C(0)-, -C(O)NH-, -NHC(S)-, ~CHp-NR7- or -CH(NIRSR9)-. Representative examples of A include -C(0)- and NCR7)-
CH;-. In one preferred embodiment, A is NR7)-CHp-. " Arepresentative example of R2 is hydrogen.
Representative examples of R3 include hydrogen and €Cy_galkyl, in particular hyd-rogen and methyl.
In one embodiment, IR? is hydroxy or Cy_galkoxy, im particular hydroxy or methoxy. In a preferred embodiment, R4 is hydroxy. In another emb=odiment, RS is hydroxy. Alternatively,
R4 and RS taken tomgether with the intervening atoms form a cyclic group having the following structure:
Y tir,, . 11 o=( 122 . Oo H
H,C wherein Y is a bivalent radical selected from -O- and ~NR13)-.
A representative example of RO is hydrogen.
A representative exammple of R7 is C1_galkyl, for exammple Cj-4alkyl, in particular methyl.
Representative exanmples of R11 include heterocyclic groups having the followin g structures: (R™), ? 18
R
{ UZ N = Rr l
R'S and no . (R ) Q 18
R
I 82 1 2
N N rR» . RT wherein the heterocyclic is linked in the 6 or 7 position to the X group as above defined, and heterocyclic groups having the following structure: 20 (R ) 0) ? R'®
WS
Lio wherein W is -C(R31)- and R31 and R19 are linked to form the bivalent radical -€CH2)¢-, and the heterocylic is linked in the (ii) or (iii) position to th_e X group as above definecl.
In one preferred embodiment, R11 is a heterocyclic group having the following s&ructure: 20 (R ) 1 R18
C10 7 8. N 2 R22
Ls :
A representative example of R13 js hydrogen.
In one embodiment, R18 is -C(O)OR29, -C(O)NHR 2-9; -C(0)CHaNO». or -C(O)CHSO9R’.
A representative example of R18 is -C(O)OR29, In one preferred embodiment, R18 is -C(O)OR?® wherein R® is hydrogen.
Representative examples of R19 include Cy _4alkyl, in particular ethyl, and C 3.7cycloalkyl, in particular cyclopropyl.
In one embodiment, R20 is halogen, in particular chl orine or fluorine, or metho xy.
In one embodiment, R30 is hydrogen or Cj.4alk=yl. A representative example of R30 js hydrogen or methyl. :
A representative example of R31 is hydrogen, or R31 and R19 are linke=d to form the bivalent radical -(CCH2)¢-.
A represeentative example of X is -U(CH2)<,B(CH2)\D-, -U(CHp)B(CF3,)\D(CH2).E-, -U(CHp),B-R*., or U(CH,)B(CH,),D-R*>..
Represe-miative examples of U, B, Dand E include the divalent radicals NR30)., -0-, S(0)z- , NR3%)C(0)- and -C(O)N(R30)-.
A repre-sentative example of R* is Cy allyl or Cy alkynyl. In one preferred embodi_rent,R* is propyl.
A repre=sentative example of d is 1 to 4, forexample 2 to 4. A particulearly preferred example of dis 2.
A repressentative example of v is 1 to 4, for example 2 or 3. A particularly preferred example is whemn each v independently is 2.
In one embodiment, X is ~-U(CHp)yB(CHL),D- or -U(CHy)yB-R* 3. wherein U is -O-, B is -
O-, aned Dis —N-. Particulalry preferred X groups are O(CH2)20(CETy),N- and -O(CH3)20- (CH2) 3-
In one= embodiment, j is 0 to 2. A representative example of jis 0 or Wb.
A repmresentative example of t is 3.
A repzxesentative example of z is 0. .
Particularly preferred compounds of thes invention are: 47-0 -(3-{4-[3-(3-Ethoxycarbonyl-1-ethyl-4-oxo-1,4-dihydro-qu_inolin-6-yl)-prop-2- ynyl ¥§-piperazin-1-yl}-propionyl)-azi€hromyecin,
47-0-(3-{4-[_ 3-(3-Ethoxycarbonyl-1 -ethyl-4- oxo-1,4-dihydro-quine® lin~6-yl)-propyl]-
piperazin-1-2yl} -propionyl)-azithromycin,
47-0-(3- {4-K 3-(3-Ethoxycarbonyl-1 -ethyl-4—oxo0-1,4-dihydro -quineolin-6-yl)-prop-2-
ynyl]-pipera-zin-1-yl} -propionyl)-6-0-methy>l-erythromycin A,
47-0-(3-{4- "13-(3-Ethoxycarbonyl-1 -ethyl-4—~oxo0-1 ,A-dihydro-quin-olin-6-yl)-prop-2- ynyl]-piperamzin-1-yl}-propionyl)-11 -O-metkayl-azithromycin, 4”-0-(3-{4—[3-(3-Ethoxycarbonyl-1 -ethyl-4 -oxo-1 ,4-dihydro-quinaolin-6-yl)-propyl}- piperazin-1—jyl}-propionyl)-11- O-methyl-az-ithromycin, 4”-0-(3-{2—[2~(3-Carboxy-7-chloro-1 -cyclopropyl-4-0xo0-1 ,4-dihsydro-quinolin-6-
ylamino)-et-hoxy]-ethoxy} -propionyl)-roxy#&hromycin, 4”-0-(3-{2—[2-(3-Carboxy-7-chloro-1 -cyclopropyl-4-oxo-1 ,4-dih=ydro-quinolin-6- ylamino)-emthoxy}-ethoxy} -propionyl)-6-O- methyl-erythromycin A, 4”-0-(3-{2 -[2-(3-Carboxy-7-chloro-1 -cycleopropyl-4-oxo-1 ,4-dih—ydro-quinolin-6- ylamino)-e—thoxy]-ethoxy} -propionyl)-azitiaromycin,
47-0-(3-{2=-[2-(3-carboxy-7-chloro-1 -cyclopropyl-4-0x0-1 ,4-dih=ydro-quinolin-6-
.ylamino)-e=thoxy]-ethoxy}-propionyl)-11 -O-methyl-azithromycim, 4”-0-(3-{2={2-(3-Carboxy-1-cyclopropyl-<3-oxo-1 ,4-dihydro-quimnolin-6-ylamino)- ethoxy]-ethhoxy} -propionyl)-azithromycin, 4”-0-(2-{33-[2-(3-Carboxy-7-chloro-1 -cycRopropyl-4-oxo-1,4-dilaydro-quinolin-6-
yloxy)-eth oxy]-propionylamino} -acetyl)-a.zithromycin 11,12-cyclic carbonate, 47-0-(2-{3-{2-(3-Carboxy-7-chloro-1 -cyc_lopropyl-4-0xo-1 ,4-dilydro-quinolin-6- ylamino)-esthoxy]-propionylamino} -acetyl )-azithromycin 11,12-acyclic carbonate, 47-0-2-{3]2-(3 -Carboxy-6-fluoro-1-cycRopropyl-8-methoxy-4—oxo-1 ,4-dihydro- quinolin-7~-ylamino)-ethoxy]-propionylammino}-ac etyl)-azithromycin 11,12-cyclic ' carbonate, 42-0-[2~(3-{2-[2-(3-Carboxy-6-fluoro-1 -cyclopropyl-4-oxo-1,4—dihydro-quinolin-7- ylamino)-- ethoxy]-ethoxy} -propionylamin_o)-acetyl] -azithromyc#in 11,12-cyclic carbonate. 4”-0-[2-(3-{2-[2-(3-Carboxy-7-chloro-1- cyclopropyl-4-oxo-1 ,4+-dihydro-quinolin-6- ylamino)—ethoxy]-ethoxy} -propionylamimmo)-acetyl]-azithromyc=in 11, 12-cyclic carbonates, 47-0[2-(3-(2-[2-(3-Carboxy-7-chloro-1-cy-clopropyl-4-oxo-1,4-dikaydro-quinolin-6- ylamino)--ethoxy]-ethoxy}-propionylamino)s -acetyl]-azithromycin,
47-0-2-[3( {2-[3-(6-Ethoxycarbonyl-7-o0x0-2,3-dihydro- 1 HE, TH-pyrido[3,2,1- ijlquinolin-9-yl)-prop-2-ynyl.amino] -ethyl} -propyl-amino)-propionylamino] -acetyl}— azithromycin, 8 0-{2-[3~( {2-[3-(6-Ethoxycarbonyl-7-ox0-2,3-dihydro-1 H _7H-pyrido[3,2,1- ij] quinolin-9 -yl)-propylamin.o]-ethyl} -propyl-amino)-propioenylamino} -acetyl}- azithromycin, 47-0-(3-{2-[2-(3-Carboxy-7 -chloro-1 -cyclopropyl-4-oxo-1 ~4-dihydro-quinolin-6- ylamino)-ethoxy]-ethoxy} -peropionyl)-9(E)-ethoxyimino -ersythromycin A, 47-0-[3-(2-{2-[2-(3-Carbox_y-7-chloro-1 -cyclopropyl-4-0xoO-1 ,4-dihydro-quinolin-6 - ylamino)-ethoxy]-ethoxy} -ethylamino)-propionyl]-6-O-methyl-erythromycin A, 4-0+3-(2-{2-[2-(3-Carboxy—6-fluoro-1 -cyclopropyl-4-oxo-1 ,=4-dihydro-quinolin-7- ylamino)-ethoxy]-ethoxy} —etBaylamino)-propionyl]-6-O-methyM-erythromycin A, 47-0-(3-{2-[2-(3 -Carboxy-7—chloro-1-cyclopropyl-4-oxo-1 ,A-clihydro-quinolin-6-ylamirmo)- ethoxy]-ethylamino} -propiorayl)-6-O-methyl-erythromycin A, 4”-0-(3- {2-[2-(3-Carboxy-6—fluoro-1-cyclopropyl-4-oxo-1,4-ihydro-quinolin-7-ylamirmo)- ethoxyl-ethylamino} -propioryl)-6-O-methyl-erythromycin A, 4”-0-(3-{2-[2~(10-Carboxy-9-0x0-3 ,A-dihydro-2H,9H-1-oxa-=4a-aza-phenanthren-6- ylamino)-ethoxy]-ethoxy} -pmopionyl)-azithromycin, 11-O-Methyl-4’’-O-(3-{2-[3 -(3-Carboxy-1-ethyl-4-0x0-1 ,4-dmhydro-quinolin-6-yl)-propo-2- ynyloxy]-ethylamino} -propi-onyl)-azithromycin, 11-O-Methyl-4’’-0-(3-{2-[3 -(3-Carboxy-1-ethyl-4-oxo-~ 1,4-d=ihydro-quinolin-6-yl)-prorooxyl- ethylamino}-propionyl)-azitThromycin, and 47-0-(3-{2-[2-(3-Carboxy-6-fluoro-1-cyclopropyl-4-oxo-1 4—dihydro-quinolin-7-ylami-no)- ethoxy]-ethoxy}-propionyl)—azithromycin A, or pharmaceutically acceptatble derivatives thereof.
Further particularly preferre d compounds of the invention are=: 42-0-(3-{2-[2-(3-Carboxy-"J -chloro-1-cyclopropyl-4-oxo-1,4 -dihydro-quinolin-6-ylam—ino)- ethoxy)-ethoxy}-propionyl) -6-O-methyl-erythromycin A 11, 712-cyclic carbamate, 47.0-(3-{2-[2-(3-Carboxy-&5-fluoro-1-cyclopropyl-4-oxo-1,4 -dihydro-quinolin-7-ylamino)- ethoxy]-ethoxy}-propionyl® -6-0-methyl-erythromycin A, 47-0-(3-{2-[2-(3-Carboxy-"7-chloro-1-ethyl-4-0xo-1 ,4-dihyd_xo-quinoline-6-ylamino)- ethoxy]-ethoxy}-propionyl)-azithromycin, }
47-0-(3-{2-[2-(3-C2arboxy-6-fluoro-1-ethyl-4-oxo-1 . 4-dihydro-quinoline-7-"ylamino}-
ethoxy]-ethoxy}-pr=opionyl)-azithromycin,
4°-0-(3- {2-[2-(3-Carboxy-1-ethyl-4-oxo-1 A-dihydr-o-quinoline-6-ylamino3-ethoxy} -ethoxy}-
propionyl)-azithroruycin,
47-0-(3-{2-[2~(3-c=arboxy-7-chloro-1-isopropyl-4-o=o-1 ,A-dihydro-quinolimne-6-ylamino)- ethoxy)-ethoxy}-p=ropionyl)-azithromycin, 47-0-(3-{2-[2-(6-CCarboxy-7-0x0-2,3-dihydro-1H,7 H-pyrido[3,2,1-}jlquincolin-9-ylamino)- ethoxy]-ethoxy} -poropionyl)-azithromycin, 4°-0-(3- {2-[2-(6-=Carboxy-7-0x0-2,3-dihydro-1H, 7 H-pyrido[3,2,1-ijjlquinclin-9-ylamino)-
ethoxyl-ethoxy}-poropionyl)-6-O-methyl-erythromyscin A, 4”-0-(3-{2-[2-(3—Carboxy-7 -chloro-1-cyclopropyl—4-oxo-1,4-dihydro-quimnolin-6-ylamino)- ethoxy]-ethoxy} -mpropionyl)- 6-O-propyl-erythrom ycin A, 47-0-(3-{2-[2-(3—Carboxy-1-cyclopropyl-4-oxo-1, 4-dihydro-quinolin-7-yloxy)-ethoxy}]- ethoxy} -propionse’l)-azithromycin,
4°-0-(3-{2-[3-( ~carboxy-1-ethyl-4-0x0-1,4-dihy dro-quinolin-6-y1)-propm-2-ynyloxy}- ethylamino} -progpionyl)-6-O-methyl-erythromycirs A, 4°°-0-(3-{2-[3-(33-Carboxy-1-ethyl-4-0x0-1 ,4-dih~ydro-quinolin-6-yl)-pro—poxy]-ethylamino}- propionyl)-6-O-rxethyl-erythromycin A, 47-0-(3-{2-[2-(3% -Carboxy-1-cyclopropyl-4-oxo-1 ,4-dihydro -quinolin-7-=yloxy)-ethoxy}-
ethoxy}-propion_yl)-6-O-methyl-erythromycin A, 4>’-0-(3-{2-[2-(3-Carboxy-1-cyclopropyl-4-oxo- 1 4-dihydro-quinolin-7—yloxy)-ethoxy]- ethoxy }-propiommyl)-9-ethyloximino-6-O-methyl-erythromycin A,
4 -0-[3-(2- {2-[_2-(3-Carboxy-7-chloro-1-cyclopropyl-4-0xo-1,4-dibydro-quinolin-6- ylamino)-ethoxses]-ethoxy}-ethylamino)-propiony1]-9-(1 -isopropoxy-cycMohexyl)oximino-
erythromycin A : 4°-0-(3-{2-[2-(3 -Carboxy-7-chloro- 1-cycloprop/l-4-oxo-1,4-dihydro-qwuinolin-6-ylamino)- ethoxy]-ethoxy 3 -propionyl)-9-(1-isopropoxy-cyclohexyl) oximino-erythmromycin A, 4”-0-(3-{2-[2-(3-Carboxy-1-cyclopropyl-4-oxo- 1 A-dihydro-quinolin-7—jyloxy)-ethoxy]-
" ethoxy} -propioznyl)-9-(1-isopropoxy-cyclohexyl Yoximino-erythromycin A,
4°-0-(3-{2-[2--(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1 ,4-dihydro-cjuinolin-6-ylamino)- ethoxy]-ethoxy~}-propionyl)-9-oxime erythromycin A, 4"?-0-(3-{2-[2~—(3-Carboxy-1-cyclopropyl-4-oxos-1 ,4-dihydro-quinolin-~7-yloxy)-ethoxy]- ethoxy} -propicenyl)-9-oxime erythromycin A,
4’-0~[3-(2- 2-[2-(3-Carboxy-7-chloro-1 -cyclopropyl-4-oxo-1 ,A-dih—ydro-quinolin-6- ylamno)-ethoxy}-ethoxy} -ethylamino )-propionyl]-9-oxime erythromycin A, 4°-Op(3-{2-[2-(3-Carboxy-1-cyclopro- pyl-T-methoxy-4-oxo-1 ,4-dih=ydro-quinolin-6- ylam-ino)-ethoxy]-ethoxy} -propionyl)—azithromycin,
47-0O-3-{2-[2-(3 -Carboxy-1-cycloprapyl-7 -dimethylamino-4-o0xo0-1- 4-dihydro-quinolin-6-
ylaomino)-ethoxy]-ethoxy} -propionyl) azithromycin,
4"-00-(3-{23-(3 —carboxy-1-ethyl-4-o=xo-1,4-dihydro-quinolin-6-y1) —propoxyl-ethoxy} - prop ionyl)-azithromycin,
4"-O-3-{2-[3 -(3-carboxy-1-ethyl-4-0sx0-1,4-dihydro-quinolin-6-yl)e -propoxy]-ethoxy}-
propeionyl)-6-O-methyl erythromycin A,
9-Ethyloximino-4"-O-(3- {2-[3-(3-car-boxy-1-ethyl-4-oxo-1 ,4-dihydiro~quinolin-6-yl)-
~ propoxyl-ethoxy} -propionyl)-erythro-mycin A, 4"-O)-(3-{2-[3-(3-Carboxy-1-ethyl-4- oxo-1,4-dihydro-quinolin-6-yM)-propoxyl-ethoxy} - propionyl)-6-O-methyl-8a-aza-8a-hoxwoerythromycin A,
4"-O-(3-{2-[3-(3-Carboxy-1 _ethyl-4—oxo-1,4-dihydro-quinolin-6-y1)-propoxyl-ethoxy} - progpionyl)-roxythromycin, 4_aD-(3-{2-[2~(3-Carboxy-7-chloro- 1-cyclopropyl-4-oxo-1,4-dihyadiro -quinolin-6-yloxy)- ethoxy]-ethoxy}-propionyl)-azithromaycin, 4"-a0-(3- {2-[3-(3-Carboxy-1-cthyl-4—ox0-1,4-dihydro~quinolin-6-y=1)-propoxy]-ethoxy} -
pro-pionyl)-6-O-methyl-11-desoxy-1 1-(R)-methylamino-erythromywcin A 11, 12-carbamate, 4"-«0-(3- {2-[3-(3-Carboxy-1-cyclopr-opyl-4-oxo-1,4-dihydro-quincolin-6-yl)-propoxy]- eth_oxy}-propionyl)-azithromycin,
4"- O-(3- {2-[3-(3-Carboxy-4-oxo-1,4}-dihydro-quinolin-6-yl)-propOxyl-ethoxy} ~propionyl)- azi thromycin,
4"—0-(3-{2-[3-(3-Carboxy-4-oxo-1-propyl-1,4-dihydro -quinolin-6=-yl)-propoxy}-ethoxy}- propionyl)-azithromycin, 4<—0-3-(2- {2-[2-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-Mihydro-quinolin-6- ylaamino)-ethoxy]-ethoxy}-ethylami no)-propionyl] -azithromycin, 4<_-0-[3-(2- {2-[2-(3-Carboxy-6-flucro-1-cyclopropyl-4-oxo-1,4-dlihydro-quinolin-7-
ylemino)-ethoxy]-ethoxy}-ethylamiino)-propionyl}-azithromycin,
4% -0-(3-{2-[2-(3-Carboxy-7-chlorcs-]-cyclopropyl-4-oxo-1 ,4-dih—ydro-quinolin-6-ylamino)- ethhoxy]-ethylamino} -propionyl)-az ithromycin, 4‘=-0-(3-{2-[2-(3-Carboxy-6-fluorae-1-cyclopropyl-4-oxo-1 ,4-dih—ydro-quinolin-7-ylamino)- etBhoxy]-ethylamino}-propionyl)-azzithromycin,
4“-0-[3-(2- € 2-[3-(3-Carboxy-1-ethyl-4-oxo- 1 4-dihydro-quinolin-6-y1)-progp-2-ynyloxy]-
ethoxy} -ethwylamino)-propionyl]-azithromycin,
4“-0-[3-(2- 22[2-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-grainolin-6-
ylamino)-etlhoxy]-ethoxy}-ethylamino)-propionyl}-6-O-methyl erythromycin A,
4“-0-(3-{2—[2-(3-Carboxy-7-chloro- 1-cyclopropyl-4-oxo-1 ,4-dihydro-quin-olin-6-ylamino)-
ethoxy] —etheoxy}-propionyl)-6-O-methyl-8a-aza-8a-homoerythromycin A,
4“-0-3-(2~ {2-[2-(3-Carboxy-T~chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-
ylamino)-ethoxy]-ethoxy} -ethylamino)-propionyl]-azithromycin,
4“-0-{3-(2—{[2-(3 ~Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-qui_nolin-6-ylamino)-
ethyl]-methmyl-amino}-ethoxy)-propionyl}-azithromycin, 4%-0-(3-{2~[2-(3-Carboxy-1-cyclopropyl-4-oxo-1 ,4-dihydro-quinolin-6-yH oxy)-ethoxy]- ethoxy}-preopionyl)-azithromycin, 4%-0-(3-{2--[2-(3-Carboxy-7-chloro-4-ox0- 1,4-dihydro-quinolin-6-yloxy)—ethoxy]-ethoxy}- propionyl)—azithromycin,
4%“-0-(3-{2-[2-(3-Carboxy-7-chloro-4-oxo- 1,4-dihydro-quinolin-6-ylamin_o)-ethoxy]- ethoxy}-pr-opionyl)-azithromycin, 4"-0-{[6-(_{2-[(2-Aminoethyl)(methyl)amimo]ethyl} thio)-1-ethyl-4-oxo-1 ,4-dihydro-3- quinolinec arboxylic acid]propionyl}-6-O-methylerythromycin A, 4"-0-{[6-C {2-[(2-Aminoethyl)(methyl)amino]ethyl} thio)-1-ethyl-4-oxo-1 ,4-dihydro-3-
quinolinec-arboxylic acid]propionyl}-azithromycin, 4”-0-{[6-C {2-[(2-Aminoethyl)oxylethyl} oxy)-1-ethyl-4-oxo-1,4-dihydro—3- quinolinec=arboxylic acid]propionyl}-6-O-ruethylerythromycin A, 4”-0-{[6~-& {2-[(2-Aminoethyl)oxy]ethyl}o xy)-1-ethyl-4-0xo-1 ,4-dihydro—3- quinolinecsarboxylic acid]propionyl} -O-(9FE)-methoxymethyloximino erythromycin A,
47°-0-{[6-« {2-[(2-Aminoethyl)oxy]ethyl}oxy)-1-ethyl-4-0xo-1,4-dihydro -3- quinolinecarboxylic acid]propionyl}-O-(9E)-hydroximino erythromycin _A, 47-0-{[1~"Ethyl-6-(3-{[2-Aminoethyl]oxy} propyl)-4-oxo-1,4-dihydro-3 ~cjuinolinecarboxylic acid] Jpro-pionyl}-O~(9E)-hydroximino erythromycin A, 4”-0-{[1—Ethyl-6-(3- {[2-(methylamino)ethyljoxy} propyl)-4-oxo-1 ,4-dibmydro-3-
quinolineecarboxylic acid] Jpropionyl}-O-(9E)-hydroximino erythromycimn A, and 47-0-{[6—({2-[(2-aminoethyl)oxy]ethyl} 0 xy)-1-ethyl-4-oxo-1,4-dibydro—3- quinoline carboxylic acid]propionyl}-6-O—methylerythromycin A, or pharmaceutically acceptable derivatives thereof.
Compounds according ®o the invention also exhibit a broad spectrum of antimicrobial activity, in particular antibacterial activity, against a wide range of clinical patinogenic microorganisms. Using a standard microtiter broth seriall dilution test, compounds- of the invention have been found to exhibit useful levels of activity against a wide r=ange of pathogenic microorganizsims. In particular, the compounds of the invention may bee active against strains of Swetaphylococcus aureus, Streptopo»coccus pneumoniae, M.- oraxella catarrhalis, Streptococ=cus pyogenes, Haemophilus influenzae, Enterococcus faecalis,
Chlamydia pneumonia .e, Mycoplasma pneumoniae and Legionella pneumophil=a. The compounds of the inwention may also be active agaimst resistant strains, for example erythromycin resistant strains. In particular, the compoumds of the invention may toe active against erythromycin resistant strains of Streptococcus pmeumoniae, Streptococcus joyogenes and Staphylococcus aumreus. :
The compounds of thee invention may therefore be used for treating a variety of" diseases caused by pathogenic rxicroorganisms, in particular bacteria, in human beings and araimals. It will be appreciated thamt reference to treatment includes acute treatment or prophylax-is as well as the alleviation of established symptoms.
Thus, according to anther aspect of the present invention we provide a compound Of formula (I) or a pharmaceutica lly acceptable derivative thereof fox use in therapy.
According to a further aspect of the invention we prov-ide a compound of formu Ja (I) or a pharmaceutically acc=eptable derivative thereof for use in the therapy or prophylaxis of systemic or topical m—icrobial infections in a human or arximal subject.
According to a furthear aspect of the invention we provide the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in the manufacture of a nmedicament . for use in the treatme=nt 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 treatmment of the human or non-huma-n animal body to combat microbial infections comprising administration to a body in need of such treatment of an effec=tive amount of a compound of formula (I) or a pharmaceutiecally acceptable derivative thereof .
While it is pmossible that, for use in therapy, a =ompound of the inventiorn may be administered as the raw chemical it is preferable to pressent the active ingredienst as a pharmaceutical : formulation eg when the agent is in admix—ture with a suitable pha~rmaceutical excipient, diluent or carrier selected with regard to thes intended route of admirnistration and standard pharmaceutical practice.
Accordingly, in one aspect, the present invemmtion provides a pharmace=utical composition or formulatiomn comprising at least one compeound of the invention ower a pharmaceutically acceptable derivative thereof in association with a pharmaceutically acceptable excipient, diluent and/or carrier. The excipient, diluent and/or carrier must be "acceptable" in the sense of being compatible with the other ingredierits of the formulation andi not deleterious to the recipient thhereof.
In anothemr aspect, the invention provides a pharmaceutical composition comprising, as : active ingredient, at least one compound of” the invention or a pharmaceutically acceptable derivative- thereof in association with a jgpharmaceutically accepteable excipient, diluent and/or cammier for use in therapy, and in pearticular, in the treatmert of human or animal subjects rsuffering from a condition susceptible to ameliorationm by an antimicrobial compouncl.
In anothesr aspect, the invention provide s a pharmaceutical commposition comprising a 25 . therapeut ically effective amount of the compounds of the present invention and a pharmaceutically acceptable excipient, dliluent and/or camer (including combinations thereof). .
There is further provided by the present iravention a process of pregparing a pharmaceutical composistion, which process comprises mizxing at least one compou=nd of the invention or a pharmaceutically acceptable derivative the-reof, together with a phar—maceutically acceptable excipien_t, 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 the=refore includes within its scope pharmaceutical compositions comprising a compound of the invention adapted for use in human or veterinary medicine. Such compositions may toe presented for use in a con ventional manner with the aid of one or more suitable exxcipients, diluents and/or carmiers. Acceptable excipients, dilwents and carriers for therape®ic use are well known in the pharmaceutical art, and are described, for example, in Rermington’s Pharmaceutical
Sci_ences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice of pharmaceutical. excipient, diluent and/or carrier c an be selected with regard to the intended route of adsmuinistration and standard pharma ceutical practice. The pharmaeceutical compositions may’ comprise as ~ or in addition to — thee excipient, diluent and/or carrier any suitable binder(s) lutoricant(s), suspending agent(s), coating agent(s), solubilising agzent(s). i
Precservatives, stabilisers, dyes amd even flavouring agents may be provided in the phmarmaceutical composition. Exam ples of preservatives include ssodium benzoate, sorbic acid amd esters of p-hydroxybenzoic aci«d. Antioxidants and suspendin_g agents may be also used .
For some embodiments, the agents of the present invention may also be used in combinatmon w_ith a cyclodextrin. Cyclodextrins are known to form inclusion sand non-inclusion comple=xes with drug molecules. Formation ofa drug-cyclodextrin comple—x 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.
Aas an alternative to direct complexation with the drug the cyclodextrin may be used ass an awmuxiliary additive, e. g. as a camier, diluent or solubiliser. Alpha-, beta- and gammma- o-yclodextrins are most commonly used and suitable examples ax=e described in WO 91/111.72,
VYWO 94/02518 and WO 98/55148.
The compounds of the invention ray be milled using known mi ling procedures such as waset rilling to obtain a particle size eappropriate for tablet formaticon and for other formulation .30 types. Finely divided (nanoparticuilate) preparations of the compounds of the invention mmay be prepared by processes known In the art, for example see Intesmational Patent Application
To. WO 02/00196 (SmithKline Bs eecham).
Claims (22)
1. A compound of formula (I) R® HC AJ. .~CH, HG on Rie on 0 9 gt OR? \ s3 7 11 R20 N R 7 : ot 12 6 CH, E . 3 3 HC" lis HC, 5), > 4 CH CH,’ 14 4 “tring cy 0 F—=CH, 1 2 ht 0] “CO rasa «© 5 ¢ 3 CH, a 3° its, 4 %, R H,C OCH, @ wherein : 10» A is a bivalent radical selected from -C(O)-, -C(O)NH-, -NHC(O)-, —NR7)-CHy-, -CHp-NR)-, -CHINR8R9)~ and -C(=NR10)-; R1 is -OC(O)(CHp)gXR 11; R2 is hydrogen or a hydroxy-1 protecting group; R3 is hydrogen, C1_4alkyl, or C_galkenyl optionally substituted by/ 9 to 10 membered fused bicyclic heteroaryl; R4 is hydroxy, Cy.galkenyloxy optionally substituted by 9 to 10 membered fused bicyclic heteroaryl, or Cj.galkoxy optionally substituted by C1.galkoxy or -O(CHp)NR7R12, RSis hydroxy, or R4 and RS taken together with the intervening atoms form a cyclic group baving the following structure: Ye, 11 o— 12 02 H,C wherein Y is a bivalent radical selected from -CHp-, -CH(CN)-, -O-, -INR13)- and - CH(SR13); R6 is hydrogen. or fluorine; ‘R7 is hydrogen or Cj_galkyl;
R83 and RY are each independently hydrogen, Cj -alkyl, -C(=NRIO)NRI4R1S or -C(O)R14, or R8 and R? together form =CH(CRI4R15)qryl, =aCH(CR14R 15)gheterocyclyl,. =CR4R15 or =C(R1HC(0O)OR14, wherein the alkyl, aryl and heterocyclyl groups are optionally substituted by wap to three groups independently se lected from R16;
RIO is -OR17, Cygalkyl, -(CHp)garyl, (CH=)gheterocyclyl or -(CH2)mO(CHp);OR, wherein each R10 group is optionally substituted by up to three groups independently selected from R16;
R11 js a hetero cyclic group having the following structure:
R®), 0 i” AN w N R% R® or a. rR) Re 0) R'®
R12 js hydrogen or Cy.galkyl; R13 js 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;
R14 and R15 are ea ch independently hydrogen or Cy.galkyl; R16 js halogen, cysano, nitro, trifluoromethyl, azido, -C(O)R21, -C(0)OR21, -OC(O)R2, - OC(O)OR21, .-NRZ2C(0)R23, -C(O)NR22R23, -NR22R.23, hydroxy, C|-galkyl, -S(O)<1- galkyl, Cj_galkoxy, -(CHp)maryl or -(CHp)mheteroaxyl, wherein the alkoxy groupe is optionally substituted by up to three groups independently selected from -NR14R15, halo gen and -OR14, and the= aryl and heteroaryl groups are optionally substituted by up to five groups independently sele cted from halogen, cyano, nitro, trifluoromethyl, azido, -C(O)RZ4, - C(O)OR24, -OC(0ODOR24, NR25C(O)R26, -C(O)NR25R26, -NR25R26, hydroxy, C{.gallky] and Cq_galkoxy; R17 is hydrogen, C}.galkyl, C3-7cycloalkyl, C3_galkeny lor a 5 or 6 membered heterocyclic group, wherein thme alkyl, cycloalkyl, alkenyl and heterocyclic groups are option=ally substituted by up toe three substituents independently selected from optionally substituted =S or 6 membered hetero cyclic group, optionally substituted 5 or 6 membered heteroaryl, -ORZT, - S(0),R?7, -NR27r=28, .CONR27R28, halogen and cyano; R18 is hydrogen, ((0)OR29, -C(O)NHR2S -C(O)CH2NO2, or -C(0)CHSO2R’;
R19 is hydrogen; C 1.4alkyl optionally substituted by hydroxy, cyano, NH,, -NH(C.4alk=yI]) or -N(C1_4alkyl)y; Cp_galkenyl optionally substituted by hydroxy, cyano, NHj, -NH(C;. alkyl) or -N(Cy_g4alkyl)p; Ci4alkoxy, C3_7eycloalkyl, —~NHy, -NH(C] 4alkyl) or -N(C1—
4alkyl)r; (C1 -4alky=1)OC(O)N(C,4alkyl) or optionally substituted phenyl or benzyl; R20 is halogen, C 14alkyl, Cy 4thioalkyl, Cy_galkoxy, -NHp, -NH(Cj.4alkyl) or -N(=C}. qalkyl)s; R21 is hydrogen, C j.jgalkyl, {(CHp)paryl or -(CHp)pheteroaryl; R22 and R23 are- each independently hydrogen, -ORI!4, C1.6alkyl, ~(CHp)qaryl or - (CHp)gheterocyclyd; . R24 js hydrogen, C 1-103lkyl, -(CHg)aryl or -(CHj) heteroaryl; R25 and R20 ares each independently hydrogen, -ORI14, Ci-galkyl, -(CHp)garyl oor - (CHj)sheterocyclyl_; R27 and R28 are ea_ch independently hydrogen, C1_4alky1 or C1 _4alkoxyCj _4alkyl;
R29 is hydrogen or C_galkyl optionally substituted by up to three groups independently selected frorm halogen, Cj.galkoxy, -OC(O)Cj-galkyl and -OC(O»)OCi_galkyl, - (CHp)qheteroc=ycelyl, -(CHp)qbeteroaryl, -(CHp)qar yl, or -(CH3)¢CscycloalkylS R30 is hydrogen, Cy_4alkyl, C3.7cycloalkyl, optionally substituted phenyl or benzyl, acetyl or benzoyl}; - R31 is hydrogen or R20 or R31 and R19 are lint<ed to form the bivalent radical -O(CH2)2-, (CHp)=-NR_7(CHy),-, -OCH;NR’-, -SCH,NR'- _CH,NR CHy-, -CH,OCHE-, -CHpSCH2-, 7 -(CH2)aNR — ; R* is hydrogen, or R32 and R19 are linked to fom the bivalent radical selected from the group —S(CHEa)y-, -NR)(CHy)-, and -O(CHz)p—; R® is C1gal kyl, C.galkenyl or Co_galkynyl; X is -U(CHpDyB(CH)yD-, -U(CH2)yB-R?-, ~U(CH2)yB(CH2)}yD(CHp)v-E-, or “U(CHp)yB(<CHp)D-R*- or X isa grow selected from: ) /\ \ —N N—R33 NE4 —N NR and H N N—R33 H U,B,Dand E are independently divalent radic-als selected from -N(R30)-, -0-,-S(0)z-, - NR30)C(0)-, -C(ONR30)- and N[C(O)R3O 1; W is -C(R3 3)- or a nitrogen atom; aislor2 b is an integ=er from 1 to 3; dis an integser from 1 to 5;
e is an integer from 2 to 4; f,g, h,m, p,q, rand s are each independently integers from O to 4; iis an integer from 1 to 6; j,k, nand z are each independently integers from 0 to 2; tis2or3; v is an integer from 1 to 8; and pharmaceutically acceptable derivatives thereof.
2. A compound accordirag to claim 1 wherein A is -C(OQ)- or -N(R_7)-CHs-.
:
3. A compound accorcling to claim 1 or claim 2 wherein d is 2.
4. A compound accorcling to any one of the preceding claim s wherein v is 2.
5. A compound according to any one of the preceding claims wherein Rll is a heterocyclic group of the following formula: (R*®) ? 18 R X AM w N rR ie or 20 (R } Q R18 N Sw ANS R* . Rr wherein the heterocyclic ds linked in the 6 or 7 position and j, rR"? R19, R® and R* are as
2.5 defined in claim 1.
6. A compound according to claim 5 wherein Rois @ C4alkyl ora C3 _ycycloalkyl.
7. A compound according to claim 5 or claim 6 whesrein Rj; is H.
8. A compound according to any one of claims 5 — "7 wherein Ris is -C(O)OR=29,
9. A compound according to any one of the preceding claims wherein Rj is h=ydrogen, Rs is hydroxy, and Rs is Ihydroxy.
10. A compound according to any one of the preceding claims wherein X is - U(CHy)yB(CHp)yD- or -U(CH2)yB-R>-.
11. A compound maccording to claim 10 wherein U iss -0- and B is -O-.
12. A compound according to claim 1 as defined #n any one of Examples W to 77, or a pharmaceutically acc eptable derivative thereof.
13. Acompound selected from: 47-0-(3-{4-]3-(3-Etlnoxycarbonyl-1-ethyl-4-oxo-1,4-dilhydro-quinolin-6-yl)-prop-~2-ynyl}- piperazin-1-yl}-propdonyl)-azithromycin,
47.0-(3- {4-[3-(3-Btiaoxycarbony!-1-ethyl-4-oxo- 1,4-diThydro-quinolin-6-y1)-prop=yl]- piperazin-1-yl} -prop-ionyl)-azithromycin, 47-0-(3-{4-[3-(3-Etlhoxycarbonyl-1-ethyl-4-oxo-1 .4-di_hydro-quinolin-6-y1)-propm-2-ynyl]- piperazin-1-yl} -propeionyl)-6-O-methyl-erythromycin A3,
47.0-(3-{4-[3-(3-Ethaoxycarbonyl-1-ethyl-4-oxo-1,4-di hydro-quinolin-6-yl)-prog=-2-ynyll- piperazin-1-yl}-propionyl)-1 1-O-methyl-azithromycin., 4”-0-(3-{4-[3-(3-Ethhoxycarbonyl-1 -ethyl-4-0x0-1,4-dmbydro-quinolin-6-yl) -propoyl}- piperazin-1-y1} -propionyl)-1 1-O-methyl-azithromycin_,
47.0-(3-{2-[2-(3-Caarboxy-7-chloro-1-cyclopropyl-4-0-x0-1,4-dihydro-quinolin-&-ylamino)- ethoxyl-ethoxy}-propionyl)-roxythromycin, 47-0-(3-{2-[2-(3-Caarboxy-7-chloro-1-cyclopropyl-4-cexo-1,4-dihydro-quinolin-€5-ylamino)- ethoxy]-ethoxy} -propionyl)-6-0-methyl-erythromycim A,
4” -0-(3-{2-[2-(3-Carboxy-7 -chloro- R cyclopropyl-4-oxo-1 ,4-dihydro—quinolin-6-ylamino)- etlhoxy]-ethoxy}-propionyl)-azithromayein, 4 -0-(3-{2-[2-(3-carboxy-7-chloro-1 -cyclopropyl-4-oxo- 1,4-dihydro—quinolin-6-ylamino)- etthoxy]-ethoxy}-propionyl)-11-O -mesthyl-azithromycin,
4.0-(3-{2-[2«3-Carboxy-1-cyclopropyl-4-oxo-1 4-dihydro-quinolin_-6-ylamino)-ethoxy]- ethoxy} -propionyl)-azithromycin, 4=>-0-(2-{3-[2-(3-Carboxy-7-chloro- 1-cyclopropyl-4-oxo-1 ,4-dihydro-quinolin-6-yloxy)- ehoxy)-propionylamino}-acetyl)-az jthromycin 11,12-cyclic carbonate,
4=°.0-(2-{3-[2-(3-Carboxy-7-chloro— 1-cyclopropyl-4-oxo-1,4-dihydro -quinolin-6-ylamino)- ethoxy}-propionylamino}-acetyl)-azzithromycin 11,12-cyclic carbonate,
4->.0-(2-{3-[2-(3 -Carboxy-6-fluoro—1-cyclopropyl-8-methoxy-4-oxo—1,4-dihydro-quinolin-7- y~lamino)-ethoxy] -propionylamino} —agcetyl)-azithromycin 11,1 2-cyclmc carbonate,
4>.0]2-(3-{2-[2-(3 -Carboxy-6-flucro-1-cyclopropyl-4-oxo-1 ,4-dihy~dro-quinolin-7- y=lamino)-ethoxy]-ethoxy} -propiony>lamino)-acetyl]-azithromycin 11 ,12-cyclic carbonate, : &”-0-[2-(3-{2-[2-(3-Carboxy-7-chkoro-1 -cyclopropyl-4-oxo-1,4-dilmydro-quinolin-6- ywlamino)-ethoxy]-ethoxy} -propiony/lamino)-acetyl]-azithromycin 11 ,12-cyclic carbonate, a”-0-[2-(3-{2-[2-(3-Carboxy-7-chlworo- 1-cyclopropyl-4-oxo0-1 ,4-dih~ydro-quinolin-6- w/lamino)-ethoxy]-ethoxy} -propionsylamino)-acetyl]-azithromycin, 7-0-{2-[3-({2-[3-(6-Ethoxycarborayl-7 -0x0-2,3-dihydro-1H,7H-py-xido[3,2,1-ij]quinolin-9- yl)-prop-2-ynylamino] -ethyl} -propyl-amino)-propionylamino) -acet-yl}-azithromycin, =0-{2-[3-({2-[3-(6-Ethoxycarbonzyl-7 ox0-2,3~dihydro-1H, 7H-pyr-ido[3,2,1 -ij]quinolin-9- =y/1)-propylamino]-ethyl} -propyl-anmino)-propionylamino] -acetyl}-az=ithromycin, ~4-0-(3-{2-[2-(3-Carboxy-7-chloro-1 -cyclopropyl-4-oxo-1,4-dihyd-ro-quinolin-6-ylamino)- «cthoxy]-ethoxy}-propionyl)-9 (E)-e thoxyimino-erythromycin A, 4"-0-[3-(2- {2-[2-(3-Carboxy-7-chYoro-1-cyclopropyl-4-oxo-1,4-dilaydro-quinolin-6- . ~ylamino)-ethoxy]-ethoxy} -ethylamino)-propionyl]-6-O-methyl-ery&thromycin A, To 4-0-03-2-(22(3 -Carboxy-6-flvaoro-1-cyclopropyl-4-oxo-1 ,4-dibbydro-quinolin-7- ylamino)-ethoxy]-ethoxy} -ethylamino)-propionyl]-6-O-methyl-eryshromycin A, 47-0-(3-{2-[2-(3 _Carboxy-7-chlor-o-1-cyclopropyl-4-oxo-1,4-dihyro-quinolin-6-ylamino)- ethoxy]-ethylamino}-propionyl)-6 —O-methyl-erythromycin A,
47.0-(3-{2-[2-(3-Carboxy-6-fluoro-1-cyclopropyl-4-oxo- 1,4-dihydlro-quinolin-7-ylamino)- ethoxy]-ethylamino}-propionyl)-6 -O-methyl-erythromycin A,
4”.0~3-{2-[2-(10-Carboxy-9-oxo--3 ,4-dihydro-2H,9H-1 -oxa-4a-az=a-phenanthren-6- ylamino)-ethoxyl-ethoxy} -propiomyl)-azithromycin,
11—0-Methyl-4’’-O-(3-{2-[3-(3-Caxboxy-1 -ethyl-4-oxo-1 ,4-dihyrdro-quinolin-6-yl)-props-2- yn=yloxy]-ethylamino}-propionyl)-eazithromycin, 11—0-Methyl-4’ »_O~(3-{2-[3-(3-Ca.tboxy-1-ethyl-4-oxo-1,4-dihsadro-quinolin-6-y1)-propoxyl- etbaylamino} -propionyl)-azithromyecin, 4°—0-(3-{2-[2(3-Carboxy-6-fluorc-1-cyclopropyl-4-oxo-1 ,4-dilhydro-quinolin-7-ylamizao)- etbaoxy]-ethoxy} -propionyl)-azithromycin A, 4” —0-(3-{2-[2-(3-Carboxy-7 -chlored-1-cyclopropyl-4-ox0-1,4-di_hydro-quinolin-6-ylami-no)- etkoxy]-ethoxy} -propionyl)-6-O-methyl-erythromycin A 11, 12—cyclic carbamate, 47—~0-(3-{2-[2-(3-Carboxy-6-fluorc-1-cyclopropyl-4-oxo- 1,4-di_hydro-quinolin-7-ylami=no)- etlnoxy]-ethoxy}-propionyl)-6-O-methyl-erythromycin A, 4 -0-(3- {2-[2-(3-Carboxy-7-chlor=o-1-ethyl-4-0xo-1,4-dihydro—quinoline-6-ylamino)- etlhoxyl-ethoxy}-propionyl)-azithreomycin,
. 4 .0-(3- {2-[2-(3-Carboxy-6-fluoreo-1-ethyl-4-oxo-1 ,4-dihydro- quinoline-7-ylamino)- etlhoxy]-ethoxy}-propionyl)-azithromycin, 4=-0-(3-{2-[2«3-Carboxy-1 -ethyl ~4-0xo0-1 ,4-dihydro-quinolines-6-ylamino)-ethoxy]-etHhoxy} - pr-opionyl)-azithromycin, 4=-0-(3-{2-[2-(3-carboxy-7-chlore-1-isopropyl-4-oxo-1,4-dihy=dro-quinoline-6-ylamin=o)- etThoxy]-ethoxy}-propionyl)-azithr-omycin, 4-0-(3-{2-[2-(6-Carboxy-7-0x0-22,3-dihydro-1H,7H-pyrido[3 =2,1-ij]quinolin-9-ylamiro)- etThoxy]-ethoxy}-propionyl)-azithr-omycin, 4 *-0-(3-{2-[2-(6-Carboxy-7-0x0-22,3-dihydro-1H,7H-pyrido[3 52, 1-ij]quinolin-9-ylamiro)- etZhoxy]-ethoxy}-propionyl)-6-O-rxuethyl-erythromycin A, 4 *-0-(3-{2-[2-(3 -Carboxy-7-chlomro-1-cyclopropyl-4-oxo-1,4-Allihydro-quinolin-6-ylam_ino)- et=hoxy]-ethoxy}-propionyl)- 6-O~-propyl-erythromycin A, 47°-0-(3-{2-[2-(3-Carboxy-1-cycleopropyl-4-0xo-1 ,4-dihydro-quuinolin-7-yloxy)-ethoxy—]- et=hoxy}-propionyl)-azithromycin,.
4=".0-(3-{2-[3-(3~carboxy-1-ethy1-4-0x0-1 ,4-dihydro-quinolin_~§-yl)-prop-2-ynyloxy]~ e®hylamino } -propionyl)-6-O-methyl-erythromycin A,
4='.0-(3-{2-[3-(3-Carboxy-1-ethys}-4-0x0-1 A-dihydro-quinolira-6-yl)-propoxy]-ethylarmino} - pmxopionyl)-6-O-methyl-erythromyycin A,
4=.0-(3-{2-[2~(3-Carboxy-1-cycl opropyl-4-oxo-1 ,4-dihydro-quinolin-7-yloxy)-ethoxy~]- esthoxy}-propionyl)-6-O-methyl-esrythromycin A, 4 >’.0-(3-{2-[2-(3 _Carboxy- 1-cyc Jopropyl-4-oxo-1,4-dihydro-cquinolin-7-yloxy)-ethox=y]- ethoxy} -propionyl)-9-ethyloximimo-6-O-methyl-erythromyein _ A,
4°’-O-[ B2-{2-[2-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydrc>-quinolin-6-
ylamino)-ethoxy]-ethoxy}-ethylamino)-propionyl]-9-(1-isopropoxy-cyck ohexyl)oximino-
erythrormycin A,
47-0-(3- -{2-[2-(3-Carboxy-7-chloro-1-cycl opropyl-4-oxo-1,4-dihydro-quiinolin-6-ylamino)- ethoxy] -cthoxy}-propionyl)-9-(1-isopropo=xy-cyclohexyl)oximino-erythr-omycin A,
4”-0-(3- -{2-[2~(3-Carboxy-1-cyclopropyl-c3¥-0x0-1,4-dihydro-quinolin-7—yloxy)-ethoxy]-
ethoxy} -propionyl)-9-(1-isopropoxy-cyclo hexyl)oximino-erythromycin _A, 4°°-0-(3-{2-[2-(3-Carboxy-7-chloro-1-cyc lopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)- ethoxy] -ethoxy}-propionyl)-9-oxime eryth romycin A,
4°°-0-(3-{2-[2-(3-Carboxy-1-cyclopropyl- 4-0x0-1,4-dihydro-quinolin-7 —yloxy)-ethoxy]- ethoxy }- -propionyl)-9-oxime erythromycin A,
4”’-0-[3-(2-{2-[2-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydreo-quinolin-6- ylamino)-ethoxy]-ethoxy}-ethylamino)-propionyl}-9-oxime erythromycin A, 4°’-0-(3-{2-[2-(3-Carboxy-1-cyclopropyl- 7-methoxy-4-oxo-1,4-dihydrc>-quinolin-6-
ylamino)-ethoxy]-ethoxy}-propionyl)-azitkaromycin, 4”’-0-(3-{2-[2-(3-Carboxy-1-cyclopropyl- 7-dimethylaminc-4-oxc-1,4-dlihydro-quinolin-6- ylamino)-ethoxy]-ethoxy} -propionyl) azithhromycin,
4"-0-(3 -{2-[3-(3-carboxy-1-ethyl-4-ox0-1 _4-dihydro-quinolin-6-yl)-progpoxy]-ethoxy}- propion_yl)-azithromycin,
4"-0-(3 -{2-[3-(3-carboxy-1-ethyl-4-0x0-1 _4-dihydro-quinolin-6-yl)-progroxy]-ethoxy}- propion_yl}-6-O-methyl erythromycin A, 9-Ethyleoximino-4"-O-(3-{2-[3-(3-carboxy—1-ethyl-4-0x0-1,4-dihydro-quainolin-6-yl)- propoxyy]-ethoxy} -propionyl)-erythromycim A,
4"-0-(3 -{2-[3-(3-Carboxy-1-ethyl-4-oxo0-1 ,4-dihydro-quinolin-6-yl)-pro poxyl-ethoxy}-
propion-yl)-6-O-methyl-8a-aza-8a-homoerysthromycin A, }
4"-0-(3 -{2-[3-(3-Carboxy-1-ethyl-4-oxo-1 ,4-dihydro-quinolin-6-yl)-pro poxy}-ethoxy}- propion=yl)-roxythromycin,
4“-0-(3 -{2-[2-(3-Carboxy-7-chloro-1-cycl opropyl-4-0xo-1,4-dihydro-quainolin-6-yloxy)- ethoxy]—ethoxy}-propionyl)-azithromycin,
4"-0-(3 -{2-[3-(3-Carboxy-1-ethyl-4-ox0-1 4-dihydro-quinolin-6-yl)-pro—poxy]-ethoxy}- propionzyl)-6-O-methyl-11-desoxy-11-(R)-mmethylamino-erythromycin A. 11,12-carbamate, 4"-0-(3—{2-[3-(3-Carboxy-1-cyclopropyl-4&-oxo-1,4-dihydro-quinolin-6-—yl)-propoxy]- ethoxy} -propionyl)-azithromycin,
4"-0-(3-{22-3-(3-Carboxy-4-0x0-1,4-dihyciro-quinolin-6-yl)-propox__yl-ethoxy}-propiony!)- azithromycin, 4"-O-(3-{2-[3-(3-Carboxy-4-0x0-1-propyl —1,4-dihydro-quinolin-6-y=1)-propoxy}-ethoxy}- propionyl) -azithromycin, : 4“-O-[3-(22-{2-[2-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dih—ydro-quinolin-6- ylamino)-esthoxy]-ethoxy}-ethylamino)-preopionyl]-azithromycin, 4%-0-[3-(22-{2-[2-(3-Carboxy-6-fluoro-1-c-yclopropyl-4-oxo-1,4-dihydro-quinolin-7- ylamino)-e=thoxy]-ethoxy}-ethylamino)-preopionyl}-azithromycin, 4%-0-(3-{2{2-(3-Carboxy-7-chloro-1-cyc lopropyl-4-oxo-1,4-dihydmro-quinolin-6-ylamino)- ethoxy]-et"hylamino}-propionyl)-azithrom_ycin, 4“-0-(3-{=2:[2-(3-Carboxy-6-fluoro-1-cyc Ropropyl-4-oxo-1,4-dihydr-o-quinolin-7-ylamino)- ethoxy]-etZhylamino }-propionyl)-azithrom-ycin, 4“-0-[3-(2-{2-[3-(3-Carboxy-1-ethyl-4-ox0- 1,4-dihydro-quinolin-6—yl)-prop-2-ynyloxy}- ethoxy} -e®hylamino)-propionyl]-azithrom —ycin, 4“-O-[3-(2-{2-[2-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dibm ydro-quinolin-6- ylamino)-esthoxy]-ethoxy} -ethylamino)-pr-opionyl]-6-O-methyl erytlhromycin A, 4“-0-(3-{=2-[2-(3-Carboxy-7-chloro-1-cyc lopropyl-4-oxo-1,4-dihydmro-quinolin-6-ylamino)- ethoxy]-et"hoxy}-propionyl)-6-O-methyl-&a-aza-8a-homoerythromyecin A,
4“.0-3-(2-{2-[2-(3-Carboxy-7-chloro-1-cyclopropyl-4-0x0-1,4-diha ydro-quinolin-6- ylamino)-thoxy]-ethoxy}-ethylamino)-pr-opionyl]-azithromycin,
4“.0-[3-(2-{[2-(3-Carboxy-7-chloro-1-cy<lopropyl-4-oxo-1,4-dihyro-quinolin-6-ylamino)- ethyl]-met-hyl-amino }-ethoxy)-propionyl]—azithromycin,
4%.0-(3-{2-[2-(3-Carboxy-1-cyclopropyl-4-0x0-1,4-dihydro-quinolmin-6-yloxy)-ethoxy]- ethoxy }-pmropionyl)-azithromycin, 4%-0-(3-{2-[2-(3-Carboxy-7-chloro-4-oxom-1,4-dihydro-quinolin-6-y=loxy)-ethoxy]-ethoxy}- propionyl)e -azithromycin,
. 4%-0-(3-{2-[2-(3-Carboxy-7-chloro-4-oxow-1,4-dihydro-quinolin-6~y=lamino)-ethoxy]- ethoxy}-pmropionyl)-azithromycin, 4"-0-{[6-C {2-[(2-Aminoethyl)(methyl)am inoJethyl}thio)-1-ethyl-4-=ox0-1,4-dihydro-3- - quinolinec=arboxylic acid]propionyl}-6-O-muethylerythromycin A,
4".0-{[6-C {2-[(2-Aminoethyl)(methyl)am-ino]ethyl} thio)-1-ethyl-4-e0x0-1,4-dihydro-3- quinolinec=arboxylic acid]propionyl}-azith xomycin, 4-0-{[6-C {2-[(2-Aminoethyl)oxy]ethyl} o>xy)-1-ethyl-4-0x0-1,4-dilydro-3- quinolinec=arboxylic acid]propionyl}-6-O-amethylerythromycin A,
47.0-{[6—({2-[(2-Aminoethyl)oxy]ethyl} oxy)-1-ethyl-4-oxo-1,4-dihydro-3- quinoline=carboxylic acid]propionyl}-O-(9E )-methoxymethyloximino erythromycin A, 47-0-{[6—~({2-[(2-Aminoethyl)oxy]ethyl} oxzy)-1-ethyl-4-oxo-1 ,4-dihydro-3- quinoline=carboxylic acid]propionyl}-O-(9E-)-hydroximino erythromycin A, 4”-0-{[1—FEthyl-6-(3-{[2-Aminoethyljoxy} goropyl)-4-oxo-1 ,4-dihydro-3-quimolinecarboxylic acid] Jprcopionyl}-O-(9E)-hydroximino erythromycin A, 47-0-{[1 -Ethyl-6-(3-{[2-(methylamino)eth-yl]oxy}propyl)-4-oxo-1,4-dihyds=o-3- ‘quinoline=carboxylic acid] Ipropionyl}-O-(S*E)-hydroximino erythromycin A_, and 47-0-{[6 :-({2-[(2-aminoethyl)oxy]ethyl} ox y)-1-ethyl-4-0xo-1,4-dihydro-3- quinoline=carboxylic acid]propionyl} -6-O-methylerythromycin A, or a phar-maceutically acceptable derivatives thereof.
14. Aw process for the preparation of a compound as claimed in claim 1 wwhich comprises: a) reactirag a compound of formula (IT) r® HC A-_J.wCH, HE on Rien,” 0% 8] OR? AV 11 ) N R 7 RQ w= 12 6\'n CH, EA 3 H,C' Jz HC, 5). z 4 CH,CHy™" 14 4] “try me LE al . al 0 o CH, “, o CH (0) [eo LITTP™ eg 5 3 CH, >» 4 . 3 ‘4, 12, %, ’ OH HC OCH, HOC(O)(CHa)gX?R 112 (In Im with a suitable activated derivative of the acid (IIT), wherein X2 and R112 are X and R11 as defined an claim 1 or groups convertible to» X and RIL to produce a compound of formual (I) wherein dis an integer from 1 to 5; b)reactimng a compound of formula (V)
= H,C A WwCH, HG cn din, 0 8 BET \ 7 R hn 11 R, 2 N Q rR 7 R £3 : ot 12 61" CH, * ) 3 v HCY lia HC sh, z 4 ow -~., ‘tay, tw, 4 , CH,CH; O14 ney o 3 CH, 1 3), 0
[0] “CO tn, (tc pa CH, CHg ra fo) gn “tity, r 4 o—A JL % (CH,n H,C OCH, MV) wit a compound of formula XaRrila (Iv), wherein Rlla js R11 as defined in claim 1 ora : 5 group convertible to RI! and Xa is ~U(CHp)yB- or a group con=vertible to -U(CHp)B- in which U is -N(R30)-, and L is suitable leaving group, to produce aa compound of formula (I) : whe: rein U is -N(R30)-; or ¢) reacting a compound of formula (V1), with a compound of formula xara (1v), rE H,C A CH, HG om
Ri. fo ® OR’ \ / : 1 2 N R 7 RO, o112 61" CH, Ee HC" . 3 H5C, 5 “ra, 2¢ 4 :CH,CH A 14 ’, tiny, LT 1 5
) 3. 0 o CH,
[0] “Qin, 1 o 3 CH, CH, > 4 (en) kL rey, R % oN ~ : H,C OCH, (vin) wherein R112 is R11 as defined ire claim 1 or a group convesrtible to Rll and X28 is - U(«CHy),B- or a group convertible to -U(CHp)yB- in which UW is N(R30)-, to produce a compound of formula (I) wherein d is 2 and U is -N(R30)-, and thewmeafter. if required, subjecting the resulting compound to one or more of the following operat®ons: i) removal of the protecting group R2, ii) converssion of XaR 11a 1p XR1 1 iii) conver sion of BaR11a to BR11, and iv) conver sion of the resultant compound of formula (I) into a pharmacesutically acceptable derivative thereof.
15. A compound as claimed in any one of claims 1 to 13 for use in ther-apy.
16. The use of a compound as claimed in any one of claims 1 to 13 in the manufacture of a medicamnent for use in the treatment or prophylaxis of systemic or topical microbial infections Zin a human or animal body.
17. The use of a compound as claimed in any one of claims 1 to 13 for use in the treatment or prophylaxis of systemic or topical microbial infections in aw human or animal body.
18. A pharmaceutical composition coxnprising at least one compound as claimed in any one of claims | to 13 in association with a pharmaceutically acceptable excipient, diluent and/or carrer.
19. A compound according to claim 1 or 13, substantially as herein described and exemplified.
20. A p=ocess according to claim 14, suabstantially as herein described ard exemplified.
21. Use of a compound according to cl aim 16 or 17, substantially as hemein described and exemplified.
22. A pharmaceutical composition according to claim 18, substamtially as herein described ard exemplified. AMENDED S HERE?
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