WO1999035157A1 - Novel erythromycin derivatives - Google Patents

Novel erythromycin derivatives Download PDF

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Publication number
WO1999035157A1
WO1999035157A1 PCT/IB1998/002100 IB9802100W WO9935157A1 WO 1999035157 A1 WO1999035157 A1 WO 1999035157A1 IB 9802100 W IB9802100 W IB 9802100W WO 9935157 A1 WO9935157 A1 WO 9935157A1
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WO
WIPO (PCT)
Prior art keywords
compound
alkyl
formula
propyl
substituted
Prior art date
Application number
PCT/IB1998/002100
Other languages
French (fr)
Other versions
WO1999035157B1 (en
Inventor
Yong-Jin Wu
Original Assignee
Pfizer Products Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to IL13672198A priority Critical patent/IL136721A0/en
Priority to PL98341647A priority patent/PL341647A1/en
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Priority to EA200000600A priority patent/EA200000600A1/en
Priority to AU15015/99A priority patent/AU759019B2/en
Priority to JP2000527553A priority patent/JP2002500231A/en
Priority to HU0100566A priority patent/HUP0100566A3/en
Priority to EP98959099A priority patent/EP1044208A1/en
Priority to BR9812992-9A priority patent/BR9812992A/en
Priority to CA002317131A priority patent/CA2317131C/en
Priority to SK977-2000A priority patent/SK9772000A3/en
Priority to KR1020007007378A priority patent/KR20010033822A/en
Priority to NZ504987A priority patent/NZ504987A/en
Publication of WO1999035157A1 publication Critical patent/WO1999035157A1/en
Publication of WO1999035157B1 publication Critical patent/WO1999035157B1/en
Priority to IS5527A priority patent/IS5527A/en
Priority to NO20003346A priority patent/NO20003346L/en
Priority to HR20000444A priority patent/HRP20000444A2/en
Priority to BG104640A priority patent/BG104640A/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Definitions

  • This invention relates to novel erythromycin derivatives that are useful as antibacterial agents and antiprotozoa agents and for other applications (e g., anticancer, atherosclerosis, oast ⁇ c motility reduction, etc ) in mammals, including man, as well as in fish and birds
  • This invention also relates to pharmaceutical compositions containing the novel compounds and to methods of treating bacterial infections and protozoa infections and in mammals, fish and birds by administering the novel compounds to mammals, fish and birds requiring such treatment.
  • Macrolide antibiotics are known to be useful in the treatment of a broad sprectrum of bacte ⁇ al infections and protozoa infections in mammals, fish and birds
  • Such antibiotics include va ⁇ ous derivatives of erythromycin A such as azithromycin which is commercially available and is referred to in United States patents 4,474,768 and 4,517,359, both of which are incorporated herein by reference in their entirety
  • Additional macrolides are referred to in U.S patent application serial number 60/063676, filed October 29, 1997 (Yong-Jin Wu), U.S. application serial number 60/063161, filed October 29, 1997 (Yong-Jin Wu), U S.
  • R is an alpha-branched C 3 -C B alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C 6 -C ⁇ , cycloalkyl group wherein the alkyl group is an alpha-branched C 2 -C 3 alkyl group; a C 3 -C 8 cycloalkyl or C 5 -C a cycloalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C C 4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more 0,-0 a 'M groups or halo atoms; or R is phenyl which may be optionally substituted with at least one
  • X 1 is 0, S or -CH 2 -, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d 5; or R is CH 2 R 2 , wherein R 24 is H, C r C 8 alkyl, C 2 -C ⁇ alkenyl, C r C ⁇ alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms, or a C 3 -C 8 cycloalkyl or C 5 -C 8 cycloalkenyl either or which may be optionally substituted by methyl or one or more 0,-Cialkyl groups or halo atoms; or a 3 to 6
  • R" is H or acyl of an organic acid of up to 18 carbon atoms.
  • the present invention further relates to compounds of the formula
  • n is selected from an integer ranging from 1 to 3
  • p is selected from an integer ranging from 1 to 3
  • q is 0 or 1
  • Z is a 4-10 membered heterocyc c or C 6 -C 10 aryl, wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -C(0)OR , -O , ⁇ o , 0,-0, 0 alkanoyl, halo, nitro, cyano, R , 4-10 membered heterocyclic, C 6 -C 10 aryl, -C(0)NR 1U R , -NHC(0)R 1D , -NHC(0)NR lu Fr, -NR I 1 D 0 DRI"I. -S CDRI-
  • R 4 is H or acyl of an organic carboxylic acid of up to 18 carbon atoms
  • R 5 and R ⁇ are each independently selected from H, C r C ⁇ alkyl, halogen- and R 5 and R 6 may each independently vary when m is greater than 1;
  • R 7 and R ⁇ are each independently selected from H, 0,-0, 8 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, 5 and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)OR 10 , - OR 10 , 0,-0, 0 alkanoyl, halo, nitro, cyano, R 10 , 4-10 membered heterocyclic, C 6 -C 10 aryl, - NR 10 R 11 , -C(O)NR 10 R 11 , -NHC(0)R 10 , -NHC(0)NR 1D R 11 , -SR 10 , -S(0)R 10 , -S0 2 R 10 and - SO ? ISlR 1P R"
  • the present invention further relates to compounds of the formula
  • R is an alpha-branched C 3 -C ⁇ alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C 3 -C 8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C 2 -C 3 alkyl group; a C 3 -C B cycloalkyl or Cg-Cg cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C 4 alkyl groups or halo atoms, or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C 4 alkyl groups or halo atoms; or R is phenyl which may be optionally
  • X 1 is 0, S or -CH-r, a, b, c, and d are each Independently selected from an integer ranging from 0 to 2 and a + b + e + d ⁇ S;
  • n is selected from an integer ranging from 1 to 3
  • p is selected from an integer ranging from 1 to 3
  • q is 0 or 1
  • n is selected from an integer ranging from 1 to 3
  • p is selected from an integer ranging from 1 to 3
  • q is 0 or 1
  • R 1 , R 2 , R 7 , and R 8 are each independently selected from H, C,-C, 2 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)OR 1Q , -OR 10 , 0,-0,- alkanoyl, halo, nitro, cyano, R 1D , 4-10 membered heterocyclic, C a -C l0 aryl, -C(O)NR 10 R 11 , -NHC(0)R 1D , -NHC(O)NR 10 R 11 , -NR 10 R 11 , -SR 10 , -S(0)R 10 , -S0 2 R 10 and -SO ⁇ R ⁇ R 11 , where the bond between C9 and the nitrogen to which 09 is linked is a double bond, R 1 s not existent, and R 2 is OR 7
  • the present invention further relates to compounds of the formula
  • R is an alpha-branched C3-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or C5-C8 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C1-C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C1-C4 alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with at least one
  • X 1 is 0, S or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d ⁇ 5; or R is CH 2 R 2 ⁇ , wherein R 2 * is H, C ⁇ -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C a alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of sa d alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms, or a C 3 -C 8 cyeloalkyl or C 5 -C a cycloalkenyl either or which may be optionally substituted by methyl or one or more C,-C 4 alkyl groups or hal
  • R 3 , R 2 , R 7 , and R B are independently selected from H, C,-C, ⁇ alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -0(O)OR 10 ,
  • R 10 and R 11 are each independently selected from H, C,-C, 0 alkyl; and R 4 is H or acyl of an organic carboxylic acid of up to 8 carbon atoms.
  • the present invention further relates to compounds of the formula
  • R is an alpha-branched C 3 -C 8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups, a C B -C 8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C 2 -C 5 alkyl group, a C 3 -C 8 cycloalkyl or C 3 -C 8 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C 4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C 4 alkyl groups or halo atoms, or R is phenyl which may be optionally
  • X 1 is O, S or -CH 2 -, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d ⁇ 5, or R is CH 2 R", wherein R 24 is H, C,-C professionalkyl, C 2 -C e alkenyl, C 2 -C B alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms or a C a -C(,cycloalkyl or C ⁇ -C ⁇ cycloalkenyl either or hich may be optionally substituted by methyl or one or more C,-C 4 alkyl groups or halo atoms, or
  • Z is a 4-10 membered heterocyclic or C ⁇ -C, 0 aryl, wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -C(0)OR 10 , -OR 10 , C,-C, 0 alkanoyl, halo, nitro, cyano, R 10 , 4-10 membered heterocyclic, C ⁇ -C 10 aryl, -C(O)NR 10 R 11 , -NH0(O)R 10 , -NHC(0)NR 1Q R u , -NR 10 R 11 , -SR 10 -S(0)R 10 -S0 2 R 10 and -S0 2 NR 1D R 11 ,
  • R 5 and R ⁇ are Independently selected from H, C C 5 alkyl, halogen and R 6 and R 6 may each vary independently when m is greater than 1
  • R 2 , R 7 , and R a are each independently selected from H, C,-C 18 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)OR 10 , -OR 10 , C,-C,o alkanoyl, halo, nitro, cyano, R 10 , 4-10 membered heterocyclic, C ⁇ -C, Q aryl, -CfOJNR ⁇ R 11 .
  • R* is H or acyl of an organic carboxylic acid of up to 18 carbon atoms
  • the preferred compounds of formula 1 include those selected from the group consisting of the compound of formula 1 wherein R is Me and R* is H, the compound of formula 1 wherein R is n-butyl and R 4 is H; the compound of formula 1 wherein R is MeS and R 4 is H, the compound of formula 1 wherein R is EtS and R 4 is H; the compound of formula 1 wherein R is cyclopropyl and R 4 ts H, the compound of formula 1 wherein R is cyclobutyl and R 4 is H, the compound of formula 1 wherein R is cyclopentyl and R" is H; and the compound of formula 1 wherein R is cyclohexyl and R 4 is H.
  • the preferred compounds of formula 2 include those selected from the group consisting of the compound of formula 2 wherein R is Me, R 4 16 H, X is NH and R 3 is 3-qu ⁇ nol ⁇ n-4-yl- propyl, the compound of formula 2 wherein R is Me, R 4 is H, X is CH 2 and R 3 is 3-qu ⁇ olin-4-yl- propyl, the compound of formula 2 wherein R - Me, R* Is H, X Is NH and R 3 is 3-(4- ⁇ henyl- ⁇ m ⁇ dazol-1 -yl)-propyl; the compound of formula 2 wherein R is Me, R 4 is H, X is CH 2 and R 3 is 3-(4-phenyl- ⁇ m ⁇ dazol-1-yl)-propyl, the compound of formula 2 wherein R is Me, R is H, X is NH and R 3 Is 3-(4 ⁇ (3-pyridinyl)- 1 H-lmldazol-1 -yl)
  • R 3 is 3-(4-phenyl- ⁇ m ⁇ dazol-1-yl)-propyl, the compound of formula 2 wherein R is n-butyl, R 4 is H, X is NH and R a is 3-(4-(3- py ⁇ diny l)-1 H- ⁇ m ⁇ dazol-1 -yl)propyl; the compound of formula 2 wherein R is n-butyl, R 4 is H, X is CH 2 and R 3 is 3-(4-(3- py ⁇ d ⁇ nyl)-1H-im ⁇ dazol-1-yl)propyl; the compound of formula 2 wherein R is MeS, R 4 is H, X is NH and R 3 is 3-qu ⁇ nolin-4-yl- propyl; the compound of formula 2 wherein R is MeS, R 4 is H; X is CH 2 and R 3 is 3-qu ⁇ nolin-4-yi- propyl; the compound of formula 2 wherein R is MeS, R 4 is
  • X is NH and R 3 is 3-(4-phenyl- imidazol-1-yl)-propyl; the compound of formula 2 wherein R is EtS, R 4 is H, X is CH 2 and R 3 is 3-(4-phenyl- ⁇ midazol-1-yl)-propyl; the compound of formula 2 wherein R is EtS, R 4 is H, X is NH and R 3 is 3-(4-(3-pyridinyl)- 1H- ⁇ midazol-1-yl)propyl; the compound of formula 2 wherein R is EtS, R 4 is H, X is CH 2 and R 3 is 3-(4-(3- ⁇ yrid ⁇ nyl)-lH-im ⁇ dazol-1-yl)propyl; the compound of formula 2 wherein R is cyclopropyl, R 4 is H, X is NH and R 3 is 3- qui ⁇ ol ⁇ n-4-yl- ⁇ ropy
  • R ⁇ is H, X is NH and R 3 is 3-(4- phenyl-imidazol-1-yl)-propyl, the compound of formula 2 wherein R is cyclohexyl, R 4 is H, X is CH 2 and R a is 3-(4- phenyl-imidazol-1-y
  • the preferred compounds of formula 3 wherein the bond between C-9 and the nitrogen to which C-9 is connected is a double bond include those selected from the group consisting of: the compound of formula 3 wherein R is Me, R 4 is H, X is NH, R 3 is 3-quinolin-4-yl-propyl and R 2 is OMe; the compound or formula 3 wnereln R is Me, R" is H, X is NH, R 3 is 3-(4- ⁇ henyl-im ⁇ dazol-
  • R 1 is H and R 2 is Me, Et, or n-Pr, the compound of formula 3 wherein R is Me, R 4 is H, X is NH, R 3 is 3-(4-(3- ⁇ y ⁇ d ⁇ qyl)-1 H- ⁇ m ⁇ dazol-1-yl)propyl, R 1 Is H and R 2 Is Me, Et, or ⁇ -Pr, the compound of formula 3 wherein R is n-butyl, R 4 is H, X is NH, R 3 is 3-qu ⁇ nol ⁇ n-4-yl- propyl R 1 is H and R 2 is Me, Et, or n-Pr, the compound of formula 3 wherein R is n-butyl, R* is H, X is NH.
  • R 3 is 3-(4-phenyl- ⁇ m ⁇ dazol-1-yl)-propyl, R 1 is H and R 2 is Me, Et, or n-Pr, the compound of formula 3 wherein R is n-buty! R* is H.
  • X is NH
  • R 3 is 3-(4-(3-pyndinyl)- 1H- ⁇ m ⁇ dazol-1-yl)propyl
  • R 1 is H and R 2 is Me, Et, or n-Pr
  • the compound of formula 3 wherein R is MeS, R 4 is H, X is NH, R 3 is 3-quinolin-4-yl- propyl, R 1 is H and R 2 is Me, Et, or n-Pr
  • the compound of formula 3 wherein R is MeS, R 4 is H, X is NH, R 3 is 3-(4-(3- ⁇ y ⁇ dinyl)- lH-irnidazol-1-y
  • the preferred compounds of formula 5 include those selected from the group consisting ot the compound of formula 5 wherein R is Me, R 4 is H, R 3 is 3-quinol ⁇ n-4-yl-pro ⁇ yl, R 7 is H, R ⁇ is H and R 2 is H, Me, or Et; the compound of formula 5 wherein R is Me, R 4 is H, R s is 3-(4-phenyl-im ⁇ dazol-1-yl)- propyl, R 7 is H, R B is H and R 2 is H, Me, or Et; the compound of formula 5 wherein R is Me, R 4 is H, R 3 is 3-(4-(3-pyr ⁇ dinyl)-1H- ⁇ m ⁇ dazol- 1-yl)propyl, R 7 is H, R ⁇ is H and R 2 is H, Me, or Et; the compound of formula 5 wherein R is n-butyl, R 4 is H, R 3 is 3-qu ⁇ nolin ⁇ 4-yl-propyl, R 7 is H, R ⁇ is
  • R 8 is H and 2 is H, Me, or Et; the compound of formula 5 wherein R is MeS, R 4 is H, R 3 is 3-(4- ⁇ henyl-imidazol-1-yl)- propyl, R 7 is R ⁇ is H and R 2 is H, Me, or Et, the compound of formula 5 wherein R Is MeS, R 4 is H, R 3 is 3-(4-(3- ⁇ y ⁇ dinyl)-1H- ⁇ midazol-1-yDpropyl, R 7 is H, R ⁇ is H and R 2 is H, Me, or Et; the compound of formula 5 wherein R is EtS, R 4 is H, R 3 is 3-quinolin-4-yl-propyl, R 7 is H, R a is H and R 2 is H, Me, or Et; the compound of formula 5 wherein R is EtS, R 4 is H, R 3 is 3-(4-phenyhmldazol-1-yt) ⁇ propyl, R 7 Is H, R 8 I
  • R 7 is H, R ⁇ is H and R 2 is H, Me, or Et; the compound of formula 5 wherein R is cyclopropyl, R 4 is H, R 3 is 3-quinol ⁇ n-4-yl-propyl, R 7 is H, R ⁇ is H and R !
  • R 3 is 3-quinolin-4-yl-propyl, R 7 is H, R 8 is H and R 2 is H, Me, or Et; the compound of formula 5 wherein R is cyclobutyl, R 4 is H, R 3 is 3-(4-phenyl- ⁇ m ⁇ dazol-l- yl)-propyt, R 7 is H, R 8 is H and R 2 is H, Me, or Et, the compound of formula ⁇ wherein R is cyclobutyl, R 4 is H, R 3 is 3-(4-(3-pyr ⁇ dinyl)-1 H- ⁇ m ⁇ dazol-1-yl)propyl, R 7 is H, R 8 is H and R 2 is H, Me, or Et, the compound of formula 5 wherein R is cyclopentyl, R 4 is H, R 3 is 3-qu ⁇ nolin-4-yl-propyl, R 7 is H, R ⁇ is H and R 2 is H, Me, or Et, the compound of formula 5 wherein R is cyclopen
  • R 7 is H, R e is H and R 2 is H, Me, or Et, the compound of formula 5 wherein R is cyclohexyl, R 4 is H, R 3 is 3-(4- ⁇ henyl- ⁇ m ⁇ dazol-l- yl)-propyl, R 7 ⁇ s H, R 8 is H and R 2 is H, Me, or Et, and the compound of formula 5 wherein R is cyclohexyl, R 4 is H, R 3 Is 3-(4-(3-pyrld ⁇ nyl)- ⁇ H- lmldazol-1-yl)propyl, R 7 is H, R ⁇ IS H and R 2 is H, Me or Et
  • the invention also relates to a pharmaceutical composition for the treatment of a bacte ⁇ al infection or a protozoa infection in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of formulas 1_, 2, 3, 4 or 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier
  • the invention also relates to a method of treating a bacterial infection or a protozoa infection in a mammal, fish, or bird which comp ⁇ ses administering to said mammal, fish or bird a therapeutically effective amount of a compound of formula 1_, 2, 3, 4 or 5 or a pharmaceutically acceptable salt thereof
  • the invention also relates to a process for preparing a compound of the formula
  • R is methyl, an alpha-branched C 3 -C 8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C 3 -C 8 cycloalkyl group wherein the alkyl group is an alpha-branched c r c B alkyl group, a C 3 -C a cycloalkyl or C S -C B cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C 4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocychc nng which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C r C 4 alkyl groups or halo atoms, or R is phenyl which
  • X 1 is 0, S or -CH 2 -, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d ⁇ 5, and
  • R 4 is H or acyl of an organic acid of up to 18 carbon atoms, which comp ⁇ ses treating a compound of the formula
  • R and R 4 are as defined in formula l ⁇ with a hydrolyzing agent.
  • the invention also relates to a process for preparing a compound of the formula
  • R, R 3 , * and R s are as defined in formula 2 and X in formula 2 is -NR 6 which comprises treating a compound of the formula
  • R and R 4 are as defined in formula 2, with an alkylating agent.
  • the Invention also relates to a process for preparing a compound of the formula
  • R, R 3 , R 4 , R £ and R 6 are as defined in formula 2 and X in formula 2 is -(CR 5 R ⁇ ) g - which comprises treating a compound of the formula
  • R is as defined in formula 2 with a compound of the formula R a - C(R 6 R 6 ) g -NH 2l wherein g is 0 or 1 and R*, R s and R ⁇ are as defined in formula 2
  • the invention also relates to a process for preparing a compound of the formula
  • R and R 4 are as defined in formula 2, by treating a compound of the formula
  • R is as defined in formula 2, with NH 2 NH 2 .
  • the invention also relates to a process for prepa ⁇ ng a compound of the formula
  • R is as defined in formula 2 which comprises treating a compound of the formula
  • R is as defined in formula 2 with carbonyldiimidazole.
  • the invention also relates to a process for preparing a compound of the formula
  • R is as defined in formula 2 which comprises treating a compound of the formula
  • R is as defined in formula 2 with a base.
  • the invention also relates to a process for preparing a compound of the formula
  • R is as defined in formula 2 which comprises treating a compound of the formula
  • R is as defined in formula 2 with an oxidizing agent.
  • the invention also relates to a process for preparing a compound of the formula
  • R is as defined in formula 2 which comprises treating a compound of the formula
  • the invention also relates to a process for preparing a compound of the formula
  • R is as defined in formula 2 which comprises treating a compound of the formula
  • R is as defined in formula 2, with trichloromethylisocyanate, ethylene carbonate or caronyyldi ⁇ midazole.
  • the invention also relates to a process for preparing a compound of the formula
  • R is as defined in formula 2 which comprises treating a compound of the formula
  • R is as defined in formula 2 with an acylating agent
  • the invention further relates to a compound of the formula
  • R is an alpha-branched C 3 -C B alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups, a Cs-C 8 cycloalkyl group wherein the alkyl group is an alpha-branched C 2 -C 5 alkyl group; a C 3 -C 8 cycloalkyl or C 3 -C 8 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C 4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C 4 alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with at
  • X 1 is O, S or -CH 2 -, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d ⁇ 5; or R is CH 2 R 24 , wherein R 24 is H, C,-C professionalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms; or a C 3 -C 8 cycloalkyl or C 3 -C 8 cyc
  • R 4 is H or acyl of an organic acid of up to 18 carbon atoms.
  • the invention also relates to a compound of the formula
  • R is an alpha-branched C 3 -C 8 alkyl, alkenyl, alkynyl alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups, a C 5 -C 8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C 2 -C 5 alkyl group, a C 3 -C a cycloalkyl or C 5 -C a cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C 4 alkyl groups or halo atoms, or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C 4 alkyl groups or halo atoms; or R is phenyl which may be optional
  • alkylthio groups, halogen atoms, hydroxyl groups, t ⁇ fluorornethyl, and cyano, or R may be with a formula (a) as shown below wherein X 1 Is O, S or -CH 2 -, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d 5;
  • n is selected from an integer ranging from 1 to 3
  • p is selected from an integer ranging from 1 to 3
  • q is 0 or 1
  • R 10 is CH 2 R 24 , wherein R 24 is H, C,-C a alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo
  • Z is a 4-10 membered heterocyclic or C 6 -C, 0 aryl, wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -C(0)OR , -OR , 1 1 - , C,-C, 0 alkanoyl, halo, nitro, cyano, R 10 , 4-10 membered
  • R 4 is H or acyl of an organic carboxylic acid of up to 18 carbon atoms
  • R s and R 6 are each independently selected from H, C,-C 6 alkyl, halogen and R s and R 6 may each independently vary when m is greater than 1;
  • R 7 and R ⁇ are each independently selected from H, C,-C, 8 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting Of -C(0)OR 1 °, - OR 10 , C.-C-o alkanoyl, halo, nitro, cyano, R 10 , 4-10 membered heterocyclic, C 8 -C, 0 aryl, -
  • the invention further relates to a compound of the formula
  • R is an alpha-branched C 3 -C 8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C 5 -C 8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C 2 -C 5 alkyl group; a C 3 -C B cycloalkyl or C 5 -C 8 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C 4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C 4 alkyl groups or halo atoms; or R is phenyl which may be optionally
  • X 1 is O, S or -CH 2 -, a, b, c, and d are each independently selected from an Integer ranging from 0 to 2 and a + b + e + d 5;
  • n is selected from an integer ranging from 1 to 3
  • p is selected from an integer ranging from 1 to 3
  • q is 0 or 1
  • R is CH 2 R 24 , wherein R 24 is H, C C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C ⁇ alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms, or a C 3 -C 8 cycloalkyl or C 3 -C 8 cycioalkenyl either or which may be optionally substituted by methyl or one or more C,-
  • n is selected from an integer ranging from 1 to 3
  • p is selected from an integer ranging from 1 to 3
  • q is 0 or 1
  • R , R S , R 7 , and R ⁇ are each independently selected from H, c,-C, 2 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)OR 10 , -OR 10 , C,-C,o alkanoyl, halo, nitro, cyano, R 1 ° 4-10 membered heterocyclic, C 6 -C 10 aryl -C(O)NR 10 R 11 , -NHC(0)R 10 , -NHC(O)NR 10 R 11 , NR 10 R 11 , -SR 10 , -S(0)R 10 , -S0 2 R 10 and -SO 2 NR 10 R 11 , where the bond between 09 and the nitrogen to which 09 is linked is a double bond, R 1 s not existent, and R 2 is OR 7 , wherein R 7 is
  • the invention also relates to a compound of the formula
  • R is an alpha-branched C3-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cyci ⁇ alkyl or C5-C3 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C1-C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C1-C4 alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with
  • X 1 is O, 5 or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d 5, or R is CH 2 R 24 , wherein R 24 is H, C,-C ⁇ alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups -3-3-
  • R 3 , R z , R 7 , and R B are independently selected from H, C,-C, 8 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)OR 10 , -OR 10 , C C, 0 alkanoyl, halo, nitro, cyano, R 10 , 4-10 membered heterocyclic, C 6 -C 1C1 aryl,
  • R 10 and R 11 are each independently selected from H, C,-C ⁇ alkyl; and R 4 is H or acyl of an organic carboxylic acid of up to 18 carbon atoms.
  • the invention also relates to a compound of the formula
  • R is an alpha-branched C 3 -C 8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups, a C,-C 0 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C 2 -C 5 alkyl group; a C 3 -C 8 cycloalkyl or C 5 -C B cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C 4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C 4 alkyl groups or halo atoms, or R is phenyl which may be optionally
  • X 1 is O, S or -CH 2 -, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d ⁇ 5, or R is CHjR 24 , wherein R 24 is H, C,-C professionalkyl, C 2 -C 8 alkenyl, C 2 -C ⁇ alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms, or a C 3 -C B cycloalkyl or C 5 -C 8 cycloalkenyl either or which may be optionally substituted by methyl or one or more C,-C 4 alkyl groups or halo atoms, or a
  • Z is a 4-10 membered heterocyclic or C 6 C, Q aryl, wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -C(0)OR 10 , -OR 10 , C,-C 10 alkanoyl, halo, nitro, cyano, R 10 , 4-10 membered heterocyclic, C 6 -C 10 aryl, -C(O)NR 10 R 11 , -NHC(D)R 10 , -NHC(O)NR 10 R 11 , -NR 10 R 11 , -SR 10 , -S(0)R 10 -S0 2 R 10 and ⁇ S0 2 NR 1 ° R 11 ,
  • R s and R 6 are independently selected from H, C r C ⁇ alkyl, halogen and R 5 and R 6 may each vary independently when m is greater than 1;
  • R z , R 7 , and R 8 are each independently selected from H, C,-C 1 ⁇ alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -0(O)OR 10 , -OR 10 , C,-C, Q alkanoyl, halo, nitro, cyano, R 0 , 4-10 membered heterocyclic, C 6 -C,o aryl, -C(O)NR 10 R 11 , -NHC(0)R 10 , -NHC(O)NR 10 R 11 , -NR 1D R 11 , -SR 10 , -S(0)R 10 , -S0 2 R 10 and -
  • R 4 is H or acyl of an organic carboxylic acid of up to 18 carbon atoms.
  • treatment includes the treatment or prevention of a bacterial infection or protozoa Infection as provided In the method of the present invention.
  • bacterial ⁇ nfection(s) or "protozoa infections; includes bacterial infections and protozoa infections that occur in mammals, fish and birds as well as disorders related to bacterial infections and protozoa infections that may be treated or prevented by administering antibiotics such as the compounds of the present invention.
  • Such bacterial infections and protozoa infections and disorders related to such infections include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumomae, Haemophilus tnfluenzae, Moraxella catarrhalts, Staphylococc ⁇ s aur ⁇ us, or P ⁇ ptosir ⁇ piococcus spp ; pharynlgltls, rheumatic fever, and glomerulo ⁇ ph ⁇ ti ⁇ related to infection by Streptococcus py ⁇ genes. Groups C and G streptococci.
  • Clostridium diptheriae, or Actmobacillus hae olyticum respiratory tract infections related to infection by Mycoplasma pneumomae, Legionella pneumophila. Streptococcus pneumomae, Haemophilus influ ⁇ nza ⁇ , or Chlamydia pne ⁇ moniae; uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, and puerperal fever related to infection by Staphylococcus aureus, coagulase-positive staphylococci (i.e., S epid ⁇ rmidis, S.
  • Staphylococcus aureus coagulase-positive staphylococci (i.e., S epid ⁇ rmidis, S.
  • Streptococcus pyogenes Streptococcus aga.acf.ae, Streptococcal groups C-F (minute- colony streptococci), virida ⁇ s streptococci, Corynebact ⁇ num minutissimum.
  • Clostridium spp., or Bartonella henselae uncomplicated acute urinary tract infections related to infection by Staphylococcus saprophyticus or Ent ⁇ rococcus spp .
  • urethritis and cervicitis and sexually transmitted diseases related to infection by Chlamydia trachornatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; toxin diseases related to infection by S. aureus (food poisoning and Toxic shock syndrome), or Groups A, .
  • ulcer ⁇ related to infection by Halicob ⁇ ct ⁇ r pylori, systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorfe ⁇ , conjunctivitis, keratitis, and dacrocystitis related to infection by Chlamydia trachornatis, Neisseria gonorrhoeae, S aureus, S pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminated Mycobact ⁇ num avium complex (MAC) disease related to infection by Mycobactdnum avium.
  • MAC Mycobact ⁇ num avium complex
  • Bacterial infections and protozoa infections and disorders related to such infections include the following: bovine respiratory disease related to infection by P. haem., P.
  • cow enteric disease related to infection by E coli or protozoa i.e , coccidia, cryptosporidia, etc.
  • the present invention also relates to a method of preparing the above compounds of formulas 1_, 2, 3, 4, and 5.
  • the compounds of the present invention can be prepared as follows .
  • the starting compounds used in the preparation of the compounds of formulas 1_, 2, 3, 4 and 5 can prepared using the methods described below and further, in International Application No. PCT/GB97/01810 filed July 4, 1997 (Peter Francis Leadlay, James Staunton, Jesus Cortes and Michael Stephen Pacey). and International Application No. PCT/GB97/01819 filed July 4, 1997 (Peter Francis Leadlay, James Staunton, and Jesus Cortes), both of which are incorporated herein by reference in their entirety.
  • the compounds of formulas 1, 2, 3, 4, and 5 can then be prepared from these starting compounds using conventional methods known to one skilled in the art.
  • the present invention also relates to the compounds of formulas 2 to 20 which, are useful in the preparation of the above compounds of formulas 1 ⁇ , 2, 3, 4 or 5 and pharmaceutically acceptable salts thereof.
  • Polyketides, and methods and means for preparing them, and specifically the novel maerolides that are useful in the preparation of the compounds Of the present invention are prepared by fermenting suitable organisms in the presence of a carboxylic acid of the formula RC0 2 H, where R is as defined the compound of formula 1
  • a preferred organism is Saccharopolyspora erythra ⁇ a preferably containing an integrated plasmid capable or directing synthesis of desired compounds
  • polyketide biosynthetic genes or portions of them which may be derived from different polyketide biosynthetic gene clusters are manipulated to allow the production of novel erythromycins.
  • Polyketides are a large and structurally diverse class of natural products that includes many compounds possessing antibiotic or other pharmacological properties, such as erythromycin, tetracyc nes, rapamycin, avermectin, polyether ionophores, and FK506.
  • antibiotic or other pharmacological properties such as erythromycin, tetracyc nes, rapamycin, avermectin, polyether ionophores, and FK506.
  • polyketides are abundantly produced by Streptomyces and related actinomycete bacteria They are sy ⁇ thesised by the repeated stepwise condensation of acylthioesters in a manner analogous to that of fatty acid biosynthesis.
  • PKS polyketide synthase
  • natural module refers to the set of contiguous domains, from a b- ketoacylsynthase ("KS”) gene to the next acyl carrier protein ("ACP”) gene, which accomplishes one cycle of polyketide chain extension.
  • KS ketoacylsynthase
  • ACP acyl carrier protein
  • combinatorial module is used to refer to any group of contiguous domains (and domain parts), extending from a first point in a first natural module, to a second equivalent point in a second natural module.
  • the first and second points will generally be in core domains which are present in all modules, i e , both at equivalent points of respective KS, AT (acyl transferase), ACP domains, or in linker regions between domains.
  • the organisation of the erythromycin producing PKS, (also known as 6- deoxyerythronolide B sy ⁇ thase, DEBS) genes contains three open reading frames encode the DEBS polypeptides The genes are organised in six repeated units designated modules
  • the first open reading frame encodes the first multi-enzyme or cassette (DEBS1) which consists of three modules- the loading module (ery-load) and two extension modules (modules 1 and 2)
  • the loading module comprises an acyl transferase and an acyl carrier protein This may be contrasted with Figure 1 of W093/13663 (referred to below) This shows ORF1 to consist of only two modules, the first of which is in fact both the loading module and the first extension module
  • Type I PKS's are particularly valuable, in that they include compounds with known utility as anthelminthics, insecticides, immunosuppressants, antifungal, and/or antibacterial agents, Because of their structural complexity, such novel polyketides are not readily obtainable by total chemical synthesis, or by chemical modifications of known polyketides
  • the Type I PKS gene assembly encodes a loading module which is followed by extension modules It is particularly useful to provide a hybrid PKS gene assembly in which the loading module is heterologous to the extension modules and is such as to lead to a polyketide having an altered starter unit As noted in in International Application PCT/GB97/01810, this is a concept quite unknown to the prior art since this does not recognise the existence of loading modules.
  • W093/13663 refers to altering PKS genes by inactivating
  • the hybrid gene assembly can be used to produce many different polyketides
  • a hybrid gene assembly may employ nucleic acid encoding an avr loading module with e extender modules.
  • a loading module may accept unnatural acid units and derivatives thereof; the avr loading module is particularly useful in this regard (Dutton et al., (1991) J Antibiot., 44 357-365).
  • a plasmid with an Int sequence will integrate into a specific attachment site [att) of a host's chromosome Transformant organisms may be capable of modifying the initial products, e.g., by carrying out all or some of the biosynthetic modifications normal in the production of erythromycins.
  • use may be made of mutant organisms such that some of the normal pathways are blocked, e g , to produce products without one or more "natural" hydroxy-groups or sugar groups, for instance as described in WO 91716334 or in Weber et a
  • use may be made of organisms in which some of the normal pathways are overexpressed to overcome potential rate-limiting steps in the production of the desired product, for instance as described in WO 97/06266 which is incorporated herein by reference in its entirety.
  • This aspect of the method is largely concerned with treating PKS gene modules as building blocks that can be used to construct enzyme systems, and thus novel erythromycin products, of desired types.
  • Logical places for making and breaking intermodular connections are be in the linking regions between modules.
  • the DNA is highly conserved here between all modular PKS's, and this may aid in the construction of hybrids that can be transcribed It may also assist in maintaining the spacing of the active sitee of the encoded enzymes, which may be important.
  • the ery_ module in producing a hybrid gene by replacing the ery_ loading module by an avr loading module, the ery_ module together with a small amount of the following ketosy ⁇ thase (KS) domain was removed,
  • the Start of the KS domain (well spaced from the active site) is highly conserved and therefore provides a suitable splicing site as an alternative to the linker region between the loading domain and the start of the KS domain
  • the excised er module was then replaced by an avr loading module.
  • acyl transferase AT
  • ACP acyl carrier protein
  • KS acyl carrier protein
  • the excised loading module would have provided a propionate starter, and the replacement is intended to provide one or more different starters.
  • Propionate may feed into the KS of the extension module from a propionate pool in the host cell, leading to dilution of the desired products This can be largely prevented by substituting an extended loading module including all or most of the KS domain.
  • the splice site may be in the end region of the KS gene, or early in the following AT gene, or the linker region between them.
  • a “combinatorial module” to be excised and/or replaced and/or inserted may extend from the corresponding domain of two natural-type modules, e.g., from the AT of one module to the AT of the next, or from KS to KS.
  • the splice sites will be in corresponding conserved marginal regions or in linker regions
  • a combinatorial module can also be a 'double' or larger multiple, for adding 2 or more modules at a time.
  • An erythromycin analogue (being a macrolide compound with a 14-membered ring) in which a substitutent R, on the C-13 position, bears a side-chain other than ethyl, generally a straight chain C3-C6 alkyl group, a branched C 3 -Cg alkyl group, a C 3 -C 8 cycloalkyl or cycioalkenyl group (optionally substituted, e g , with one or more hydroxy, C 1 _ 4 alkyl or alkoxy groups or halogen atoms), or a 3-6 membered heterocycle containing O or S, saturated or fully or partially unsaturated, optionally substituted (as for cycloalkyl), or R is phenyl which may be optionally substituted with at least one substituent selected from C,-C 4 alkyl, C,-C 4 alkoxy and C,-C 4 alkylthio groups, halogen atoms,
  • X 1 is O, S or -CH 2 -, a. b, c, and d are each independently 0 to 2 and a + b + c + d ⁇ 5
  • Preferred candidates for the C-13 substituent R are the groups of carboxylate units RCOOR', usable as substrates by an avr starter module, or rapamycin starter variants
  • Preferred substrates are the carboxylic acid ⁇ R"COOH
  • Alternative substrates that can be effectively used are carboxylic acid salts, carboxylic acid esters, or amides
  • Preferred esters are N-acetyl- cysteamine thioesters which can readily be utilised as substrates by the avr starter module as illustrated by Dutton et al.
  • amides are N-acyl imidazoles
  • suitable substrates would be ammo acids of the formula RCH(NH 2 )COOH, glyoxylic acids of the formula RCOCOOH, methylami ⁇ e derivatives of the formula RCH 2 NH 2 , methanol derivatives of the formula RCH 2 OH, aldehydes of the formula RCHO or substituted alka ⁇ olc acids of the formula R(CH 2 ) distractCOQH wherein ⁇ is 2, 4, or 6
  • Other possibilities include n-butyrate, cyclopropyl carboxylate, cyclobutyl carboxylate, cyclopentyl carboxylate cyclohexyl carboxylate,
  • the erythromycin analogue may correspond to the initial product of a PKS (6- deoxyerythronolide) or the product after one or more of the normal biosynthetic steps These comprise- 6-hydroxylat ⁇ on, 3-0-glycosylat ⁇ on, 5-0-glycosylat ⁇ on 12-hydroxylat ⁇ on; and specific sugar methylation
  • the analogues may include those corresponding to 6-deoxyerythronol ⁇ de B, erythromycin A, and various intermediates and alternatives thereof.
  • unnatural starter unite preferably, but not restricted to the carboxylic acid analogues of the unnatural starter units
  • a preferred approach involves introduction of the starter unit into fermentation broths of the erythromycin-producing organism, an approach which is more effective for transformed organisms capable of producing erythromycins.
  • the starter unit analogue can also be introduced to alternative preparations of the erythromycin-producing organisms, for example, fractionated or unfractionated broken-cell preparations. Again, this approach is equally effective for transformed organisms capable of producing erythromycins.
  • one or more segments of DNA encoding individual modules or domains within a heterologous Type I PKS have been used to replace the DNA encoding, respectively, individual modules or domains within the DEBS genes of an erythromycin-pro'ducing organism.
  • Loading modules and extension modules drawn from any natural or non-natural Type I PKS are suitable for this "donor" PKS but particularly suitable for this purpose are the components of Type I PKS's for the biosynthesis of erythromycin, rapamycin, avermectin, tetronasin, oleandomycin, monensi ⁇ , amphote ⁇ cin, and rifamycin, for which the gene and modular organisation is known through gene sequence analysis, at least in part
  • Particularly favourable examples of the loading modules of the donor PKS are those loading modules showing a relaxed specificity, for example, the loading module of the avermectin (avr)-produc ⁇ ng PKS of Streptomyces avermitilis; or those loading modules possessing an unusual specificity, for example, the loading modules of the rapamycin-, FK506- and ascomycin-producing PKS's, all of which naturally accept a shikimate-dorived starter unit.
  • a preferred embodiment is when the donor PKS DNA includes a segment encoding a loading module In such a way that this loading module becomes linked to the DEBS genes on the chromosome
  • a hybrid PKS produces valuable and novel erythromycin products when cultured under suitable conditions as described herein
  • the novel erythromycin products contain a starter unit typical of those used by the avr PKS
  • Saccharopolyspora erythraea strains containing such hybrid PKS are found to produce 14-membered macrolides containing starter units typically used by the avr PKS.
  • erythromycin PKS placed under the control of a Type II PKS promoter and activator gene.
  • desired genes present on an SCP2 * -derived plasmid are placed under the control of the bidirectional actl promoter derived from the acti ⁇ orhodin biosynthetic gene cluster of Streptomyces coelicolor, and in which the vector also contains the structural gene encoding the specific activator protein Act ll-orf 4.
  • the recombinant plasmid is introduced into Saccharopolyspora erythraea, under conditions where either the introduced PKS genes, or PKS genes already present in the host strain, are expressed under the control of the actl promoter
  • the recombinant strains can produce more than ten-fold erythromycin product than when the same PKS genes are under the control of the natural promoter, and the specific erythromycin product is also produced precociously in growing culture, rather than only during the transition from growth to stationary phase.
  • Such erythromycins are useful as antibiotics and for many other purposes in human and veterinary medicine.
  • the activator and promoter are derived from the actinorhodin PKS gene cluster and the act
  • the activator and promoter are derived from the actinorhodin PKS gene cluster and the act
  • the PKS genes under this heterologous control are hybrid Type I PKS genes whose construction is described herein, more than ten-fold hybrid polyketide product can be obtained compared to the same hybrid Type I PKS genes not under such control.
  • the hybrid Type I PKS genes are the ery PKS genes in which the loader module is replaced by the avr loading module, a ten-fold increase is found in the total amounts of novel 14-membered macrolides produced by the genetically engineered cells when cultured under suitable conditions as described herein
  • the suitable and preferred means of growing the untransformed and genetically- engineered erythromycin-producing cells, and suitable and preferred means for the isolation, identification, and practical utility of the novel erythromycins are described more f ⁇ lly, in International Application PCT/GB97/01810,
  • Erythromycin derivatives described in International Application PCT/GB97/01810 are produced by fermentation of an untransformed or transformed organism capable of producing erythromycins, including but not limited to Saccharopolyspora species, Streptomyces g ⁇ seoplanus, Nocardia sp., Micromonospora sp., Arthobacter sp , and Streptomyces antibioticus, but excluding S. coelicolor.
  • Particularly suitable m this regard are untransformed and transformed strains of Saccharopolyspora erythraea, for example NRRL 2338, 18643, 21484.
  • Particularly preferred transformed strains are those in which the erythromycin loading module has been replaced with the loading module from the avermectin producer, Streptomyces avermitilis, or the rapamycin producer, Streptomyces hygroscopicus.
  • the preferred method of producing compounds is by fermentation of the appropriate organism in the presence of the appropriate carboxylic acid of the formula R,COOH, wherein R, is as defined in formulae 1_ or 2 of International Application PCT/GB97/01810, or is R of the compounds of the present invention, or a salt, ester (particularly preferable being the N- acetylcysteamine thioester), or amide thereof or oxidative precursor thereof
  • R is as defined in formulae 1_ or 2 of International Application PCT/GB97/01810, or is R of the compounds of the present invention, or a salt, ester (particularly preferable being the N- acetylcysteamine thioester), or amide thereof or oxidative precursor thereof
  • the acid or derivative thereof is added to the fermentation either at the time of inoculation or at intervals during the fermentation. Production of the compounds may be monitored by removing samples from the fermentation, extracting with an organic solvent and following the appearance of the compounds by chromatography, for example using high pressure liquid
  • the best yields of the compounds from formulae 1 or 2 are generally by gradually adding the acid or derivative to the fermentation, for example by daily addition over a period of several days.
  • the medium used for the fermentation may be a conventional complex medium containing assimilable sources of carbon, nitrogen and trace elements
  • Me refers to methyl.
  • Et refers to ethyl.
  • Pr refers to propyl.
  • Ac refers to acyl
  • hydroxy protecting group includes acetyl, benzyloxyearbonyl, and various hydroxy protecting groups familiar to those skilled in the art include the groups referred to in T W Greene, P. G. M. Wuts, "Protective Groups In Organic Synthesis,” (J. Wiley & Sons, 1991)
  • halo as used herein, unless otherwise indicated, Includes fluoro, chloro, bromo or todo.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovarrid hydrocarbon radicals having straight, cyclic or branched moieties, or mixtures thereof. It is to be understood that where cyclic moieties are intended, at least three carbons in said alkyl must be present. Such cyclic moieties include cyclopropyl, cyclobutyl and cyclopentyl.
  • alkoxy as used herein, unless otherwise indicated, includes -O-alkyl groups wherein alkyl is as defined above
  • aryl as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl
  • 4-10 membered heterocyclic as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from 0, S and N, wherein each heterocyclic group has from 4-10 atoms in its ring system.
  • Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
  • the heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxo moieties
  • An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidme)
  • An example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is qumolinyl.
  • non-aromatic heterocychc groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothie ⁇ yl tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrol ⁇ nyl, indolmyl, 2H-pyranyl, 4H- ⁇ yranyl, dioxanyl.
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, py ⁇ midinyl, pyrazolyl, triazolyl, pyrazi ⁇ yl, tetrazolyl, furyl, thienyl, isoxazolyi, thiazoiyi, oxazolyl, isoth ⁇ ----olyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, i ⁇ dazolyl, mdolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pte ⁇ dinyl, punnyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, be ⁇ zoxazo
  • a group derived from pyrrole may be C- attached or N-attached where such is possible.
  • a group derived from pyrrole may be ⁇ yrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached)
  • phrases "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention.
  • the compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of the present invention are those that form non-toxic acid addition salts, _ , salts containing pharmacologically acceptable anions, s ch a ⁇ the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pa ⁇ tothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate
  • Those compounds of the present invention that are acidic In nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of the present invention.
  • Certain compounds of the present invention may have asymmetric centers and therefore exist in different enantlomerlc and dlasiereomic forms
  • This invention relates to the use of all optical isomers and ster ⁇ oisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them.
  • the present invention includes the compounds of the present invention, and the pharmaceutically acceptable salts thereof, wherein one or more hydrogen, carbon or other atoms are replaced by isotopes thereof.
  • Such compounds may be useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays. Detalled Description of the Invention
  • the compounds of of the present invention may be prepared according to Schemes 1-3 described below.
  • the compounds of the present invention are readily prepared.
  • the compounds desribed below used in the preparation of the compounds of formulas 1_, 2, 3, 4 and 5 can prepared using the methods described in International Application No. PCT/GB97/01810 filed July 4. 1997 (Peter Francis Leadlay, James Staunton, Jesus Cortes and Michael Stephen Pacey), and International Application No PCT/GB97/01819 filed July 4, 1997 (Peter Francis Leadlay, James Staunton, and Jesus Cortes), both of which are Incorporated herein by reference in their entirety.
  • the compounds of formula of the present invention can be prepared using substantially the same procedures as described by Wata ⁇ abe er a/ (Journal of Antibiotics, 1993, 46,1161- 1167) as illustrated in Scheme 1
  • the starting compounds of formula 6 can be prepared using the methods described in International Application No. PCT/GB97/01810 filed July 4, 1997 (Peter Francis Leadlay, James Staunton, Jesus Cortes and Michael Stephen Pacey), and international Application No PCT/GB97/01819 filed July 4, 1997 (Peter Francis Leadlay, James Staunton, and Jesus Cortes), both of which are incorporated herein by reference in their entirety.
  • oximatio ⁇ of the compound of formula 6 can be effected by treating the compound of formula ⁇ using methods known to one skilled In the art, such as treatment with NH 2 OH «HCl in a polar solvent such as pyridine at a temperature of from about 40 to ⁇ O'O for a period of from about 8 to about 50 hours to give a compound of formula 7.
  • the oxime hydroxyl group of the compound of formula 7 can be protected using methods known to one skilled in the art, such as by protecting the oxime hydroxyl group as a benzyl group by using benzyl chloride or benzyl bromide in the presence of a base such as potassium hydroxide in a solvent such as DMF
  • the compound of formula 9 can be prepared from the compound of formula 8 using methods known to one skilled in the art, such as by treatment with 1- (trimethylsilyl)-imidazole in a solvent such as ethyl acetate Methylation of the compound of formula 9 can be carried out using methods known to one skilled in the art such as by treatment with a methylating agent such as methyl iodide and a base such as potassium hydroxide in a solvent such as a mixture of DMSO (methyl sulfoxide) and THF (tetrahdrofuran) to afford the compound of formula 0.
  • a methylating agent such as methyl iodide
  • Elimination of the benzyl and silyl groups of the compound of formula 10 can be achieved at the same time using methods known to one skilled in the art such as by catalytic transfer hydrogenation using palladium on carbon, formic acid and ammonium formate in a solvent such as methanol to generate a compound of formula of 11.
  • the compound of formula ___[ can be converted to compound of formula _ ⁇ 2 via deoximation using using methods known to one skilled in the art, by treatment with a hydrolyzing agent, such as by treatment with sodium bisulfite in a solvent such as methanol at a temperature of about 40 to about 80°C for a period of about 1 to about 50 hours 5
  • a hydrolyzing agent such as by treatment with sodium bisulfite in a solvent such as methanol at a temperature of about 40 to about 80°C for a period of about 1 to about 50 hours 5
  • Scheme 2 describes the synthesis of the compounds of formula 2, wherein X is -NR 5
  • the starting compound of formula 12_ can be prepared according to Scheme 1.
  • the acylation of 0 the C-4" and C-2' hydroxyls or the compound of formula 12_ can be effected by treating compound of formula 12 with a suitable acylating agent known to one skilled in the art, such as for example, acetic anhydride in a solvent such as dichloromethane in the presence of a base such as 4-d ⁇ methylaminopyridine (DMAP) at room temperature for a period of about 10 to about 30 hours to afford diacetate of the compound of formula 13
  • the compound of formula 13 can be S converted into the carbonate of the compound of formula 14 under a variety of conditions known to one skilled in the art, such as, for example, tnchloromethyl isocyanate, or ethylene carbonate in the presence of a base, or carbonyldiimidazole in the presence of a base.
  • Cleavage of the cladinose moiety of the compound of formula 14 can be carried out under suitable acidic conditions known to one skilled in the art, such as aqueous hydrochloric acid in ethanol to afford 0 the compound of formula 15_
  • suitable acidic conditions such as aqueous hydrochloric acid in ethanol to afford 0 the compound of formula 15_
  • the hydroxyl group of the compound of formula 15 can be oxidized using an oxidizing agent, to generate ketolide of the compound of formula 16_ under a variety of conditions known to one skilled in the art, such as 1-(3-d ⁇ methylam ⁇ opropyl)-3-ethylcarbodiimide hydrochloride and pyridium trifluroacetate in the presence of DMSO.
  • B-elimination of the carbonate of the compound of formula __$ can be conducted under suitable basic conditions 5 known to one skilled in the art, such as DBU at 50-80"C gave enone 17_.
  • the acyl imidazole of the compound of formula 18 can be prepared from the compound of formula T7 using methods known to one skilled in the art, such as, for example, by treatment with carbonyldiimidazole in the presence of a base such as sodium hydride.
  • the compound of formula 1 ⁇ _ undergoes cyclization to give carbazate 19_ using methods known by one skilled in the art, such as, by treatment with 0 NH 2 NH 2 in a solvent such as MeCN at a temperature of about 60 to about 100°C for a period of about 5 to about 28 hours
  • the compound of formula 19_ can be converted to the compound of formula 20 through reductive alkylation following substantially the same procedures as described by Patel ⁇ t al (J. Med. Chem., 1996, 38, 41 ⁇ 7-4210.
  • Scheme 3 describes the synthesis of compounds of formula 2, wherein X is -(CR 5 R ⁇ ) 8 -, 5 where g is 0 or 1.
  • the starting compound of formula 18 can be prepared according to Scheme 2 Treatment of the acyl imidazole of the compound of formula 18_w ⁇ th a compound of the formula
  • the synthesis of the compounds of formula 5 can be prepared from the compound of formula 3, wherein X is -NR 5 -, following substantially the same synthetic sequence as described in U.S. application serial number 60/063161 , filed October 29, 1997 (Yong-Jin Wu).
  • the compounds of the present invention may have asymmetric carbon atoms and 5 therefore exist in different enantiomeric and diastereomeric forms.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization
  • Enantiomers may be separated by converting the enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound (e g , 0 alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g , 0 alcohol
  • the compounds of the present invention that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must 5 be pharmaceutically acceptable for administration to mammals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • the desired salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
  • Those compounds of the present invention that are acidic in nature are capable of forming base salts with various cations.
  • For compounds that are to be administered to mammals, fish or birds such salts must be pharmaceutically acceptable
  • base salts include the alkali metal or alkaline- earth metal salts and particularly the sodium, amine and potassium salts These salts are all prepared by conventional techniques
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non- toxic base salts with the acidic compounds of the present invention.
  • Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium, magnesium, va ⁇ oue amine cations, etc. These salts can easily e prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable bases with cations such as sodium, potassium, calcium, magnesium, various amine cations, etc., and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiomet ⁇ c quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product,
  • the activity of the compounds of the present invention against bacterial and protozoa pathogens is demonstrated by the compound's ability to inhibit growth of defined strains of human (Assay I) or animal (Assays II and III) pathogens
  • Assay I employs conventional methodology and interpretation criteria and is designed to provide direction for chemical modifications that may lead to compounds that circumvent defined mechanisms of macrolide resistance.
  • Assay I a panel of bacterial strains is assembled to include a variety of target pathogenic species, including representatives of macrolide resistance mechanisms that have been characterized.
  • msrA encodes a component of an efflux system in staphylococci that prevents the entry of macrolides and streptogram s while mefA E encodes a transmembrane protein that appears to efflux only macrolides.
  • Inactivation of macrolide antibiotics can occur and can be mediated by either a phosphorylation of the 2'-hydroxyl ( ph) or by cleavage of the macrocyclic lactone (esterase)
  • the strains may be characterized using conventional polymerase chain reaction (PCR) technology and/or by sequencing the resistance determinant The use of PCR technology in this application is described in J.
  • Assay II is utilized to test for activity against Pasteurella multocida and Assay 111 is, utilized to te ⁇ t for activity against Pasteurella h ⁇ emolytic ⁇ .
  • Assay II This assay is based on the liquid dilution method in microliter format.
  • a single colony of P multocida (strain 59A067) is inoculated into 5 ml of brain heart infusion (BHI) broth.
  • the test compounds are prepared by solubilizing 1 mg of the compound in 125 ⁇ l of dimethylsulfoxide (DMSO). Dilutions of the test compound are prepared using uninoculated BHI broth.
  • the concentrations of the test compound used range from 200 ⁇ g/ml to 0.098 ⁇ g/ml by two-fold serial dilutions. The P.
  • multocida inoculated BHI is diluted with uni ⁇ oculated BHI broth to make a 10 4 cell suspension per 200 ⁇ l, The BHI cell suspensions are mixed with respective serial dilutions of the test compound, and incubated at 37°C for 18 hours, The minimum inhibitory concentration (MIC) is equal to the concentration of the compound exhibiting 100% inhibition of growth of P. multocida as determined by compa ⁇ son with an uninoculated control.
  • This assay is based on the agar dilution method using a Steers Replicator. Two to five colonies isolated from an agar plate are inoculated into BHI broth and incubated overnight at 37 °C with shaking (200 rpm). The next morning, 300 ⁇ l of the fully grown P. haemolytica preculture is inoculated into 3 ml of fresh BHI broth and is incubated at 37*C with shaking (200 rpm) The appropriate amounts of the test compounds are dissolved In ethanol and a series of two-fold serial dilutions are prepared Two ml of the respective serial dilution is mixed with 18 ml of molten BHI agar and solidified. When the inoculated P.
  • haemolytica culture reaches 0 5 McFarland standard density, about 5 ⁇ l of the P haemolytica culture is inoculated onto BHI agar plates containing the various concentrations of the test compound using a Steers Replicator and incubated for 18 hours at 37 4 C.
  • Initial concentrations of the te ⁇ t compound range from 100-200 ⁇ g/ml.
  • the MIC is equal to the concentration of the test compound exhibiting 100% inhibition of growth of P. haemolytica as determined by comparison with an uninoculated control,
  • the in jvo activity of the compounds of formula (I) can be determined by conventional animal protection studies well known to those skilled In the art, usually carried out In mice.
  • mice are allotted to cages (10 per cage) upon their arrival, and allowed to acclimate for a minimum of 48 hours before being used. Animals are inoculated with 0.5 ml of a 3 x 10 3 CFU/ml bacterial suspension (P multocida strain 59A006) intrapentoneally. Each experiment has at least 3 non-medicated control groups including one infected with 0 1X challenge dose and two infected with 1X challenge dose; a 10X challenge data group may also be used. Generally, all mice in a given study can be challenged within 30-90 minutes, especially if a repeating syringe (such as a Cornwall® syringe) is used to administer the challenge.
  • a repeating syringe such as a Cornwall® syringe
  • the first compound treatment is given. It may be necessary for a second person to begin compound dosing if all of the animals have not been challenged at the end of 30 minutes.
  • the routes of administration are subcutaneous or oral doses. Subcutaneous doses are administered into the loose skin in the back of the neck whereas oral doses are given by means of a feeding needle. In both cases, a volume of 02 ml is used per mouse. Compounds are administered 30 minutes, 4 hours, and 24 hours after challenge. A control compound of known efficacy administered by the same route is included in each test. Animals are observed daily, and the number of survivors in each group is recorded The P. multocida model monitoring continues for 96 hours (four days) post challenge
  • the PD 50 is a calculated dose at which the compound tested protects 50% of a group of mice from mortality due to the bacterial infection which would be lethal in the absence of drug treatment
  • the compounds of formula 1, 2, 3, 4 and 5 may be ad instered through oral, parenteral, topical, or rectal routes in the treatment of bacterial and protozoa infections.
  • these compounds are most desirably administered in dosages ranging from about 0,2 mg per kg body weight per day
  • mg/kg/day to about 200 mg/kg/day in single or divided doses (i.e., from 1 to 4 doses per day), although variations will necessarily occur depending upon the species, weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 4 mg/kg/day to about 50 mg/kg/day is most desirably employed.
  • Variations may nevertheless occur depending upon the species of mammal, fish or bird being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • the active compounds may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by the routes previously indicated, and such administration may be carried out in single or multiple doses.
  • the active compounds may be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories. Jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like, Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the active compounds are present in such dosage forms at concentration levels ranging from about 5,0% to about 70% by weight
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various dismtegrants such as starch (and preferably corn, potato or tapioca starch), algl ⁇ lc acid and certain complex silicates, together with granulation binders like polyvlnylpyrrolldone, sucrose, gelatin and acacia Additionally, lubricating agents such as magnesium stearate. sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the aotive oompound may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of an active compound in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • the aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic
  • the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes.
  • the preparation of all these solutions under 3ter ⁇ le conditions l ⁇ readily accomplished by standard pharmaceutical techniques will known to those skilled in the art Additionally, it is also possible to administer the active compounds of the present invention topically and this may be done by way of creams, jellies, gels, pastes, patches, ointments and the like, in accordance with standard pharmaceutical practice, For administration to animals other than humans, such as cattle or domestic animals, the active compounds may be administered in the feed of the animals or orally as a drench composition.
  • the active compounds may also be admmstered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearyiamlne or phosphatidyleholines,
  • the active compounds may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvi ⁇ ylpyrrolidone, pyra ⁇ copolymer, polyhydroxypropylmethacrylamide phenyl, polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoylre3idue3.
  • the active compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacryiates and cross-linked or amphipathic block copolymers of hydrogels
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacryiates and cross-linked or amphipathic block copolymers of hydrogels
  • Example 2 13-Cyclobutyl ⁇ rythromycin A 9-(0-be ⁇ zylo ⁇ ime) To a solution of 13-cyclobutylerythromycin A 9-ox ⁇ me (2.85 g, 3.67 mmol) in DMF (N,N- dimethylformamide) (20 ml-) were added benzyl chloride (0 51 mL g, 4,41 mmol) and 85% KOH power (0.29 g, 441 mmol), and the mixture was stirred in an ice-bath for 75 min The reaction mixture was treated with H 2 0 and extracted with EtOAc (X5).
  • DMF N,N- dimethylformamide
  • Example 3 2',4"-0-Bis(t ⁇ methy
  • Example 5 13-Cyclobutyl-6-0-methylerythromycin A 9-oxime
  • 2',4"-0-Bis(trimethylsilyl)-13-cyclobutyl-6-0-methylerythromycin A 9-(0- benzyloxime) (1.31 g, 1 28 mmol) in MeOH (13 mL) were added 10% Pd-C (206 mg), formic acid (0.82 mL, 21 ,79 mmol), and ammonium formate (137 mg, 2,18 mmol), and the reaction mixture was heated at 60°C for 2 hour6.
  • the catalyst was filtered off, and the filtrate, after addition of H 2 0, was made basic with 2N NaOH.
  • Example 7 2',4"-D ⁇ -0-Acetyl-13-cydobutyl-6- ⁇ -methylerythromycin A To a solution of 13-cyclobutyl-6-0-methylerythromycin A (327 mg, 0,42 mmol) in CH 2 CI 2 (4 0 mL) were added Ac 2 0 (120 uL, 1.26 mmol) and DMAP (41 mg, 0.34 mmol) and the reaction mixture was stirred at room temperature for 18 hours. Sat.
  • Example 11 2'-0-Acetyl-10,11 -a ⁇ hydro-13-cyclobutyl-5-0-desosaminyl-6-0-methy l-3-oxo- erythronolide A
  • DBU 378 uL, 2.53 mmol
  • the reaction mixture was heated at 90°C for 2 hours, Sat. NaH 2 P0 4 was added, and the aqueous solution was extracted with EtOAc (X5).
  • Example 12 2'-0-Acetyl-10, 11-anhydro-13-cyclobutyl-5-0-desosam ⁇ nyl-12-0-imidazolylcarbo ⁇ yl-6-0- methyl-3-oxoerythronolide A
  • 2'-O-acetyl-10,11-anhydro-13-cyclobutyl-5-O-desosaminyl-6-O-methyl-3- oxoerythronolide A 61 mg, 0.10 mmol
  • THF 1.2 mL
  • NaH 95% purity, 5mg, 0.20 mmol
  • CDI 49 mg, 0.30 mmol
  • Example 14 13-Cyclobutyl-11 -deoxy-5-0-desosam ⁇ nyl-6-0-methyl-3-oxo-11 -(3-qu ⁇ nol ⁇ n-4-yl- propyl ⁇ dene)hydrazoerythronol ⁇ de A, 1 1 ,12-carbamate
  • 13-cycl ⁇ butyl-11-deoxy-5-0-desosam ⁇ yl-11-hydraz ⁇ -6-0-methyl-3- oxoerythronolide A 11 12-carbamate obtained from example 13 in toluene (1 0 L) was added 3-(4-qu ⁇ nol ⁇ nyl)prop ⁇ onaldehyde (27 mg, 0 14 mmol) and the reaction mixture is heated at 90*C for 15 hours EtOH is evaporated in vacuo to give the title compound as a white solid MS m/z 821 (M+H)
  • Example 16 13-Cyclobutyl-11-deoxy-5-0-desosam ⁇ nyl-6-0-methyl-3-oxo-11-(3-qu ⁇ nol ⁇ n-4-yl- ⁇ ropyl)hydrazoerythronol ⁇ de A, 11 ,12-carbamate
  • MeOH MeOH
  • NaBH 3 CN 60 mg, 0 96 mmol
  • HOAc 88 uL, 1 53 mmol
  • Example 16 13-Cyclobutyl-11-deoxy-5-0-desosaminyl-11-6-0-methyl-3-oxo-11-(4-(4-(3-pyridinyl)-1 H- lmldazol-1-yl)butyl)aml ⁇ oerythronollde A, 11 ,12-carbamate

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Abstract

The invention relates to novel erythromycin derivatives, particularly ones with novel C-13 R13 substituents, and to pharmaceutically acceptable salts thereof. The compounds of this invention are useful as antibacterial agents and antiprotozoa agents and for other applications (e.g., anticancer, atherosclerosis, gastric motility reduction, etc.) in mammals, including man, as well as in fish and birds. The invention also relates to pharmaceutical compositions containing such compounds and to methods of treating bacterial protozoa infections by administering such compounds. The invention also relates to methods of preparing such compounds and to intermediates useful in such preparation.

Description

NOVEL ERYTHROMYCIN DERIVATIVES
Background of the Invention This invention relates to novel erythromycin derivatives that are useful as antibacterial agents and antiprotozoa agents and for other applications (e g., anticancer, atherosclerosis, oastπc motility reduction, etc ) in mammals, including man, as well as in fish and birds This invention also relates to pharmaceutical compositions containing the novel compounds and to methods of treating bacterial infections and protozoa infections and in mammals, fish and birds by administering the novel compounds to mammals, fish and birds requiring such treatment.
Macrolide antibiotics are known to be useful in the treatment of a broad sprectrum of bacteπal infections and protozoa infections in mammals, fish and birds Such antibiotics include vaπous derivatives of erythromycin A such as azithromycin which is commercially available and is referred to in United States patents 4,474,768 and 4,517,359, both of which are incorporated herein by reference in their entirety Additional macrolides are referred to in U.S patent application serial number 60/063676, filed October 29, 1997 (Yong-Jin Wu), U.S. application serial number 60/063161, filed October 29, 1997 (Yong-Jin Wu), U S. application serial number 60/054866, filed August 6, 1997(Hιroko Masamune, Yong-Jin Wu, Takushi Kaneko and Paul R McGuirk), U S. application serial number 60/049980, filed June 11, 1997 (Brian S. Bronk, Michael A. Letavic, Takushi Kaneko and Bingwei V Yang), U S. application serial number 60/049348, filed June 11, 1997 (Bnan S Bronk, Hengmiao Cheng, E. A Glaser, Michael A. Letavic, Takushi Kaneko and Bingwei V, Yang), International Application No PCT/GB97/01810 filed July 4, 1997 (Peter Francis Leadlay, James Stauntoπ, Jesus Cortes and Michael Stephen Pacey), International Application No. PCT/GB97/01819 filed July 4, 1997 (Peter Francis Leadlay, James Staunton, and Jesus Cortes), U.S. application serial no, 60/070343, filed January 2, 1998, (Dirlam), U.S. application serial no, 60/070358, filed January 2, 1998 (Yong-Jin Wu) and U.S. application serial no. 60\097075, filed August 19, 1998 (Hengmiao Cheng, Michael A. Letavic, Carl B. Ziegler, Jason K, Dutra, Brian S. Bronk), all of which are incorporated herein by reference in their entirety. Like azithromycin and other macrolide antibiotics, the novel macrolide compounds of the present invention possess potent activity against various bacterial infections and protozoa infections as described below. Summary of the Invention The present invention relates to compounds of the formula
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein:
R is an alpha-branched C3-CB alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C6-C<, cycloalkyl group wherein the alkyl group is an alpha-branched C2-C3 alkyl group; a C3-C8 cycloalkyl or C5-Ca cycloalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more 0,-0 a'M groups or halo atoms; or R is phenyl which may be optionally substituted with at least one substituent selected from C,-C4 alkyl, C,-C4 alkoxy and CrC alkylthio groups, halogen atoms, hydroxyl groups, trifluoro nethyl, and cyano; or R may be with a formula (a) as 3hown below
Figure imgf000004_0002
wherein X1 is 0, S or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d 5; or R is CH2R2 , wherein R24 is H, CrC8alkyl, C2-Cβalkenyl, CrCβalkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms, or a C3-C8cycloalkyl or C5-C8cycloalkenyl either or which may be optionally substituted by methyl or one or more 0,-Cialkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more Ct-C,alkyl groups or halo atoms; or a group of the formula SR23 wherein R23 is Cι-Cβalkyl, C CBalkenyl, C2- C8alkynyl, C3-Cacyc|oalkyl, C3-Cacycloalkenyl, phenyl or substituted phenyl wherein the substituent is CrC4alkyl, CrC4alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms; and
R" is H or acyl of an organic acid of up to 18 carbon atoms.
The present invention further relates to compounds of the formula
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein:
R Is an alpha-branched C3-CB alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C5-CB cycloalkylalkyl group wherein the alkyl group is an alpha-branched C C5 alkyl group; a C3-CB cycloalkyl or Cβ-Cβ cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or eulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more CrC4 alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with at least one substituent selected from CrC4 alkyl, CrC4 alkoxy and CrC4 alkylthio groups, halogen atoms, hydroxyl groups, trifiuoromethyl, and cyano; or R may be with a formula (a) as shown below
Figure imgf000006_0001
wherein X1 is O, S or -CH -, a, b, c, and d are each Independently selected from an integer ranging from 0 to 2 and a + b + o + d « 5;
X is -(CR5Rβ)g- or -NR5-, wherein g is 0 or 1; wherein when X is -NR6-, X and R3 optionally may be taken together to form -N=CR7R8, or when X is -NR5-, X and R3 optionally may be taken together to form a heterocyclic of the formula
Figure imgf000006_0002
wherein n is selected from an integer ranging from 1 to 3, p is selected from an integer ranging from 1 to 3, q is 0 or 1, and RB is selected from CH2, O, S, C=0, C=S, S02, -CH-CH-, - CH(OH)CH(OHK and NH; or when X is -NR5-, X and Ra together form a heterocyclic as defined above having substituents selected from the group consisting of -C(0)OR10, -OR10, C.-C-0 alkanoyl, halo, nitro, cyano. R10. 4-10 membered heterocyclic, C6-C,0 aryl, -C(0)NR DR12, -NHC(0)R10, - NHC(O)NR10R", -NR10R11, -SR10, -S(0)R1°, -S02R10 and -SO2NR10R11, or R is CHZR24, wherein R24 is H, C,-C8alkyl, C2-C8alkenyl, C2-CBalkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to β carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms; or a C3-C8cycloalkyl or C5-CBcyc|oalkeπyl either or which may be optionally substituted by methyl or one or more CrC4alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms; or a group of the formula SR23 wherein R23 is C.,-CBalkyl, C Cβalkenyl, C2- CBalkynyl, C3-C8cycloalkyl, C3-C8cycloalkenyl, phenyl or substituted phenyl wherein the substituent is CrC4alkyl, C C4alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more CrC4alkyl groups or halo atoms, R1D and R11 are each independently selected from H, CrC1D alkyl; or R3 is selected from H, C(=0)Z, C(=0)OZ, (CR5R6)mZ , C(=0)R7, C(=0)OR7, (CRsRs)mR7, wherein m is an integer ranging from 0 to 6,
Z is a 4-10 membered heterocyc c or C6-C10 aryl, wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -C(0)OR , -O ,ιo , 0,-0,0 alkanoyl, halo, nitro, cyano, R , 4-10 membered heterocyclic, C6-C10 aryl, -C(0)NR1UR , -NHC(0)R1D, -NHC(0)NRluFr, -NR I1D0DRI"I. -S CDRI-
S(0)R1U -S02R1U and -S02NR ,110u R oi1l.
R4 is H or acyl of an organic carboxylic acid of up to 18 carbon atoms;
R5 and Rβ are each independently selected from H, CrCβ alkyl, halogen- and R5 and R6 may each independently vary when m is greater than 1; and
R7 and Rβ are each independently selected from H, 0,-0,8 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, 5 and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)OR10, - OR10, 0,-0,0 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, C6-C10 aryl, - NR10R11, -C(O)NR10R11, -NHC(0)R10, -NHC(0)NR1DR11, -SR10, -S(0)R10, -S02R10 and - SO?ISlR1PR"
The present invention further relates to compounds of the formula
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof, wherein:
R is an alpha-branched C3-Cβ alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C3-C8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C3 alkyl group; a C3-CB cycloalkyl or Cg-Cg cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C4 alkyl groups or halo atoms, or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4 alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with at least one substituent selected from C^C. alkyl, C,-C. alkoxy and C,-C4 alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano; or R may be with a formula (a) as shown below
Figure imgf000008_0001
wherein X1 is 0, S or -CH-r, a, b, c, and d are each Independently selected from an integer ranging from 0 to 2 and a + b + e + d ^ S;
X is -(CRSR6)0- or -NR5-, wherein g is 0 or 1, wherein when X is -NR5-, X and R3 optionally may be taken together to form -N=CR7RS, or when X is -NRS-, X and R3 optionally may be taken together to form a heterocyclic of the formula
Figure imgf000008_0002
wherein n is selected from an integer ranging from 1 to 3, p is selected from an integer ranging from 1 to 3, q is 0 or 1 , and R9 is selected from CH2, O, S, C-O, C=S, S02, -CH=CH-, -CH(OH)CH(OH)-, and NH; or when X is -NR6-, X and R3 together form a heterocyclic as defined above having substituents selected from the group consisting of -C(0)0R1ώ, -OR10, C.-C.B alkanoyl, halo, nitro. cyano. R'°, 4-10 membered heterocyclic, C6-C,Q aryl, -C(O)NR10R11, -NHC(0)R1°, -NHC(O)NR10Rn, -NR10R11, -SR10, -S(0)R10, -S02R1D and -SO2NR10R11; or R is CH2R24, wherein R24 is H, C,-Cβalkyl, C2-CBalkenyl, Cz-C8alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms; or a C3-C8cycloalkyl or C5-C8cycloalkenyl either or which may be optionally substituted by methyl or one or more CrC4alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms; or a group of the formula SR23 wherein R23 is C,-C8alkyl, C2-Cβalkenyl, C2- C8alkynyl, C3-C„cycloalkyl, C6-CBcycloalkenyl, phenyl or substituted phenyl wherein the substituent is C,-C4alkyl, C,-C4alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms, R1D and R11 are each independently selected from H, 0,-C1o alkyl; or R3 is selected from H, C(=0)Z, C(=0)OZ, (CR )^ , C(=0)R7, C(=0)OR7, (CRδR6)mR7 wherein m is selected from an integer ranging from 0 to 6, Z is a 4-10 membered heterocyclic or Cβ-C,0 aryl; wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting αf -C(0)OR10, -0R1D. C,-C10 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, Cβ-C,0 aryl, -C(O)NR10R11, -NHC(0)R10, -NHC(O)NR10R11, -NR10R11, -SR10, -S(0)R1ύ -S02R'° and -S02NR1° R11; R is H or acyl of an organic carboxylic acid of up to 18 carbon atoms,
R5 and Rβ are each independently selected from H, C,-C6 alkyl, halogen: and R5 and R6 may each independently vary when m is greater than 1; where the bond between 09 and the nitrogen to which 09 is linked is a single bond, R1 and R2 together with the nitrogen atom to which they are linked optionally may together form -N=CR7Ra, or R1 and R2 together with the nitrogen atom to which they are linked optionally may together form a heterocyclic of the formula
Figure imgf000009_0001
wherein n is selected from an integer ranging from 1 to 3, p is selected from an integer ranging from 1 to 3, q is 0 or 1 , and R9is selected from CH2l O, S, C=0, C=S, S02, -CH=CH-, -CH(OH)CH(OH)-, and NH, or X and R3 together form a heterocyclic as defined above having substituents selected from the group consisting of -C(0)OR10, -OR10. C,-C10 alkanoyl. halo, nitro, cyano, R10, 4-10 membered heterocyclic, C„-C,D aryl, -C(O)NRl0R11, -NH0(O)R10, -NHC OJNR^R11, -NR10R11, -SR10, -S(0)R1C, -S02R10 and -S02NR1Q R11; and
R1, R2, R7, and R8 are each independently selected from H, C,-C,2 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)OR1Q, -OR10, 0,-0,- alkanoyl, halo, nitro, cyano, R1D, 4-10 membered heterocyclic, Ca-Cl0 aryl, -C(O)NR10R11, -NHC(0)R1D, -NHC(O)NR10R11, -NR10R11, -SR10, -S(0)R10, -S02R10 and -SO^R^R11, where the bond between C9 and the nitrogen to which 09 is linked is a double bond, R1 s not existent, and R2 is OR7, wherein R7 is defined as above.
The present invention further relates to compounds of the formula
Figure imgf000010_0001
or a pharmaceutically acceptable salt thereof, wherein:
R is an alpha-branched C3-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or C5-C8 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C1-C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C1-C4 alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with at least one substituent selected from C1-C alkyl, C1-C4 alkoxy and C1-C4 alkylthio groups, halogen atoms, hydroxyl groups, tπfluoromβthyl, and cyano, or R may be with a formula (a) as shown below
Figure imgf000010_0002
wherein X1 is 0, S or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d < 5; or R is CH2R2Λ, wherein R2* is H, Cι-C8alkyl, C2-C8alkenyl, C2-Caalkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of sa d alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms, or a C3-C8cyeloalkyl or C5-Cacycloalkenyl either or which may be optionally substituted by methyl or one or more C,-C4alkyl groups or halo atoms, or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms; or a group of the formula SR23 wherein R23 is C,-C8alkyl, Cz-C8alkenyl, C2- CBalkynyl, C3-CBcycloalkyl, CrC8cycloaikenyl, phenyl or substituted phenyl wherein the substituent is C,-C4alkyl, C,-C4alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms;
R3, R2, R7, and RB are independently selected from H, C,-C,β alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -0(O)OR10,
OR , C,-C10 alkanoyl, halo, nitro, cyano, R , 4-10 membered heterocyclic, Cβ-C,o aryl,
-C(O)NR10R", -NH0(O)Rlu, -NHC(0)NR1 .ODRr, 11 -NR 0R11, -SR - 1I0U, -S(0)R' , -SOzR 10 and -S02NR1qRn; and
R10 and R11 are each independently selected from H, C,-C,0 alkyl; and R4 is H or acyl of an organic carboxylic acid of up to 8 carbon atoms. The present invention further relates to compounds of the formula
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof, wherein:
R is an alpha-branched C3-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups, a CB-C8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group, a C3-C8 cycloalkyl or C3-C8 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4 alkyl groups or halo atoms, or R is phenyl which may be optionally substituted with at least one substituent selected from Ci-C* alkyl, C,-C4 alkoxy and C,-C4 alkylthio groups, halogen atoms, hydroxyl groups, tπfluoromethyl and cyano, or R may be with a formula (a) as shown below
Figure imgf000012_0001
wherein X1 is O, S or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d < 5, or R is CH2R", wherein R24 is H, C,-C„alkyl, C2-Cealkenyl, C2-CBalkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms or a Ca-C(,cycloalkyl or Cβ-Cβcycloalkenyl either or hich may be optionally substituted by methyl or one or more C,-C4alkyl groups or halo atoms, or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms, or a group of the formula SR23 wherein R23 is C,-Cβalkyl, C2-C,alkenyl, C-.- C„alkynyl, Ca-Cβcycloalkyl, C3-C8cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C,-C4alkyl, C,-C4alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms R10 and R11 are independently selected from H, C,-C„- alkyl
R3 is selected from H, C(=0)2, C(=0)OZ, (CR5R")mZ, C(=0)R7, C(=0)OR7, (CR6Re)mR7 wherein m is selected from an integer ranging from 0 to 6,
Z is a 4-10 membered heterocyclic or Cβ-C,0 aryl, wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -C(0)OR10, -OR10, C,-C,0 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, Cβ-C10 aryl, -C(O)NR10R11, -NH0(O)R10, -NHC(0)NR1QRu, -NR10R11, -SR10 -S(0)R10 -S02R10 and -S02NR1D R11,
R5 and Rβ are Independently selected from H, C C5 alkyl, halogen and R6 and R6 may each vary independently when m is greater than 1 , R2, R7, and Ra are each independently selected from H, C,-C18 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)OR10, -OR10, C,-C,o alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, Cβ-C,Q aryl, -CfOJNR^R11. -NHC(0)R10, -NHC(O)NR10R", -NR10R11, -SR10, -S(0)R10, -S02R10 and -SO2NR 0R11, and
R* is H or acyl of an organic carboxylic acid of up to 18 carbon atoms The preferred compounds of formula 1 include those selected from the group consisting of the compound of formula 1 wherein R is Me and R* is H, the compound of formula 1 wherein R is n-butyl and R4 is H; the compound of formula 1 wherein R is MeS and R4 is H, the compound of formula 1 wherein R is EtS and R4 is H; the compound of formula 1 wherein R is cyclopropyl and R4 ts H, the compound of formula 1 wherein R is cyclobutyl and R4 is H, the compound of formula 1 wherein R is cyclopentyl and R" is H; and the compound of formula 1 wherein R is cyclohexyl and R4 is H.
The preferred compounds of formula 2 include those selected from the group consisting of the compound of formula 2 wherein R is Me, R4 16 H, X is NH and R3 is 3-quιnolιn-4-yl- propyl, the compound of formula 2 wherein R is Me, R4 is H, X is CH2 and R3 is 3-quιπolin-4-yl- propyl, the compound of formula 2 wherein R - Me, R* Is H, X Is NH and R3 is 3-(4-ρhenyl- ιmιdazol-1 -yl)-propyl; the compound of formula 2 wherein R is Me, R4 is H, X is CH2 and R3 is 3-(4-phenyl- ιmιdazol-1-yl)-propyl, the compound of formula 2 wherein R is Me, R is H, X is NH and R3 Is 3-(4~(3-pyridinyl)- 1 H-lmldazol-1 -yl)propyl , the compound of formula 2 wherein R is Me, R4 is H, X is CH2 and R3 is 3-(4-(3- pyπdmyl)-1H-ιmιdazol-1-yl)propyl; the compound of formula 2 wherein R is n-butyl, R4 Is H, X is NH and R3 is 3-quιnolιn-4- yl-propyl, the compound of formula 2 wherein R is n-butyl, R4 is H, X is CH2 and R3 is 3-quιnolιn-4- yl-propyl, the compound of formula 2 wherein R is n-butyl, R4 is H, X is NH and R3 is 3-(4-phenyl- ιmιdazol-1-yl)-propyl, the compound of formula 2 wherein R is n-butyl, R4 is H, X is CH. and R3 is 3-(4-phenyl- ιmιdazol-1-yl)-propyl, the compound of formula 2 wherein R is n-butyl, R4 is H, X is NH and Ra is 3-(4-(3- py πdiny l)-1 H-ιmιdazol-1 -yl)propyl; the compound of formula 2 wherein R is n-butyl, R4 is H, X is CH2 and R3 is 3-(4-(3- pyπdιnyl)-1H-imιdazol-1-yl)propyl; the compound of formula 2 wherein R is MeS, R4 is H, X is NH and R3 is 3-quιnolin-4-yl- propyl; the compound of formula 2 wherein R is MeS, R4 is H; X is CH2 and R3 is 3-quιnolin-4-yi- propyl; the compound of formula 2 wherein R is MeS, R4 is H, X is NH and R3 is 3-(4-phenyl- ιmιdazol-1-yl)-propyl; the compound of formula 2 wherein R Is MeS, R4 is H, x is CH2 and R3 i3 3-(4-ρhenyl- ιmιdazol-1-yl)-propyl, the compound of formula 2 wherein R is MeS, R4 is H, X is NH and R3 is 3-(4-(3- py ridiny 1)-1 H-imidazol- 1 -y |)propy I; the compound of formula 2 wherein R is MeS, R* is H, X Is CH2 and R3 is 3-(4-(3- pyridmyl)-1 H-imιdazol-1 -yl)propyl, the compound of formula 2 wherein R is EtS, R4 is H, X is NH and R3 is 3-quιnolin- -yl- propyl; the compound of formula 2 wherein R is EtS, R4 is H, X is CH2 and R3 is 3-quiπolιn-4-yl- propyl; the compound of formula 2 wherein R is EtS, R4 is H. X is NH and R3 is 3-(4-phenyl- imidazol-1-yl)-propyl; the compound of formula 2 wherein R is EtS, R4 is H, X is CH2 and R3 is 3-(4-phenyl- ιmidazol-1-yl)-propyl; the compound of formula 2 wherein R is EtS, R4 is H, X is NH and R3 is 3-(4-(3-pyridinyl)- 1H-ιmidazol-1-yl)propyl; the compound of formula 2 wherein R is EtS, R4 is H, X is CH2 and R3 is 3-(4-(3- ρyridιnyl)-lH-imιdazol-1-yl)propyl; the compound of formula 2 wherein R is cyclopropyl, R4 is H, X is NH and R3 is 3- quiπolιn-4-yl-ρropy|; the compound of formula 2 wherein R is cyclopropyl, R4 is H, X is CH2 and R3 is 3- quinolin-4-yl-propyl, the compound of formula 2 wherein R is cyclopropyl, R4 is H, X is NH and R3 is 3-(4- phenyl-imidazol-1 -yl)-ρropyl; the compound of formula 2 wherein R is cyclopropyl, R4 is H, X is CH2 and R3 is 3-(4- phenyl-imιdazol-1-yl)-ρropyl; the compound of formula 2 wherein R is cyclopropyl, R4 is H, X is NH and R3 is 3-(4-(3- pyπdιπyl)-1 H-imidazol- -yl)propyl; the compound of formula 2 wherein R is cyclopropyl, R4 is H, X is CH2 and R3 is 3-(4-(3- py ridιnyl)-1 H-ιmιdazol-1 -yl)propyl; the compound of formula 2 wherein R is cyclobutyl, R* is H, X is NH and R8 is 3-qulnolιn-
4-yl-propyl, the compound of formula 2 wherein R is cyclobutyl, R4 is H, X is CH2 and R3 is 3- quιnolin-4-yl-propyl, the compound of formula 2 wherein R is cyclobutyl, R4 is H, X is NH and R3 is 3-(4- phenyl-ιmidazol-1 -yl)-propyl; the compound of formula 2 wherein R is cyclobutyl, R4 is H, X is CH2 and R3 is 3-(4- phenyl-ιmidazol-1 -y l)-propy I; the compound of formula 2 wherein R is cyclobutyl, R4 is H, X is NH and R3 is 3-(4-(3- pyridinyl)-lH-imidazol-1-yl)propyl; the compound of formula 2 wherein R is cyclobutyl, R4 is H, X is CH2 and R3 is 3-(4-(3- ρyrιdiπyl)-1H-imιdazol-l-yl)propyl; the compound of formula 2 wherein R is cyclopentyl, R4 is H, X is NH and R3 is 3- quιnolin-4-yl-propyl; the compound of formula 2 wherein R is cyclopentyl, R4 is H, X "ra CH2 and R3 is 3- quiπθlin-4-yl-proρyl; the compound of formula 2 wherein R is cyclopentyl, R4 is H, X is NH and R3 is 3-(4- phenyl-ιmιdazol-1-yl)-propyl, the compound of formula 2 wherein R is cyclopentyl, R4 is H, x is CH2 and Ra is 3-(4- phenyl-lmldazol-1 -y|)-propy|; the compound of formula 2 wherein R is cyclopentyl, R4 is H, X is NH and R3 is 3-(4-(3- pyridinyl)-lH-imιdazol-1-yl)propyl, the compound of formula 2 wherein R is cyclopentyl, R4 is H, X is CH2 and R3 is 3-(4-(3- pyridιnyl)-l H-lmldazoi-1 -yl)propyl, the compound of formula 2 wherein R is cyclohexyl, R4 is H, X is NH and R3 is 3-quinolιn- 4-yl-proρyl, the compound of formula 2 wherein R is cyclohexyl, R4 is H, X is CH2 and R' is 3- quιnolin-4-yl-propyl; the oompound of formula 2 wherein R is cyclohexyl. Rβ is H, X is NH and R3 is 3-(4- phenyl-imidazol-1-yl)-propyl, the compound of formula 2 wherein R is cyclohexyl, R4 is H, X is CH2 and Ra is 3-(4- phenyl-imidazol-1-y|)-propyl; the compound of formula 2 wherein R is cyclohexyl, R4 is H, X is NH and R3 is 3-(4-(3- pyπdinyl)-1 H-ιmidazol-1 -yl)propyl; and the compound of formula 2 wherein R is cyclohexyl, R4 is H, X is CH2 and R3 is 3-(4-(3- pyrιdιnyl)-1H-ιmιdazol-1-yl)propyl.
The preferred compounds of formula 3 wherein the bond between C-9 and the nitrogen to which C-9 is connected is a double bond include those selected from the group consisting of: the compound of formula 3 wherein R is Me, R4 is H, X is NH, R3 is 3-quinolin-4-yl-propyl and R2 is OMe; the compound or formula 3 wnereln R is Me, R" is H, X is NH, R3 is 3-(4-ρhenyl-imιdazol-
1-yl)-propyl and R2 is OMe, the compound of formula 3 wherein R is Me, R4 is H, X is NH, R3 is 3-(4-(3-pyπdιnyl)-1H- ιmιdazol-1-yl)propyl and R2 is OMe; the compound of formula 3 wherein R is n-butyl, R4 is H, X Is NH, R3 Is 3-quιnolιn-4-yl- propyl and R2 is OMe; the compound of formula 3 wherein R is n-butyl, R4 is H, X is NH, R3 is 3-(4-phenyl- ιmιdazol-1-yl)-propyl and R2 is OMe; the compound of formula 3 wherein R is n-butyl, R4 is H, X is NH, R° is 3-(4-(3-pyrιdιnyl)- 1H-ιmιdazol-l-yl)propyi and R2 is OMe, the compound of formula 3 wherein R is MeS, R4 is H, X is NH, R3 is 3-quinolιn-4-yl- propyl and R2 is OMe; the compound of formula 3 wherein R is MeS, R4 is H, X is NH, R3 is 3-(4-phenyl- ιmidazol-1-yl)-proρyl and R2 is OMe; the compound of formula 3 wherein R is MeS, R4 is H, X is NH, R3 is 3-(4-(3-pyndinyl)- 1H-imidazol-1-yl)propyl and R2 is OMe, the compound of formula 3 wherein R is EtS, R4 is H, X is NH, R3 is 3-quιnolin-4-yl-propyl and Rz is OMe, the compound of formula 3 wherein R tø EtS, RΛ iε H, X is NH, R3 is 3-(4-phenyl- ιmidazol-1-yl)-propyl and R2 is OMe, the compound of formula 3 wherein R is EtS, R4 is H, X is NH, R3 is 3-(4-(3-ρyrιdιnyl)-1H- imιdazol-1-yl)propyl and R2 is OMe; the compound of formula 3 wherein R is cyclopropyl, R4 is H, X is NH, R3 is 3-quιnolιn-4- yl-ρropyl and R2 is OMe; the compound of formula 3 wherein R is cyclopropyl, R4 is H, X is NH, R3 is 3-(4-phenyl- ιmιdazol-1-yl)-propyl and R2 is OMe the compound of formula 3 wherein R is cyclopropyl, R4 is H, X is NH, R3 is 3-(4-(3- pyπdιnyl)-1H-ιmιdazol-1-yl)propyl and R2 is OMe the compound of formula 3 wherein R is cyclobutyl, R4 is H, X is NH, R3 is 3-quιnolιn-4- yl-propyl and R2 is OMe; the compound of formula 3 wherein R is cyclobutyl, R4 is H, X is NH, R3 is 3-(4-ρhenyi- ιmιdazol-1-y])-propyl and R2 is OMe, the compound of formula 3 wherein R is cyclobutyl, R4 is H, X is NH, R3 is 3-(4-(3- ρyrιdιnyl)-1H-ιmιdazol-1-yl)propyl and R2 is OMe, the compound of formula 3 wherein R is cyclopentyl, R4 is H, X is NH, R3 is 3-quιnolιn-4- yl-propyl and R* is OMe; the compound of formula 3 wherein R is cyclopentyl, R4 is H, X is NH, R3 is 3-(4-phenyl- ιmιdazol-1-yl)-propyl and R2 is OMe; the compound of formula 3 wherein R is cyclopentyl, R4 is H, X is NH, R3 is 3-(4-(3- pyπdιnyi)-1H-ιrnιdazol-1-yl)proρyl and Rz is OMe, the compound of formula 3 wherein R is cyclohexyl, R4 te H, X is NH, R3 is 3-quιnolιπ-4- yl-propyl and R2 is OMe the compound of formula 3 wherein R is cyclohexyl, R4 is H, X is NH, R3 is 3-(4-phenyl- ιmιdazol-1-yl)-propyl and R2 is OMe; and the compound of formula 3 wherein R is cyclohexyl, R4 is H, x is NH, R3 ιβ 3-(4-(3 pyrιdιnyl)-1H-ιmιdazol-1-yl)propyl and R2 is OMe
Other preferred compounds of formula 3, wherein the bond between C-9 and the nitrogen to which C-9 is connected is a single bond, include those wherein: the compound of formula 3 wherein R4 is H, X is NH, R3 is 3-quιnolln-4-yl-propyl, R1 Is H and R2 Is Me, Et, or π-Pr, the compound of formula 3 wherein R is Me, R* is H, X is NH, R3 is 3-(4-phenyi-ιmιdazol-
1-yl)-ρropy!; R1 is H and R2 is Me, Et, or n-Pr, the compound of formula 3 wherein R is Me, R4 is H, X is NH, R3 is 3-(4-(3-ρyπdιqyl)-1 H- ιmιdazol-1-yl)propyl, R1 Is H and R2 Is Me, Et, or π-Pr, the compound of formula 3 wherein R is n-butyl, R4 is H, X is NH, R3 is 3-quιnolιn-4-yl- propyl R1 is H and R2 is Me, Et, or n-Pr, the compound of formula 3 wherein R is n-butyl, R* is H, X is NH. R3 is 3-(4-phenyl- ιmιdazol-1-yl)-propyl, R1 is H and R2 is Me, Et, or n-Pr, the compound of formula 3 wherein R is n-buty! R* is H. X is NH R3 is 3-(4-(3-pyndinyl)- 1H-ιmιdazol-1-yl)propyl, R1 is H and R2 is Me, Et, or n-Pr, the compound of formula 3 wherein R is MeS, R4 is H, X is NH, R3 is 3-quinolin-4-yl- propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of formula 3 wherein R is MeS, R4 is H, X is NH, R3 is 3-(4-phenyl- ιmιdazol-1-yl)-propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of formula 3 wherein R is MeS, R4 is H, X is NH, R3 is 3-(4-(3-ρyπdinyl)- lH-irnidazol-1-y|)ρropyl R1 is H and Rz is Me, Et, or n-Pr, the compound of formula 3 wherein R is EtS, R4 is H, X is NH, R3 is 3-quinolin-4-yl- propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of formula 3 wherein R is EtS, R4 is H, X is NH, R3 is 3-(4-phenyl- ιmidazol-1-yl)-propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of formula 3 wherein R is EtS, RΛ is H, X Is NH, R3 Is 3-(4-(3-pyridinyl)-l H- ιmidazol-1-yl)propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of formula 3 wherein R is cyclopropyl, R4 is H, X is NH, R3 is 3-quinolιn-4- yl-propyl, R1 is H and R2 is Me, Et, or n-Pr the compound of formula 3 wherein R is cyclopropyl, R" is H, X is NH, R3 Is 3-(4-phenyl- ιmldazol-1-yl)-propyl, R1 is H and R2 i3 Me, Et, or n-Pr, the compound of formula 3 wherein R is cyclopropyl, R4 is H, X is NH, R3 is 3-(4-(3- ρyridinyl)-lH-imidazol-1-yl)propyl, R1 is H and R2 is Me, Et, or n-Pr, the compound of formula 3 wherein R is cyclobutyl, R4 is H, X is NH,R3 is 3-quinolin-4-yl- propyl, R is H and R* is Me. Et, or n-Pr; the compound of formula 3 wherein R is cyclobutyl, R4 is H, X is NH, R3 is 3-(4-phenyl- imidazol-1-yl)-propyl, R1 is H and R2 is Me, Et, or n-Pr, the compound of formula 3 wherein R is cyclobutyl, R4 is H, X is NH,R3 is 3-(4-(3- pyπdinyl)-1H-imidazol-1-yl)propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of formula 3 wherein R is cyclopentyl, R* is H, X is NH, R3 is 3-quιnolin-4- yl-propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of formula 3 wherein R is cyclopentyl, R4 is H, X is NH, R3 is 3-(4-phenyl- ιmidazol-l-yl)-propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of formula 3 wherein R is cyclopentyl, R4 is H, X is NH, R3 is 3-(4-(3- pyndinyl)-1H-imidazol-1-yl)ρropyl, R is H and R2 is Me, Et, or n-Pr; the compound of formula 3 wherein R is cyclohexyl, R4 is H, X is NH, R3 is 3-quinolin-4- yl-propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of formula 3 wherein R is cyclohexyl, R4 is H, X is NH, R3 is 3-(4-phenyl- ιmιdazol-1-yl)-proρyl, R is H and R2 is Me, Et, or n-Pr, and the compound of formula 3 wherein R is cyclohexyl, R4 is H, X is NH, R3 is 3-(4-(3- pyπdιnyl)-1H-imιdazol-1-yl)propyl, R is H and R2 is Me, Et, or n-Pr.
The preferred compounds of formula 5 include those selected from the group consisting ot the compound of formula 5 wherein R is Me, R4 is H, R3 is 3-quinolϊn-4-yl-proρyl, R7 is H, Rβ is H and R2 is H, Me, or Et; the compound of formula 5 wherein R is Me, R4 is H, Rs is 3-(4-phenyl-imιdazol-1-yl)- propyl, R7 is H, RB is H and R2 is H, Me, or Et; the compound of formula 5 wherein R is Me, R4 is H, R3 is 3-(4-(3-pyrιdinyl)-1H-ιmιdazol- 1-yl)propyl, R7 is H, Rβ is H and R2 is H, Me, or Et; the compound of formula 5 wherein R is n-butyl, R4 is H, R3 is 3-quιnolin~4-yl-propyl, R7 is H, Rβ is H and Rz is H, Me, or Et; the compound of formula 5 wherein R is n-butyl, R" is H, R3 is 3-(4-phenyl-ιmidazol-1-yl)- propyl, R7 is H, Rβ is H and R2 is H, Me, or Et; the compound of formula 5 wherein R is n-butyl, R4 is H, R3 is 3-(4-(3-pyridinyl)-1 H- imιdazol-1-yl)propyl, R1 is H, R7is H, Rβ is H and R* is H, Me, or Et; the compound of formula 5 wherein R is MeS, R4 is H, R3 is 3-quinolin--ι~yl-propyl, R7 |S
H, R8 is H and 2 is H, Me, or Et; the compound of formula 5 wherein R is MeS, R4 is H, R3 is 3-(4-ρhenyl-imidazol-1-yl)- propyl, R7is Rβis H and R2 is H, Me, or Et, the compound of formula 5 wherein R Is MeS, R4 is H, R3 is 3-(4-(3-ρyπdinyl)-1H- ιmidazol-1-yDpropyl, R7 is H, Rβ is H and R2 is H, Me, or Et; the compound of formula 5 wherein R is EtS, R4 is H, R3 is 3-quinolin-4-yl-propyl, R7 is H, Ra is H and R2 is H, Me, or Et; the compound of formula 5 wherein R is EtS, R4 is H, R3 is 3-(4-phenyhmldazol-1-yt)~ propyl, R7 Is H, R8 Is H and R2 is H, Me, or Et; the compound of formula 5 wherein R is EtS, R4 is H, R3 is 3-(4-(3-pyrιdιnyl)-1H-ιmιdazol-
1-yl)propyl, R7is H, Rβis H and R2 is H, Me, or Et; the compound of formula 5 wherein R is cyclopropyl, R4 is H, R3 is 3-quinolιn-4-yl-propyl, R7 is H, Rβ is H and R! is H, Me, or Et, the compound of formula 5 wherein R is cyclopropyl, R4 is H, R3 is 3-(4-phenyl-imidazol- 1-yl)-propyl, R7 is H, R8 is H and R2 is H, Me, or Et; the compound of formula 5 wherein R is cyclopropyl, R4 is H, R3 is 3-(4-(3-pyrιdιnyl)-1H- imidazol-1-yl)ρropyl, R7 is H, R8 is H and R2 is H, Me, or Et; the compound of formula 5 wherein R is cyclobutyl, R4 is H. R3 is 3-quinolin-4-yl-propyl, R7 is H, R8 is H and R2 is H, Me, or Et; the compound of formula 5 wherein R is cyclobutyl, R4 is H, R3 is 3-(4-phenyl-ιmιdazol-l- yl)-propyt, R7 is H, R8 is H and R2 is H, Me, or Et, the compound of formula β wherein R is cyclobutyl, R4 is H, R3 is 3-(4-(3-pyrιdinyl)-1 H- ιmιdazol-1-yl)propyl, R7 is H, R8 is H and R2 is H, Me, or Et, the compound of formula 5 wherein R is cyclopentyl, R4 is H, R3 is 3-quιnolin-4-yl-propyl, R7 is H, Rβ is H and R2 is H, Me, or Et, the compound of formula 5 wherein R is cyclopentyl, R4 is H, R3 is 3-(4-phenyl-ιmιdazol- 1-yl)-propyl, R7 is H, R8 is H and R2 is H, Me, or Et; the compound of formula 5 wherein R is cyclopentyl, R4 is H, R3 is 3-(4-(3-pyrιdιπyl)-1 H- ιmιdazol-1-yl)propyl, R7 ιs H, Rβ ιs H and R2 is H, Me, or Et, the compound of formula 5 wherein R Is cyclohexyl, R is H, R3 i3 3-quιnolιn-4-yl-proρyl,
R7 is H, Re is H and R2 is H, Me, or Et, the compound of formula 5 wherein R is cyclohexyl, R4 is H, R3 is 3-(4-ρhenyl-ιmιdazol-l- yl)-propyl, R7ιs H, R8 is H and R2 is H, Me, or Et, and the compound of formula 5 wherein R is cyclohexyl, R4 is H, R3 Is 3-(4-(3-pyrldιnyl)-ι H- lmldazol-1-yl)propyl, R7 is H, Rβ IS H and R2 is H, Me or Et
The invention also relates to a pharmaceutical composition for the treatment of a bacteπal infection or a protozoa infection in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of formulas 1_, 2, 3, 4 or 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier The invention also relates to a method of treating a bacterial infection or a protozoa infection in a mammal, fish, or bird which compπses administering to said mammal, fish or bird a therapeutically effective amount of a compound of formula 1_, 2, 3, 4 or 5 or a pharmaceutically acceptable salt thereof
The invention also relates to a process for preparing a compound of the formula
Figure imgf000021_0001
or a pharmaceutically acceptable salt thereof, wherein:
R is methyl, an alpha-branched C3-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C3-C8 cycloalkyl group wherein the alkyl group is an alpha-branched crcB alkyl group, a C3-Ca cycloalkyl or CS-CB cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocychc nng which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more CrC4 alkyl groups or halo atoms, or R is phenyl which may be optionally substituted with at least one substituent selected from C,-C4 alkyl, C,-C4 alkoxy and C,-C4 alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano, or R may be with a formula (a) as shown below
Figure imgf000021_0002
wherein X1 is 0, S or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d < 5, and
R4 is H or acyl of an organic acid of up to 18 carbon atoms, which compπses treating a compound of the formula
Figure imgf000022_0001
22
wherein R and R4 are as defined in formula l^with a hydrolyzing agent.
The invention also relates to a process for preparing a compound of the formula
Figure imgf000022_0002
wherein R, R3, * and Rs are as defined in formula 2 and X in formula 2 is -NR6 which comprises treating a compound of the formula
Figure imgf000023_0001
wherein R and R4 are as defined in formula 2, with an alkylating agent.
The Invention also relates to a process for preparing a compound of the formula
Figure imgf000023_0002
wherein R, R3, R4, R£ and R6 are as defined in formula 2 and X in formula 2 is -(CR5Rβ)g- which comprises treating a compound of the formula
Figure imgf000024_0001
wherein R is as defined in formula 2 with a compound of the formula Ra- C(R6R6)g-NH2l wherein g is 0 or 1 and R*, Rs and Rε are as defined in formula 2 The invention also relates to a process for preparing a compound of the formula
Figure imgf000024_0002
wherein R and R4 are as defined in formula 2, by treating a compound of the formula
Figure imgf000025_0001
wherein R is as defined in formula 2, with NH2NH2.
The invention also relates to a process for prepaπng a compound of the formula
Figure imgf000025_0002
wherein R is as defined in formula 2 which comprises treating a compound of the formula
Figure imgf000026_0001
wherein R is as defined in formula 2 with carbonyldiimidazole.
The invention also relates to a process for preparing a compound of the formula
Figure imgf000026_0002
wherein R is as defined in formula 2 which comprises treating a compound of the formula
Figure imgf000026_0003
wherein R is as defined in formula 2 with a base.
The invention also relates to a process for preparing a compound of the formula
Figure imgf000027_0001
wherein R is as defined in formula 2 which comprises treating a compound of the formula
Figure imgf000027_0002
wherein R is as defined in formula 2 with an oxidizing agent.
The invention also relates to a process for preparing a compound of the formula
Figure imgf000028_0001
wherein R is as defined in formula 2 which comprises treating a compound of the formula
Figure imgf000028_0002
14 wherein R is as defined in formula 2 with an acid.
The invention also relates to a process for preparing a compound of the formula
Figure imgf000029_0001
14
wherein R is as defined in formula 2 which comprises treating a compound of the formula
Figure imgf000029_0002
wherein R is as defined in formula 2, with trichloromethylisocyanate, ethylene carbonate or caronyyldiϊmidazole.
The invention also relates to a process for preparing a compound of the formula
Figure imgf000030_0001
wherein R is as defined in formula 2 which comprises treating a compound of the formula
Figure imgf000030_0002
wherein R is as defined in formula 2 with an acylating agent
The invention further relates to a compound of the formula
Figure imgf000031_0001
or a pharmaceutically acceptable salt thereof, wherein:
R is an alpha-branched C3-CB alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups, a Cs-C8 cycloalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or C3-C8 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4 alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with at least one substituent selected from C,-C alkyl, C,-C4 alkoxy and C,-C4 alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano; or R may be with a formula (a) as shown below
Figure imgf000031_0002
wherein X1 is O, S or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d < 5; or R is CH2R24, wherein R24 is H, C,-C„alkyl, C2-C8alkenyl, C2-C8alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms; or a C3-C8cycloalkyl or C3-C8cyc|oalkenyl either or which may be optionally substituted by methyl or one or more C,-C4alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms, or a group of the formula SR23 wherein R23 is C,-Caalkyl, C2-C8alkenyl, C_- C8alkynyl, C3-C8cycloalkyl, C5-C8cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C,-C4alkyl, C,-C alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic πng which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms, and
R4 is H or acyl of an organic acid of up to 18 carbon atoms.
The invention also relates to a compound of the formula
Figure imgf000032_0001
or a pharmaceutically acceptable salt thereof, wherein
R is an alpha-branched C3-C8 alkyl, alkenyl, alkynyl alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups, a C5-C8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group, a C3-Ca cycloalkyl or C5-Ca cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C4 alkyl groups or halo atoms, or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4 alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with at least one substituent selected from C,-C4 alkyl C,-C4 alkoxy and Q _-C . alkylthio groups, halogen atoms, hydroxyl groups, tπfluorornethyl, and cyano, or R may be with a formula (a) as shown below
Figure imgf000033_0001
wherein X1 Is O, S or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d 5;
X is -(CR5Rβ)g- or -NR5-, wherein g is 0 or 1 ; wherein when X is -NR5-, X and R3 optionally may be taken together to form -N=CR7R8, or when X is -NR5-, X and R3 optionally may be taken together to form a heterocyclic of the formula
Figure imgf000033_0002
wherein n is selected from an integer ranging from 1 to 3, p is selected from an integer ranging from 1 to 3, q is 0 or 1 , and R* is selected from CH2, O, S, 0=O, C=S, S02, -CH=CH-, - CH(OH)CH(OH)-, and NH; or when X Is -NRS-, x and R3 together form a heterocyclic as defined above having substituents selected from the group consisting of -C(0)OR10, -OR10. Cι-C,0 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, C8-C,Q aryl, -C(O)NR10R12, -NHC(0)R10, - NHC(O)NR10R11, -NR^R11, -SR10, -S(0)R10, -S02R'° and -S02NR1DRn; or R is CH2R24, wherein R24 is H, C,-Caalkyl, C2-C8alkenyl, C2-C8alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms; or a C3-CBcycloalkyl or C6-C8cycloalkenyl either or which may be optionally substituted by methyl or one or more C,-C4alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms; or a group of the formula SR23 wherein R23 is C,-C8alkyl, C2-C8alkenyl, C2- C8alkynyl, C3-C8cycloalkyl, C5-C8cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C1-C4alkyl, C,-C4alkoχy or halo, or a 3 to 6 membered oxygen or sulphur-coπtainmg heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C_alkyl groups or halo atoms; R10 and R11 are each independently selected from H, C,-C,0 alkyl; or R3 is selected from H, C(=0)Z, C(=O)0Z, (CR5R6)mZ , C(=0)R7, C(=0)OR7, (CR5R6)mR7, wherein m is an integer ranging from 0 to 6,
Z is a 4-10 membered heterocyclic or C6-C,0 aryl, wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -C(0)OR , -OR , 11- , C,-C,0 alkanoyl, halo, nitro, cyano, R 10 , 4-10 membered
- .aa .\ heterocyclic, C6-C,n aryl, -C(0)NR1UR1, 1 -NHC(0)R10, -NHC(0)NR 0R11, NR10R11, -SR10, S(0)R1q -S02R10 and -S02NR10 R11,
R4 is H or acyl of an organic carboxylic acid of up to 18 carbon atoms, Rs and R6 are each independently selected from H, C,-C6 alkyl, halogen and Rs and R6 may each independently vary when m is greater than 1; and
R7 and Rβ are each independently selected from H, C,-C,8 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting Of -C(0)OR1°, - OR10, C.-C-o alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, C8-C,0 aryl, -
NR10R11, -C(O)NR10R11, -NH0(O)R10, -NHC(O)NR10R , -SR10, -S(0)R10, -S02R10 and
SO,NR10R11.
The invention further relates to a compound of the formula
Figure imgf000034_0001
or a pharmaceutically acceptable salt thereof, wherein
R is an alpha-branched C3-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-CB cycloalkyl or C5-C8 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4 alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with at least one substituent selected from C,-C4 alkyl. 0,-CΛ alkoxy and C,-C4 alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano; or R may be with a formula (a) as shown below:
Figure imgf000035_0001
wherein X1 is O, S or -CH2-, a, b, c, and d are each independently selected from an Integer ranging from 0 to 2 and a + b + e + d 5;
X is -(CR^6),- or -NR5-, wherein g is 0 or 1 , wherein when X is -NR5-, X and R3 optionally may be taken together to form -N=CR7Rβ, or when X is -NR5-, X and R3 optionally may be taken together to form a heterocyclic of the formula
Figure imgf000035_0002
wherein n is selected from an integer ranging from 1 to 3, p is selected from an integer ranging from 1 to 3, q is 0 or 1 , and R9 is selected from CH2, O, S, C=0, C=S, S02, -CH=CH-, -CH(OH)CH(OH)-, and NH; or when X is -NR5-, X and R3 together form a heterocyclic as defined above having substituents selected from the group consisting of -C(0)OR10, -OR10, C _-C_0 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, Cβ-C,α aryl. -C(0)NR1ύR11, -NH0(O)R10, -NHC(O)NR10R11, -NRWR", -SR10, -S(0)R10, -S02R10 and -SO2NR10R11; or R is CH2R24, wherein R24 is H, C C8alkyl, C2-C8alkenyl, C2-Cβalkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms, or a C3-C8cycloalkyl or C3-C8cycioalkenyl either or which may be optionally substituted by methyl or one or more C,-C4alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C,-C alkyl groups or halo atoms, or a group of the formula SR23 wherein R23 is C,-CBalkyl, C2-CBalkeπyl, C2- Cβalkynyl, C3-C8cycloalkyl, C5-C8cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C,-C4alkyl, C,-C4alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms, R10 and R11 are each independently selected from H, C,-C1D alkyl or R3 is selected from H, C(=0)Z, C(=0)OZ, (CR5Rβ)mZ , C(=0)R7, C(=0)OR7 (CR5R6) R7 wherein m is selected from an integer ranging from 0 to 6, Z is a 4-10 membered heterocyclic or C6-C10 aryl, wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -C(0)OR1D, -OR10, C,-C10 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, C6-C,0 aryl, -0(O)NR1QR11, -NH0(O)R10, -NHC(O)NR10R11, -NR10R11, -SR10, -S(0)R10 -S02R1° and -S02NR10 R11, R" Is H or acyl of an organic carboxylic acid of up to 18 carbon atoms,
R5 and Rε are each independently selected from H, C,-C6 alkyl, halogen and R5 and R6 may each independently vary when m is greater than 1 , where the bond between 09 and the nitrogen to which 09 is linked is a single bond, R1 and R* together with the nitrogen atom to which they are linked optionally may together form -N=CR7Rβ, or R1 and R2 together with the nitrogen atom to which they are linked optionally may together form a heterocyclic of the formula
Figure imgf000036_0001
wherein n is selected from an integer ranging from 1 to 3, p is selected from an integer ranging from 1 to 3, q is 0 or 1, and R9 is selected from CHZ, O, S, 0=0, C=S, S02, -CH=CH-, -CH(OH)CH(OH)-, and NH, or X and R3 together form a heterocyclic as defined above having substituents selected from the group consisting of -C(0)OR10, -OR10, C,-C,0 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, C6-C10 aryl, -C(O)NR10R11, -NHC(0)R10, -NHC(O)NRl0R11, -NR10R11, -SR10, -S(0)R10, -S02R10 and -S02NR10 R11, and
R , RS, R7, and Rβ are each independently selected from H, c,-C,2 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)OR10, -OR10, C,-C,o alkanoyl, halo, nitro, cyano, R1° 4-10 membered heterocyclic, C6-C10 aryl -C(O)NR10R11, -NHC(0)R10, -NHC(O)NR10R11, NR10R11, -SR10, -S(0)R10, -S02R10 and -SO2NR10R11, where the bond between 09 and the nitrogen to which 09 is linked is a double bond, R1 s not existent, and R2 is OR7, wherein R7 is defined as above
The invention also relates to a compound of the formula
Figure imgf000037_0001
or a pharmaceutically acceptable salt thereof, wherein
R is an alpha-branched C3-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cyciαalkyl or C5-C3 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C1-C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C1-C4 alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with at least one substituent selected from C1-C4 alkyl, C1-C4 alkoxy and C1-C4 alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl. and cyano, or R may be with a formula (a) as shown below
Figure imgf000037_0002
wherein X1 is O, 5 or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d 5, or R is CH2R24, wherein R24 is H, C,-Cβalkyl, C2-C8alkenyl, C2-C8alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups -3-3-
or by one or mora halo atoms, or a C3-CBcycloalkyl or C5-C8cycloalkenyl either or which may be optionally substituted by methyl or one or more C,-C4alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms; or a group of the formula SR23 wherein R23 is C,-C8alkyl, C2-C8alkeπyl, Cz- C8alkynyl, C3-C8cycloalkyl, C3-CBcyc|oalkenyl, phenyl or substituted phenyl wherein the substituent is C,-C4alkyl, C,-C4alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms,
R3, Rz, R7, and RB are independently selected from H, C,-C,8 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)OR10, -OR10, C C,0 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, C6-C1C1 aryl,
-C(O)NR10R11, -NHC(0)R10, -NHC(O)NR10R11, -NR,0R11, -SR10, -S(0)R10, -S02R 10 and -SO2NR 0R1'; and
R10 and R11 are each independently selected from H, C,-Cια alkyl; and R4 is H or acyl of an organic carboxylic acid of up to 18 carbon atoms. The invention also relates to a compound of the formula
Figure imgf000038_0001
or a pharmaceutically acceptable salt thereof, wherein-
R is an alpha-branched C3-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups, a C,-C0 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or C5-CB cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4 alkyl groups or halo atoms, or R is phenyl which may be optionally substituted with at least one substituent selected from C,-C4 alkyl, C,-C4 alkoxy and C,-C4 alkylthio groups, halogen atoms, hydroxyl groups, tπfluoromethyl, and cyano, or R may be with a formula (a) as shown below
Figure imgf000039_0001
wherein X1 is O, S or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d < 5, or R is CHjR24, wherein R24 is H, C,-C„alkyl, C2-C8alkenyl, C2-Cβalkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms, or a C3-CBcycloalkyl or C5-C8cycloalkenyl either or which may be optionally substituted by methyl or one or more C,-C4alkyl groups or halo atoms, or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms; or a group of the formula SR23 wherein R23 is C,-Cβalkyl, C2-Cβalkenyl, Ca- C8alkynyl, C3-C8cycloalkyl, C5-C8cyc|oalkenyl, phenyl or substituted phenyl wherein the substituent is C,-C4alkyl, C,-C4alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms, R10 and R11 are independently selected from H, C,-C,β alkyl,
R3 is selected from H, C(=0)Z, 0(=O)OZ, (CR6Rβ)mZ, 0(=O)R7, C(=0)OR7, (CRsR6)mR7 wherein m is selected from an integer ranging from 0 to 6,
Z is a 4-10 membered heterocyclic or C6 C,Q aryl, wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -C(0)OR10, -OR10, C,-C10 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, C6-C10 aryl, -C(O)NR10R11, -NHC(D)R10, -NHC(O)NR10R11, -NR10R11, -SR10, -S(0)R10 -S02R10 and ~S02NR1° R11,
Rs and R6 are independently selected from H, CrCβ alkyl, halogen and R5 and R6 may each vary independently when m is greater than 1; Rz, R7, and R8 are each independently selected from H, C,-C1β alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -0(O)OR10, -OR10, C,-C,Q alkanoyl, halo, nitro, cyano, R 0, 4-10 membered heterocyclic, C6-C,o aryl, -C(O)NR10R11, -NHC(0)R10, -NHC(O)NR10R11, -NR1DR11, -SR10, -S(0)R10, -S02R10 and -SO2NR10R11; and
R4 is H or acyl of an organic carboxylic acid of up to 18 carbon atoms.
The term "treatment", as used herein, unless otherwise indicated, includes the treatment or prevention of a bacterial infection or protozoa Infection as provided In the method of the present invention.
As used herein, unless otherwise indicated, the term "bacterial ιnfection(s)" or "protozoa infections; includes bacterial infections and protozoa infections that occur in mammals, fish and birds as well as disorders related to bacterial infections and protozoa infections that may be treated or prevented by administering antibiotics such as the compounds of the present invention. Such bacterial infections and protozoa infections and disorders related to such infections include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumomae, Haemophilus tnfluenzae, Moraxella catarrhalts, Staphylococcυs aurβus, or Pβptosirβpiococcus spp ; pharynlgltls, rheumatic fever, and glomeruloπβphπtiβ related to infection by Streptococcus pyαgenes. Groups C and G streptococci. Clostridium diptheriae, or Actmobacillus hae olyticum; respiratory tract infections related to infection by Mycoplasma pneumomae, Legionella pneumophila. Streptococcus pneumomae, Haemophilus influβnzaβ, or Chlamydia pneυmoniae; uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, and puerperal fever related to infection by Staphylococcus aureus, coagulase-positive staphylococci (i.e., S epidβrmidis, S. hemolyticus, etc ), Streptococcus pyogenes , Streptococcus aga.acf.ae, Streptococcal groups C-F (minute- colony streptococci), viridaπs streptococci, Corynebactβnum minutissimum. Clostridium spp., or Bartonella henselae; uncomplicated acute urinary tract infections related to infection by Staphylococcus saprophyticus or Entβrococcus spp . urethritis and cervicitis; and sexually transmitted diseases related to infection by Chlamydia trachornatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; toxin diseases related to infection by S. aureus (food poisoning and Toxic shock syndrome), or Groups A, . and C streptococci; ulcerβ related to infection by Halicobβctβr pylori, systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorfeπ, conjunctivitis, keratitis, and dacrocystitis related to infection by Chlamydia trachornatis, Neisseria gonorrhoeae, S aureus, S pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminated Mycobactβnum avium complex (MAC) disease related to infection by Mycobactdnum avium. or Mycobactenum intracellulare; gastroenteritis related to infection by Campyhbactβr jejuni, intestinal protozoa related to infection by Cryptosporidium spp., odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by Bordetella pertussis; gas gangrene related to infection by Clostridium perfringβπs or Bacteroides spp.; and atherosclerosis related to infection by Helicαbacter pylori or Chlamydia pneumoniaβ. Bacterial infections and protozoa infections and disorders related to such infections that may be treated or prevented in animals include the following: bovine respiratory disease related to infection by P. haem., P. multocida, Mycoplasma bovis, or Bordetella spp,; cow enteric disease related to infection by E coli or protozoa (i.e , coccidia, cryptosporidia, etc.); dairy cow mastitis related to infection by Staph. aureus, Strep, uberis, Strep, agalactiae, Strep, dysgalactiae, Klebsiβlla spp., Corynebacterium, or Enterococcus spp.; swine respiratory disease related to infection by A. pleuro., P. multocida, or Mycoplasma spp.; swine enteric disease related to infection by E. coll, Lawsonla intracellularls, Salmonella, or Seφulina hyodyisinteriaβ; cow footrot related to infection by Fusobacterium spp.; cow metritis related to infection by E. coli; cow hairy warts related to infection by Fusobacterium necrophorum or Bacteroides nodosus; cow pink-eye related to infection by Moraxella bovis; cow premature abortion related to infection by protozoa (i.e. neosporium); urinary tract infection in dogs and cats related to infection by E coli; skin and soft tissue infections in dogs and cats related to infection by Staph. epidβrmidis, Staph. intermedius, cαagulase neg. Staph. or P. multocida; and dental or mouth infections in dogs and cats related to infection by Alcaligenes spp., Bacteroides spp., Clostridium spp,, Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella. Other bacterial infections and protozoa infections and disorders related to such infections that may be treated or prevented in accord with the method of the present invention are referred to in J, P. Sanford et al,, "The Sanford Guide To Antimicrobial Therapy," 26th Edition, (Antimicrobial Therapy, Inc., 1996).
The present invention also relates to a method of preparing the above compounds of formulas 1_, 2, 3, 4, and 5. The compounds of the present invention can be prepared as follows . The starting compounds used in the preparation of the compounds of formulas 1_, 2, 3, 4 and 5 can prepared using the methods described below and further, in International Application No. PCT/GB97/01810 filed July 4, 1997 (Peter Francis Leadlay, James Staunton, Jesus Cortes and Michael Stephen Pacey). and International Application No. PCT/GB97/01819 filed July 4, 1997 (Peter Francis Leadlay, James Staunton, and Jesus Cortes), both of which are incorporated herein by reference in their entirety. The compounds of formulas 1, 2, 3, 4, and 5 can then be prepared from these starting compounds using conventional methods known to one skilled in the art.
The present invention also relates to the compounds of formulas 2 to 20 which, are useful in the preparation of the above compounds of formulas 1^, 2, 3, 4 or 5 and pharmaceutically acceptable salts thereof.
Polyketides, and methods and means for preparing them, and specifically the novel maerolides that are useful in the preparation of the compounds Of the present invention are prepared by fermenting suitable organisms in the presence of a carboxylic acid of the formula RC02H, where R is as defined the compound of formula 1 A preferred organism is Saccharopolyspora erythraβa preferably containing an integrated plasmid capable or directing synthesis of desired compounds In producing such novel polyketides, polyketide biosynthetic genes or portions of them, which may be derived from different polyketide biosynthetic gene clusters are manipulated to allow the production of novel erythromycins.
Polyketides are a large and structurally diverse class of natural products that includes many compounds possessing antibiotic or other pharmacological properties, such as erythromycin, tetracyc nes, rapamycin, avermectin, polyether ionophores, and FK506. In particular, polyketides are abundantly produced by Streptomyces and related actinomycete bacteria They are syπthesised by the repeated stepwise condensation of acylthioesters in a manner analogous to that of fatty acid biosynthesis. The greater structural diversity found among natural polyketides arises from the selection of (usually) acetate or propionate as "starter" or "extender" units; and from the differing degree of processing of the b-keto group observed after each condensation Examples of processing steps include reduction to b-hydroxyacyl-, reduction followed by dehydration to 2-enoyl-, and complete reduction to the saturated acylthioester The Stereochemical outcome of these processing steps is also specified for each cycle of chain extension The biosynthesis of polyketides is initiated by a group of chain-forming enzymes known as polyketide syntheses. Two classes of polyketide synthase (PKS) have been descnbed in actinomycetes, However, the novel polyketides and processes which are used in preparing the compounds the present invention are syntheslsed by Type I PKS's, represented by the PKS's for the maerolides erythromycin, avermectin and rapamycin, and consist of a different set or "module" of enzymes for each cycle of polyketide chain extension (Cortes, J. et al. Nature (1990) 348:176-178; Doπadio, S. et al. Science (1991) 252:675-679, MacNeil, D. J. et al. Gene (1992), 115-119-125, Schwecke, T. et al. Proc. Natl. Acad. Sci. USA (1995) 92:7839-7843). Note: The term "natural module" as used herein refers to the set of contiguous domains, from a b- ketoacylsynthase ("KS") gene to the next acyl carrier protein ("ACP") gene, which accomplishes one cycle of polyketide chain extension. The term "combinatorial module" is used to refer to any group of contiguous domains (and domain parts), extending from a first point in a first natural module, to a second equivalent point in a second natural module. The first and second points will generally be in core domains which are present in all modules, i e , both at equivalent points of respective KS, AT (acyl transferase), ACP domains, or in linker regions between domains. The organisation of the erythromycin producing PKS, (also known as 6- deoxyerythronolide B syπthase, DEBS) genes contains three open reading frames encode the DEBS polypeptides The genes are organised in six repeated units designated modules The first open reading frame encodes the first multi-enzyme or cassette (DEBS1) which consists of three modules- the loading module (ery-load) and two extension modules (modules 1 and 2) The loading module comprises an acyl transferase and an acyl carrier protein This may be contrasted with Figure 1 of W093/13663 (referred to below) This shows ORF1 to consist of only two modules, the first of which is in fact both the loading module and the first extension module
In-frame deletion of the DNA encoding part of the ketoreductase domain of module 5 in DEBS has been shown to lead to the formation of erythromycin analogues 5,6-dιdeoxy-3- -mycarosyl-5-oxoerythronolιde B, 5,θ-dideoχy-5-oxoerythronolιde B and 5,6-dιdeoxy-6,S -epoxy-5-oxoerythronolιde B (Donadio, S et al. Science, (1991 ) 252 675-679) Likewise, alteration of active site residues in the enoylreductase domain of module 4 in DEBS, by genetic engineering of the corresponding PKS-encoding DNA and its introduction into Saccharopolyspora erythraea, led to the production of β,7-anhydroerythromycιn C (Donadio S, et al Proc Natl. Acad. Sci. USA (1B93) 90 7119-7123).
International Patent Application number WO 93/13663, which is incorporated herein by reference in its entirety, describes additional types of genetic manipulation of the DEBS genes that are capable of producing altered polyketides However, many such attempts are reported to have been unproductive (Hutchinson C. R and Fuju, I, Annu Rev. Microbiol (1095) 48.201-238, at p.231) The complete DNA sequence of the genes from Strβptomyces hygroscopicus that encode the modular Type 1 PKS governing the biosynthesis of the macrocyclic immunosuppressant polyketide rapamycin has been disclosed (Schwecke, T et al. (1995) Proc Natl. Acad. Sci USA 92:7839-7843) The DNA sequence is deposited in the EMBL-Genbank Database under the accession number X86780 The complex polyketides produced by modular Type I PKS's are particularly valuable, in that they include compounds with known utility as anthelminthics, insecticides, immunosuppressants, antifungal, and/or antibacterial agents, Because of their structural complexity, such novel polyketides are not readily obtainable by total chemical synthesis, or by chemical modifications of known polyketides As described in International Application PCT.GB97/01810, the Type I PKS gene assembly encodes a loading module which is followed by extension modules It is particularly useful to provide a hybrid PKS gene assembly in which the loading module is heterologous to the extension modules and is such as to lead to a polyketide having an altered starter unit As noted in in International Application PCT/GB97/01810, this is a concept quite unknown to the prior art since this does not recognise the existence of loading modules. W093/13663 refers to altering PKS genes by inactivating a single function (i.e. a single enzyme) or affecting "an entire module" by deletion, insertion, or replacement thereof. The loading assembly, in their terms, is not a module.
If the loading module is one which accepts many different carboxylic acid units, then the hybrid gene assembly can be used to produce many different polyketides For example, a hybrid gene assembly may employ nucleic acid encoding an avr loading module with e extender modules. A loading module may accept unnatural acid units and derivatives thereof; the avr loading module is particularly useful in this regard (Dutton et al., (1991) J Antibiot., 44 357-365). In addition, it is possible to determine the specificity of the natural loading module for unnatural starter units and to take advantage of the relaxed specificity of the loading module to generate novel polyketides. Thus, International Application PCT/3B97/01810 de3cπbeβ the unexpected ability of the ery loading module to incorporate unnatural carboxylic acids and derivatives thereof to produce novel erythromyciπs in erythromycin-producing strains containing only DEBS genes. Of course one may also make alterations within a product polyketide particularly by replacing an extension module by one that gives a ketide unit at a different oxidation state and/or with a different stereochemistry It has generally been assumed that the stereochemistry of the methyl groups in the polyketide chain is determined by the acyltransferase, but it is, in fact, a feature of other domains of the PKS and thus open to variation only by replacement of those domains, individually or by module replacement Methyl and other substituents can be added or removed by acyltransferase domain replacement or total module replacement. Consequently, it also becomes apparent tα those skilled in the art that it is possible to combine the use of the relaxed substrate specificity of the erythromycin loading module with extension module replacement and hybrid loading module substitution with extension module replacement as a mechanism to produce a wide range of novel erythromycins, Thus, international Application PCT/GB97/01810 describes the production of novel erythromycins by non-transformed organisms and also such gene assemblies, vectors containing such gene assemblies, and transformant organisms that can express them to produce novel erythromycins in transformed organisms. Transformant organisms may harbour recombinant plasmids, or the plasmids may integrate. A plasmid with an Int sequence will integrate into a specific attachment site [att) of a host's chromosome Transformant organisms may be capable of modifying the initial products, e.g., by carrying out all or some of the biosynthetic modifications normal in the production of erythromycins. However, use may be made of mutant organisms such that some of the normal pathways are blocked, e g , to produce products without one or more "natural" hydroxy-groups or sugar groups, for instance as described in WO 91716334 or in Weber et a| (1985) J Bacteπol 164:425-433 which are incorporated herein by reference in their entirety. Alternatively, use may be made of organisms in which some of the normal pathways are overexpressed to overcome potential rate-limiting steps in the production of the desired product, for instance as described in WO 97/06266 which is incorporated herein by reference in its entirety.
This aspect of the method is largely concerned with treating PKS gene modules as building blocks that can be used to construct enzyme systems, and thus novel erythromycin products, of desired types. This generally involves the cutting out and the assembly of modules and multi-module groupings. Logical places for making and breaking intermodular connections are be in the linking regions between modules. However, it may be preferable to make cuts and joins actually within domains (i.e., the enzyme-coding portions), close to the edges thereof. The DNA is highly conserved here between all modular PKS's, and this may aid in the construction of hybrids that can be transcribed It may also assist in maintaining the spacing of the active sitee of the encoded enzymes, which may be important. For example, in producing a hybrid gene by replacing the ery_ loading module by an avr loading module, the ery_ module together with a small amount of the following ketosyπthase (KS) domain was removed, The Start of the KS domain (well spaced from the active site) is highly conserved and therefore provides a suitable splicing site as an alternative to the linker region between the loading domain and the start of the KS domain The excised er module was then replaced by an avr loading module.
In fact, when substituting a loading module, it may be desirable to replace not just the loading module domains (generally acyl transferase (AT) and acyl carrier protein (ACP)), but also the KS at the start of the following extension module. Typically, the excised loading module would have provided a propionate starter, and the replacement is intended to provide one or more different starters. Propionate, however, may feed into the KS of the extension module from a propionate pool in the host cell, leading to dilution of the desired products This can be largely prevented by substituting an extended loading module including all or most of the KS domain. (The splice site may be in the end region of the KS gene, or early in the following AT gene, or the linker region between them.)
When replacing "modules", one is not restricted to "natural" modules. For example, a "combinatorial module" to be excised and/or replaced and/or inserted may extend from the corresponding domain of two natural-type modules, e.g., from the AT of one module to the AT of the next, or from KS to KS. The splice sites will be in corresponding conserved marginal regions or in linker regions A combinatorial module can also be a 'double' or larger multiple, for adding 2 or more modules at a time.
International Application PCT/GB97/01810 describes novel erythromycins obtainable by mean6 of the previous aspects. These are included in the following description.
An erythromycin analogue (being a macrolide compound with a 14-membered ring) in which a substitutent R, on the C-13 position, bears a side-chain other than ethyl, generally a straight chain C3-C6 alkyl group, a branched C3-Cg alkyl group, a C3-C8 cycloalkyl or cycioalkenyl group (optionally substituted, e g , with one or more hydroxy, C1_4 alkyl or alkoxy groups or halogen atoms), or a 3-6 membered heterocycle containing O or S, saturated or fully or partially unsaturated, optionally substituted (as for cycloalkyl), or R is phenyl which may be optionally substituted with at least one substituent selected from C,-C4 alkyl, C,-C4 alkoxy and C,-C4 alkylthio groups, halogen atoms, tπfluoromethyl, and cyano, or R may be a group with a formula (a) as shown below
Figure imgf000046_0001
wherein X1 is O, S or -CH2-, a. b, c, and d are each independently 0 to 2 and a + b + c + d < 5 Preferred candidates for the C-13 substituent R are the groups of carboxylate units RCOOR', usable as substrates by an avr starter module, or rapamycin starter variants Preferred substrates are the carboxylic acidβ R"COOH Alternative substrates that can be effectively used are carboxylic acid salts, carboxylic acid esters, or amides Preferred esters are N-acetyl- cysteamine thioesters which can readily be utilised as substrates by the avr starter module as illustrated by Dutton et al. in EP 0350187 which is incorporated herein by reference in its entirety Preferred amides are N-acyl imidazoles Other alternative substrates that may be used are derivatives which are oxidative precursors for the carboxylic acids, thus, for example suitable substrates would be ammo acids of the formula RCH(NH2)COOH, glyoxylic acids of the formula RCOCOOH, methylamiπe derivatives of the formula RCH2NH2, methanol derivatives of the formula RCH2OH, aldehydes of the formula RCHO or substituted alkaπolc acids of the formula R(CH2)„COQH wherein π is 2, 4, or 6 Thus examples of preferred substrates include isobutyrate (R=ι-Pr) and 2-methylbutyrate (R=1-methylpropyl) Other possibilities include n-butyrate, cyclopropyl carboxylate, cyclobutyl carboxylate, cyclopentyl carboxylate cyclohexyl carboxylate, cycloheptanyl carboxylate, cyclohexenyl carboxylates, cycloheptenyl carboxylates, and πng- methylated variants of the cyclic carboxylates and the aforementioned derivatives thereof
The erythromycin analogue may correspond to the initial product of a PKS (6- deoxyerythronolide) or the product after one or more of the normal biosynthetic steps These comprise- 6-hydroxylatιon, 3-0-glycosylatιon, 5-0-glycosylatιon 12-hydroxylatιon; and specific sugar methylation Thus the analogues may include those corresponding to 6-deoxyerythronolιde B, erythromycin A, and various intermediates and alternatives thereof. (ii) Erythromycin analogues differing from the corresponding 'natural' in the oxidation state of one or more of the ketide units (i.e. selection of alternatives from the group: -CO-, - CH(OH)-, =CH-, and -CH2-),
The stereochemistry of any -CH(OH)- is also independently selectable, (iii) Erythromycin analogues differing from the corresponding 'natural' compound in the absence of a 'natural' methyl side-chain. (This is achievable by use of a variant AT). Normal extension modules use either C2 or C3 units to provide unmethylated and methylated ketide units. One may provide unmethylated units where methylated units are natural (and vice versa, in systems where there are naturally unmethylated units) and also provide larger units, e.g., C4 to provide ethyl substituents. (iv) Erythromycin analogues diffeπng from the corresponding 'natural' compound in the stereochemistry of 'natural' methyl; and/or ring substituents other than methyl,
(v) Erythromycin analogues having the features of two or more of sections (i) to (iv). (vi) Derivatives of any of the above which have undergone further processing by noπ- PKS enzymes, e.g., one or more of hydroxylation, epoxidation, glycosylation, and methylation International Application PCT/GB97/01810 describes methods for the production of the novel erythromycins useful in the preparation of the compounds of the present invention. In the simplest method, unnatural starter unite (preferably, but not restricted to the carboxylic acid analogues of the unnatural starter units) are introduced to untransformed organisms capable of producing erythromycins A preferred approach involves introduction of the starter unit into fermentation broths of the erythromycin-producing organism, an approach which is more effective for transformed organisms capable of producing erythromycins. However, the starter unit analogue can also be introduced to alternative preparations of the erythromycin-producing organisms, for example, fractionated or unfractionated broken-cell preparations. Again, this approach is equally effective for transformed organisms capable of producing erythromycins. In another method, one or more segments of DNA encoding individual modules or domains within a heterologous Type I PKS (the "donor" PKS) have been used to replace the DNA encoding, respectively, individual modules or domains within the DEBS genes of an erythromycin-pro'ducing organism. Loading modules and extension modules drawn from any natural or non-natural Type I PKS, are suitable for this "donor" PKS but particularly suitable for this purpose are the components of Type I PKS's for the biosynthesis of erythromycin, rapamycin, avermectin, tetronasin, oleandomycin, monensiπ, amphoteπcin, and rifamycin, for which the gene and modular organisation is known through gene sequence analysis, at least in part Particularly favourable examples of the loading modules of the donor PKS are those loading modules showing a relaxed specificity, for example, the loading module of the avermectin (avr)-producιng PKS of Streptomyces avermitilis; or those loading modules possessing an unusual specificity, for example, the loading modules of the rapamycin-, FK506- and ascomycin-producing PKS's, all of which naturally accept a shikimate-dorived starter unit. Unexpectedly, both the untransformed and genetically engineered erythromycin-producing organisms when cultured under suitable conditions have been found to produce non-natural erythromycins, and where appropriate, the products are found to undergo the same processing as the natural erythromycin
International Application PCT/GB97/01810 further describes a plasmid containing "donor" PKS DNA is introduced into a host cell under conditions where the plasmid becomes integrated into the DEBS genes on the chromosome of the erythromycin-producing strain by homologous recombination, to create a hybrid PKS. A preferred embodiment is when the donor PKS DNA includes a segment encoding a loading module In such a way that this loading module becomes linked to the DEBS genes on the chromosome Such a hybrid PKS produces valuable and novel erythromycin products when cultured under suitable conditions as described herein Specifically, when the loading module of the DEBS genes is replaced by the loading module of the avermectin-producing (avr) PKS, the novel erythromycin products contain a starter unit typical of those used by the avr PKS, Thus, when the loading module of the ery PKS is replaced by the avr loading module, Saccharopolyspora erythraea strains containing such hybrid PKS are found to produce 14-membered macrolides containing starter units typically used by the avr PKS.
As noted in International Application PCT/GB97/01810, it is unexpected that the
14-membered macrolide polyketides produced by such recombinant cells of S. erythraea are found to Include derivatives of erythromycin A, showing that the several processing steps required for the transformation of the products of the hybrid PKS into novel and therapeutically valuable erythromycin A derivatives are correctly carried out International Application PCT/GB97/01810 describes the unexpected and surprising finding that transcription oτ any of the hybrid erythromycin genes can be specifically increased when the hybrid genes are placed under the control of a promoter for a Type II PKS gene linked to a specific activator gene for that promoter. It is particularly remarkable that when a genetically engineered cell containing hybrid erythromycin genes under such control is cultured under conditions suitable for erythromycin production, significantly enhanced levels of the novel erythromycin are produced Such specific increases in yield of a valuable erythromycin product are also seen for natural erythromycin PKS placed under the control of a Type II PKS promoter and activator gene. In a preferred embodiment, desired genes present on an SCP2*-derived plasmid are placed under the control of the bidirectional actl promoter derived from the actiπorhodin biosynthetic gene cluster of Streptomyces coelicolor, and in which the vector also contains the structural gene encoding the specific activator protein Act ll-orf 4. The recombinant plasmid is introduced into Saccharopolyspora erythraea, under conditions where either the introduced PKS genes, or PKS genes already present in the host strain, are expressed under the control of the actl promoter
Such strains produce the desired erythromycin product and the activator flene requires only the presence of the specific promoter in order to enhance transcriptional efficiency from the promoter This is particularly surprising in that activators of the Actll-orf4 family do not belong to a recognised class of DNA-binding proteins. Therefore it would be expected that additional proteins or other control elements would be required for activation to occur in a heterologous host not known to produce actinorhodin or a related isochromaπequmone pigment. It is also surpnsing and useful that the recombinant strains can produce more than ten-fold erythromycin product than when the same PKS genes are under the control of the natural promoter, and the specific erythromycin product is also produced precociously in growing culture, rather than only during the transition from growth to stationary phase. Such erythromycins are useful as antibiotics and for many other purposes in human and veterinary medicine. Thus, when the genetically engineered cell is Saccharopolyspora erythraea, the activator and promoter are derived from the actinorhodin PKS gene cluster and the act|/actll-orf4-regulated ery PKS gene cluster is housed in the chromosome, following the site-specific integration Of a low copy number plasmid vector, culturing of these cells under suitable conditions can produce more than ten-fold total 14-membered macrolide product than in a comparable strain not under such heterologous control. When in such a genetically engineered cell of S. erythraea the PKS genes under this heterologous control are hybrid Type I PKS genes whose construction is described herein, more than ten-fold hybrid polyketide product can be obtained compared to the same hybrid Type I PKS genes not under such control. Specifically, when the hybrid Type I PKS genes are the ery PKS genes in which the loader module is replaced by the avr loading module, a ten-fold increase is found in the total amounts of novel 14-membered macrolides produced by the genetically engineered cells when cultured under suitable conditions as described herein The suitable and preferred means of growing the untransformed and genetically- engineered erythromycin-producing cells, and suitable and preferred means for the isolation, identification, and practical utility of the novel erythromycins are described more fμlly, in International Application PCT/GB97/01810,
Erythromycin derivatives described in International Application PCT/GB97/01810 are produced by fermentation of an untransformed or transformed organism capable of producing erythromycins, including but not limited to Saccharopolyspora species, Streptomyces gπseoplanus, Nocardia sp., Micromonospora sp., Arthobacter sp , and Streptomyces antibioticus, but excluding S. coelicolor. Particularly suitable m this regard are untransformed and transformed strains of Saccharopolyspora erythraea, for example NRRL 2338, 18643, 21484. Particularly preferred transformed strains are those in which the erythromycin loading module has been replaced with the loading module from the avermectin producer, Streptomyces avermitilis, or the rapamycin producer, Streptomyces hygroscopicus. The preferred method of producing compounds is by fermentation of the appropriate organism in the presence of the appropriate carboxylic acid of the formula R,COOH, wherein R, is as defined in formulae 1_ or 2 of International Application PCT/GB97/01810, or is R of the compounds of the present invention, or a salt, ester (particularly preferable being the N- acetylcysteamine thioester), or amide thereof or oxidative precursor thereof The acid or derivative thereof is added to the fermentation either at the time of inoculation or at intervals during the fermentation. Production of the compounds may be monitored by removing samples from the fermentation, extracting with an organic solvent and following the appearance of the compounds by chromatography, for example using high pressure liquid chromatography. Incubation is continued until the yield of the compound of formulae 1_ or 2 has been maximised, generally for a period of 4 to 10 days. A preferred level of each addition of the carboxylic acid or derivative thereof is between 0.05 and 4.0 g/L. The best yields of the compounds from formulae 1 or 2 are generally by gradually adding the acid or derivative to the fermentation, for example by daily addition over a period of several days. The medium used for the fermentation may be a conventional complex medium containing assimilable sources of carbon, nitrogen and trace elements
The wide range of starter units accepted by the avr loading module has been comprehensively established in previous studies (for example European Patent Applications 0 214 731, 0 350 187, 0 317 148 Which are Incorporated herein in their entirety). Consequently, it should be understood that the invention is not limited to the specific detail of these examples and simply serve to confirm the effectiveness of the avr loading module. Furthermore, the examples using the pIGIor pND30 construct clearly demonstrate the capability of the actl promoter and its cognate activator gene actll-orf4 to ehance the expression of the novel compounds of this invention when linked to the avr loading module. It is also apparent from the examples that untransformed strains of Saccharopolyspora erythraea are also readily capable of taking up exogenously-supplied substrates to generate novel erythromycin polyketides. Consequently, it is also apparent to those skilled in the art that specific novel compounds of this invention can be readily produced by selection of the appropriate erythromycin producing strain (optionally incorporating the plG1 or pND30 plasmid into the desired strain), and supplementing the fermentation with the appropriate starter unit Thus, 6-deoχyerythromycιn and 6,12- dideoxyerythromyein derivatives of the present invention can be readily produced using Saccharopolyspora erythraea NRRL 18643 or NRRL 21484 as indicated in U S. 5,141 ,926 and WO 97/0Θ266 Similarly, UΘΘ of the Saccharopolyspora erythraea strains described by Weber et al in J. Bactenol., 164:425-433, 1991 can also be employed to obtain the desired novel analogues of the present invention For example, strain UW24 can be used (optionally transformed by plG1 or pND30) to obtain novel analogues of erythronolide B.
The term "Me", as used herein, unless otherwise indicated, refers to methyl. The term "Et", as used herein, unless otherwise indicated, refers to ethyl. The term "Pr", as used herein, unless otherwise indicated, refers to propyl The term "Ac", as used herein, unless otherwise indicated, refers to acyl
The term "hydroxy protecting group", as used herein, unless otherwise indicated, includes acetyl, benzyloxyearbonyl, and various hydroxy protecting groups familiar to those skilled in the art include the groups referred to in T W Greene, P. G. M. Wuts, "Protective Groups In Organic Synthesis," (J. Wiley & Sons, 1991) The term "halo", as used herein, unless otherwise indicated, Includes fluoro, chloro, bromo or todo.
The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovaient hydrocarbon radicals having straight, cyclic or branched moieties, or mixtures thereof. It is to be understood that where cyclic moieties are intended, at least three carbons in said alkyl must be present. Such cyclic moieties include cyclopropyl, cyclobutyl and cyclopentyl.
The term "alkoxy", as used herein, unless otherwise indicated, includes -O-alkyl groups wherein alkyl is as defined above
The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl The term The term "4-10 membered heterocyclic", as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from 0, S and N, wherein each heterocyclic group has from 4-10 atoms in its ring system. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxo moieties An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidme) An example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is qumolinyl. Examples of non-aromatic heterocychc groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothieπyl tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolιnyl, indolmyl, 2H-pyranyl, 4H-ρyranyl, dioxanyl. 1 ,3- dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothieπyl. dlhydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabιcyclo[3 1.0]heχanyl, 3- azabιcyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyπmidinyl, pyrazolyl, triazolyl, pyraziπyl, tetrazolyl, furyl, thienyl, isoxazolyi, thiazoiyi, oxazolyl, isothι----olyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, iπdazolyl, mdolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteπdinyl, punnyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, beπzoxazolyl, quiπazoliπyl, quinoxalmyl, napnthyrldlnyl, and furopyridinyl. The foregoing groups, as derived from the compounds listed above, may be C- attached or N-attached where such is possible. For instance, a group derived from pyrrole may be ρyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached)
The phrase "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention. The compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of the present invention are those that form non-toxic acid addition salts, _ , salts containing pharmacologically acceptable anions, s ch aε the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, paπtothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesuifonate, p-toiuenesulfonate and pamoate [^e., l , '-methylene-bis-(2- hydroxy-3-naphthoate)] salts The compounds of the present invention that include an ammo moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
Those compounds of the present invention that are acidic In nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of the present invention.
Certain compounds of the present invention may have asymmetric centers and therefore exist in different enantlomerlc and dlasiereomic forms This invention relates to the use of all optical isomers and sterβoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them.
The present invention includes the compounds of the present invention, and the pharmaceutically acceptable salts thereof, wherein one or more hydrogen, carbon or other atoms are replaced by isotopes thereof. Such compounds may be useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays. Detalled Description of the Invention The compounds of of the present invention may be prepared according to Schemes 1-3 described below.
Scheme 1
Figure imgf000053_0001
Figure imgf000053_0002
Scheme 1 continued
Figure imgf000054_0001
Figure imgf000054_0002
Scheme 1 continued
Figure imgf000055_0001
Figure imgf000055_0002
Scheme 1 continued
Figure imgf000056_0001
-56-
Scheme 2
Figure imgf000057_0001
12
Figure imgf000057_0002
Scheme 2 continued
Figure imgf000058_0001
14
Figure imgf000058_0002
Scheme 2 continued
Figure imgf000059_0001
Figure imgf000059_0002
Scheme 2 continued
Figure imgf000060_0001
Figure imgf000060_0002
Scheme 2 continued
Figure imgf000061_0001
Scheme 3
Figure imgf000062_0001
-81-
The compounds of the present invention are readily prepared. The compounds desribed below used in the preparation of the compounds of formulas 1_, 2, 3, 4 and 5 can prepared using the methods described in International Application No. PCT/GB97/01810 filed July 4. 1997 (Peter Francis Leadlay, James Staunton, Jesus Cortes and Michael Stephen Pacey), and International Application No PCT/GB97/01819 filed July 4, 1997 (Peter Francis Leadlay, James Staunton, and Jesus Cortes), both of which are Incorporated herein by reference in their entirety.
The compounds of formula of the present invention can be prepared using substantially the same procedures as described by Wataπabe er a/ (Journal of Antibiotics, 1993, 46,1161- 1167) as illustrated in Scheme 1 The starting compounds of formula 6 can be prepared using the methods described in International Application No. PCT/GB97/01810 filed July 4, 1997 (Peter Francis Leadlay, James Staunton, Jesus Cortes and Michael Stephen Pacey), and international Application No PCT/GB97/01819 filed July 4, 1997 (Peter Francis Leadlay, James Staunton, and Jesus Cortes), both of which are incorporated herein by reference in their entirety. With reference to step 1 of Scheme 1, oximatioπ of the compound of formula 6 can be effected by treating the compound of formula β using methods known to one skilled In the art, such as treatment with NH2OH«HCl in a polar solvent such as pyridine at a temperature of from about 40 to δO'O for a period of from about 8 to about 50 hours to give a compound of formula 7. The oxime hydroxyl group of the compound of formula 7 can be protected using methods known to one skilled in the art, such as by protecting the oxime hydroxyl group as a benzyl group by using benzyl chloride or benzyl bromide in the presence of a base such as potassium hydroxide in a solvent such as DMF The compound of formula 9 can be prepared from the compound of formula 8 using methods known to one skilled in the art, such as by treatment with 1- (trimethylsilyl)-imidazole in a solvent such as ethyl acetate Methylation of the compound of formula 9 can be carried out using methods known to one skilled in the art such as by treatment with a methylating agent such as methyl iodide and a base such as potassium hydroxide in a solvent such as a mixture of DMSO (methyl sulfoxide) and THF (tetrahdrofuran) to afford the compound of formula 0. Elimination of the benzyl and silyl groups of the compound of formula 10 can be achieved at the same time using methods known to one skilled in the art such as by catalytic transfer hydrogenation using palladium on carbon, formic acid and ammonium formate in a solvent such as methanol to generate a compound of formula of 11. The compound of formula ___[ can be converted to compound of formula _\2 via deoximation using using methods known to one skilled in the art, by treatment with a hydrolyzing agent, such as by treatment with sodium bisulfite in a solvent such as methanol at a temperature of about 40 to about 80°C for a period of about 1 to about 50 hours 5 The synthesis of the compound of formula 1_ wherein the R group contains a sulfur functionality will vary from the above description in that a sulfur containing functionality can be derived from other functional groups using conventional methods know to one skilled in the art,
Scheme 2 describes the synthesis of the compounds of formula 2, wherein X is -NR5 The starting compound of formula 12_ can be prepared according to Scheme 1. The acylation of 0 the C-4" and C-2' hydroxyls or the compound of formula 12_ can be effected by treating compound of formula 12 with a suitable acylating agent known to one skilled in the art, such as for example, acetic anhydride in a solvent such as dichloromethane in the presence of a base such as 4-dιmethylaminopyridine (DMAP) at room temperature for a period of about 10 to about 30 hours to afford diacetate of the compound of formula 13 The compound of formula 13 can be S converted into the carbonate of the compound of formula 14 under a variety of conditions known to one skilled in the art, such as, for example, tnchloromethyl isocyanate, or ethylene carbonate in the presence of a base, or carbonyldiimidazole in the presence of a base. Cleavage of the cladinose moiety of the compound of formula 14 can be carried out under suitable acidic conditions known to one skilled in the art, such as aqueous hydrochloric acid in ethanol to afford 0 the compound of formula 15_ The hydroxyl group of the compound of formula 15, can be oxidized using an oxidizing agent, to generate ketolide of the compound of formula 16_ under a variety of conditions known to one skilled in the art, such as 1-(3-dιmethylamιπopropyl)-3-ethylcarbodiimide hydrochloride and pyridium trifluroacetate in the presence of DMSO. B-elimination of the carbonate of the compound of formula __$ can be conducted under suitable basic conditions 5 known to one skilled in the art, such as DBU at 50-80"C gave enone 17_. The acyl imidazole of the compound of formula 18 can be prepared from the compound of formula T7 using methods known to one skilled in the art, such as, for example, by treatment with carbonyldiimidazole in the presence of a base such as sodium hydride. The compound of formula 1 θ_ undergoes cyclization to give carbazate 19_ using methods known by one skilled in the art, such as, by treatment with 0 NH2NH2 in a solvent such as MeCN at a temperature of about 60 to about 100°C for a period of about 5 to about 28 hours The compound of formula 19_ can be converted to the compound of formula 20 through reductive alkylation following substantially the same procedures as described by Patel βt al (J. Med. Chem., 1996, 38, 41Θ7-4210.
Scheme 3 describes the synthesis of compounds of formula 2, wherein X is -(CR5Rβ)8-, 5 where g is 0 or 1. The starting compound of formula 18 can be prepared according to Scheme 2 Treatment of the acyl imidazole of the compound of formula 18_wιth a compound of the formula
R -C(R .55RRββ))gg--NNHH22,, Wwhheerree:in g is 0 or 1 , and R , R , R are defined as above, can afford the compound of formula 21 -03-
5 The synthesis of the compound of formula 2 wherein the R group contains a sulfur functionality will vary from the above description in that a sulfur containing functionality can be derived from other functional groups using conventional methods know to one skilled in the art.
The synthesis of compounds of formula 3, wherein the bond between C-9 and the nitrogen to which C-9 is connected is a double bond, and R1 is not existent, z is OR7, can be o prepared from compound of formula 2 following substantially the same synthetic sequence as described in U.S. patent application serial number 60/049349, filed June 11 , 1997 (Yong-Jin Wu)
The synthesis of the compounds of formula 3, wherein the bond between C-9 and the nitrogen to which C-9 is connected is a single bond, can be prepared from the compound of formula 3, wherein the bond between C9 and the nitrogen to which 09 is connected is a double 5 bond, R1 is not existent, and R2 is OH, following substantially the same synthetic sequence as described in U.S. patent application serial number 60/063676, filed October 29, 1997 (Yong-Jin Wu).
The synthesis of the compounds of formula 4 can be prepared from the compound of formula 2 following substantially the same synthetic sequence as described In PCT application 0 WO 97/17356, published May 1997.
The synthesis of the compounds of formula 5 can be prepared from the compound of formula 3, wherein X is -NR5-, following substantially the same synthetic sequence as described in U.S. application serial number 60/063161 , filed October 29, 1997 (Yong-Jin Wu).
The compounds of the present invention may have asymmetric carbon atoms and 5 therefore exist in different enantiomeric and diastereomeric forms. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization Enantiomers may be separated by converting the enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound (e g , 0 alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. The use of all such isomers, including diastereomer mixtures and pure enantiomers, are considered to be part of the present invention.
The compounds of the present invention that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must 5 be pharmaceutically acceptable for administration to mammals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
Those compounds of the present invention that are acidic in nature are capable of forming base salts with various cations. For compounds that are to be administered to mammals, fish or birds such salts must be pharmaceutically acceptable Where a pharmaceutically acceptable salt is required, it may be desirable to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter to a pharmaceutically acceptable salt in a process analogous to that described above relating to the conversion of pharmaceutically unacceptable acid addition salts to pharmaceutically acceptable salts. Examples of base salts include the alkali metal or alkaline- earth metal salts and particularly the sodium, amine and potassium salts These salts are all prepared by conventional techniques The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non- toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium, magnesium, vaπoue amine cations, etc These salts can easily e prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable bases with cations such as sodium, potassium, calcium, magnesium, various amine cations, etc., and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometπc quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product,
The activity of the compounds of the present invention against bacterial and protozoa pathogens is demonstrated by the compound's ability to inhibit growth of defined strains of human (Assay I) or animal (Assays II and III) pathogens
Assay I Assay I, described below, employs conventional methodology and interpretation criteria and is designed to provide direction for chemical modifications that may lead to compounds that circumvent defined mechanisms of macrolide resistance. In Assay I, a panel of bacterial strains is assembled to include a variety of target pathogenic species, including representatives of macrolide resistance mechanisms that have been characterized. Use of this panel enables the chemical structure/activity relationship to be determined with respect to potency, spectrum of activity, and structural elements or modifications that may be necessary to obviate resistance mechanisms, Bacterial pathogens that comprise the screening panel are shown in the table below, in many cases, both the macrollde-susceptibie parent strain and the macrollde-resistaπt strain derived from it are available to provide a more accurate assessment of the compound's ability to circumvent the resistance mechanism Strains that contain the gene with the designation of βrmA/ermB/ermC are resistant to macrolides, iincosamides, and streptogramin B antibiotics due to modifications (methylation) of 23S rRNA molecules by an Erm methylase, thereby generally prevent the binding of all three structural classes. Two types of macrolide efflux have been described; msrA encodes a component of an efflux system in staphylococci that prevents the entry of macrolides and streptogram s while mefA E encodes a transmembrane protein that appears to efflux only macrolides. Inactivation of macrolide antibiotics can occur and can be mediated by either a phosphorylation of the 2'-hydroxyl ( ph) or by cleavage of the macrocyclic lactone (esterase) The strains may be characterized using conventional polymerase chain reaction (PCR) technology and/or by sequencing the resistance determinant The use of PCR technology in this application is described in J. Sutcliffe et al., "Detection Of Erythromycin-Resistant Determinants By PCR", Antimicrobial Agents and Chemotherapy, 40(11), 2562-2566 (1096). The antibacterial assay is performed in microtiter trays and interpreted according to Performance Standards for Antimicrobial Disk Susceptibility Tests - Sixth Edition; Approved Standard, published by The National Committee for Clinical Laboratory Standards (NCCLS) guidelines; the minimum inhibitory concentration (MIC) is used to compare strains acr AB or acr AB-like indicates that an intnnsia multidrug efflux pump exists in the strain. Compounds are initially dissolved in dimethylsulfoxide (DMSO) as 40 mg/ml stock solutions.
Figure imgf000068_0001
Assay II is utilized to test for activity against Pasteurella multocida and Assay 111 is, utilized to teβt for activity against Pasteurella hβemolyticβ.
Assay II This assay is based on the liquid dilution method in microliter format. A single colony of P multocida (strain 59A067) is inoculated into 5 ml of brain heart infusion (BHI) broth. The test compounds are prepared by solubilizing 1 mg of the compound in 125 μl of dimethylsulfoxide (DMSO). Dilutions of the test compound are prepared using uninoculated BHI broth. The concentrations of the test compound used range from 200 μg/ml to 0.098 μg/ml by two-fold serial dilutions. The P. multocida inoculated BHI is diluted with uniπoculated BHI broth to make a 104 cell suspension per 200 μl, The BHI cell suspensions are mixed with respective serial dilutions of the test compound, and incubated at 37°C for 18 hours, The minimum inhibitory concentration (MIC) is equal to the concentration of the compound exhibiting 100% inhibition of growth of P. multocida as determined by compaπson with an uninoculated control. Assay III
This assay is based on the agar dilution method using a Steers Replicator. Two to five colonies isolated from an agar plate are inoculated into BHI broth and incubated overnight at 37 °C with shaking (200 rpm). The next morning, 300 μl of the fully grown P. haemolytica preculture is inoculated into 3 ml of fresh BHI broth and is incubated at 37*C with shaking (200 rpm) The appropriate amounts of the test compounds are dissolved In ethanol and a series of two-fold serial dilutions are prepared Two ml of the respective serial dilution is mixed with 18 ml of molten BHI agar and solidified. When the inoculated P. haemolytica culture reaches 0 5 McFarland standard density, about 5 μl of the P haemolytica culture is inoculated onto BHI agar plates containing the various concentrations of the test compound using a Steers Replicator and incubated for 18 hours at 374C. Initial concentrations of the teβt compound range from 100-200 μg/ml. The MIC is equal to the concentration of the test compound exhibiting 100% inhibition of growth of P. haemolytica as determined by comparison with an uninoculated control,
The in jvo activity of the compounds of formula (I) can be determined by conventional animal protection studies well known to those skilled In the art, usually carried out In mice.
-Θ8-
Mice are allotted to cages (10 per cage) upon their arrival, and allowed to acclimate for a minimum of 48 hours before being used. Animals are inoculated with 0.5 ml of a 3 x 103 CFU/ml bacterial suspension (P multocida strain 59A006) intrapentoneally. Each experiment has at least 3 non-medicated control groups including one infected with 0 1X challenge dose and two infected with 1X challenge dose; a 10X challenge data group may also be used. Generally, all mice in a given study can be challenged within 30-90 minutes, especially if a repeating syringe (such as a Cornwall® syringe) is used to administer the challenge. Thirty minutes after challenging has begun, the first compound treatment is given. It may be necessary for a second person to begin compound dosing if all of the animals have not been challenged at the end of 30 minutes. The routes of administration are subcutaneous or oral doses. Subcutaneous doses are administered into the loose skin in the back of the neck whereas oral doses are given by means of a feeding needle. In both cases, a volume of 02 ml is used per mouse. Compounds are administered 30 minutes, 4 hours, and 24 hours after challenge. A control compound of known efficacy administered by the same route is included in each test. Animals are observed daily, and the number of survivors in each group is recorded The P. multocida model monitoring continues for 96 hours (four days) post challenge
The PD50 is a calculated dose at which the compound tested protects 50% of a group of mice from mortality due to the bacterial infection which would be lethal in the absence of drug treatment
The compounds of formula 1, 2, 3, 4 and 5 the pharmaceutically acceptable salts thereof (hereinafter "the active compounds"), may be ad instered through oral, parenteral, topical, or rectal routes in the treatment of bacterial and protozoa infections. In general, these compounds are most desirably administered in dosages ranging from about 0,2 mg per kg body weight per day
(mg/kg/day) to about 200 mg/kg/day in single or divided doses (i.e., from 1 to 4 doses per day), although variations will necessarily occur depending upon the species, weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 4 mg/kg/day to about 50 mg/kg/day is most desirably employed.
Variations may nevertheless occur depending upon the species of mammal, fish or bird being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day. The active compounds may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by the routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the active compounds may be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories. Jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like, Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the active compounds are present in such dosage forms at concentration levels ranging from about 5,0% to about 70% by weight
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various dismtegrants such as starch (and preferably corn, potato or tapioca starch), alglπlc acid and certain complex silicates, together with granulation binders like polyvlnylpyrrolldone, sucrose, gelatin and acacia Additionally, lubricating agents such as magnesium stearate. sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral adιni3tration, the aotive oompound may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of an active compound in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under 3terιle conditions lε readily accomplished by standard pharmaceutical techniques will known to those skilled in the art Additionally, it is also possible to administer the active compounds of the present invention topically and this may be done by way of creams, jellies, gels, pastes, patches, ointments and the like, in accordance with standard pharmaceutical practice, For administration to animals other than humans, such as cattle or domestic animals, the active compounds may be administered in the feed of the animals or orally as a drench composition.
The active compounds may also be admmstered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearyiamlne or phosphatidyleholines,
The active compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyviπylpyrrolidone, pyraπ copolymer, polyhydroxypropylmethacrylamide phenyl, polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoylre3idue3. Furthermore, the active compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacryiates and cross-linked or amphipathic block copolymers of hydrogels
The following Examples further illustrate the method and intermediates of the present invention. It is to be understood that the present invention is not limited to the specific details of the Examples provided below.
Example 1 13-Cyclobutylerythromyciπ A 9-oxime
To a solution of 13-cyclobutylerythromycin A (3.67 g, 4 83 mmol) in pyridine (50 L) was added NH2OH-HCl (2.68 g, 38.57 mmol) and the resulting solution was heated at 60°C for 16 h The reaction mixture was made basic with sat. NaHC03 and extracted with CH2CI2 (X4). The combined organic layers were washed with HsO (X2) and brine (X1). dried over Na2S0 , and evaporated in vacuo The crude product was purified by silica gel flash chromatography (0 3% NH3-H20-3% MeOH-96,7% CH2Cl2) to afford the title compound as a white solid (2.85 g). MS: m/z 775 (M+H).
Example 2 13-Cyclobutylθrythromycin A 9-(0-beπzyloχime) To a solution of 13-cyclobutylerythromycin A 9-oxιme (2.85 g, 3.67 mmol) in DMF (N,N- dimethylformamide) (20 ml-) were added benzyl chloride (0 51 mL g, 4,41 mmol) and 85% KOH power (0.29 g, 441 mmol), and the mixture was stirred in an ice-bath for 75 min The reaction mixture was treated with H20 and extracted with EtOAc (X5). The combined organic layers were washed with H20 (X2) and brine (X1), dried over Na2S04, and evaporated in vacuo The crude product was purified by silica gel flash chromatography (1% NH3*H2O-10% MeOH-89% CH2CI2) to afford the title compound as a white solid. MS: m/z 865 (M+H)
Example 3 2',4"-0-Bis(tπmethy|sιlyl)-13-cyclobutyl-erythromycin A 9-(0-benzyloxιme) A mixture of chlorotrimethylsilane (0.36 mL, 2.84 mmol) and 1-trlmethylsllyllmldazole
(0.42 mL, 2.84 mmol) in EtOAc (2 mL) was added to a solution of 13-cyclobutylerythromycιn A 9- (O-benzyloxime) (1.23 g, 1.42 mmol) in EtOAc (10 mL) at room temperature, and the resulting solution was stirred at room temperature for 45 min. The reaction mixture was then diluted with hexane (25 mL) and washed with H20 (2X25 mL), The washings were extracted with hexane (2X15 mL), and the combined organic layers were washed with H20 (X2) and brine (X1), dried over Na2S04, and evaporated in vacuo to afford the title compound as a white solid MS: m/z 1009 (M+H)
Example 4 2',4"-0-Bιs(tπmethylsily l)-l 3-cyclobuty l-6-O-methylerythromycln A 9-(O-beπzyl0xime) To a solution of 2',4"-0-Bis(trιmethylsιlyl)-13-cyclobu-ylerythromycin A 9-(0- benzyloxime) (1.42 g, 1.41 mmol) in 1 ; 1 mixture of DMSO and THF (22 mL) were added Mel (0,14 mL, 1.83 mmol) and then 85% KOH power (102 mg, 1.55 mmol), and the resulting mixture was stirred with ice-cooling for 1 5 hours The reaction mixture was treated with H20 and extracted with hexane (X4). The combined organic layers were washed with HzO (X2) and brine (X1), dried over Na2S04, and evaporated in vacuo to give the title compound as a white solid (1.31 g)
MS m z 1024 (M+H).
Example 5 13-Cyclobutyl-6-0-methylerythromycin A 9-oxime To a solution of 2',4"-0-Bis(trimethylsilyl)-13-cyclobutyl-6-0-methylerythromycin A 9-(0- benzyloxime) (1.31 g, 1 28 mmol) in MeOH (13 mL) were added 10% Pd-C (206 mg), formic acid (0.82 mL, 21 ,79 mmol), and ammonium formate (137 mg, 2,18 mmol), and the reaction mixture was heated at 60°C for 2 hour6. The catalyst was filtered off, and the filtrate, after addition of H20, was made basic with 2N NaOH. Most methanol was evaporated in vacuo, and the residue was extracted with CH2CI2 (X4), The combined organic layers were washed with H20 (X2) and brine (X1), dried over Na2S04, and evaporated in vacuo to give the title compound as a white solid (956 mg).
MS m/z 789 (M+H) Example 6
13-Cyciobutyl-6-0-methylerythromycin A To a solution of l3-cyclobutyl-6-0-methylerythromycin A 9-oxime (931 mg, 1.18 mmol) in EtOH (4 3 mL) and H20 (4.3 mL) were added formic acid (107 uL, 2.83 mmol) and sodium bisulfite (500 mg, 4.84 mmol) and the reaction mixture was heated at 80°C for 1 J5 hours The reaction mixture was diluted with H20, made basic with 1 NaOH, and extracted with CH2CI2 (X3). The combined organic layers were washed with H20 (X2) and brine (X1), dried over NazS04, and evaporated in vacuo The crude product was purified by silica gel flash chromatography (1 % NH3ΗzO-10% MeOH-89% CH2CI2) to give the title compound (337 mg) as a white solid (956 mg) MS: m/z 774 (M+H).
Example 7 2',4"-Dι-0-Acetyl-13-cydobutyl-6-θ-methylerythromycin A To a solution of 13-cyclobutyl-6-0-methylerythromycin A (327 mg, 0,42 mmol) in CH2CI2 (4 0 mL) were added Ac20 (120 uL, 1.26 mmol) and DMAP (41 mg, 0.34 mmol) and the reaction mixture was stirred at room temperature for 18 hours. Sat. NaHC03 was added the reaction mixture was extracted with CH2CI2 (X3) The combined organic layers were washed with H20 (X2) and brine (X1 ), dried over Na2S04, and evaporated in vacuo to give the title compound as a white solid (363 mg)
MS: m/z 858 (M+H). Example 8
2',4"-Di-0-acetyl-13-cyclobutyl-6-0-methylerythromycin A, 11 , 12-carboπate To a solution of 2',4"-di-0-acetyl-13-cyclobutyl-6-0-methylerythromycin A (363 mg, 0 42 mmol) in CH2CI2 (4.0 mL) was added trichlcroacetyl isocyaπate (0 15 L, 1 27 mmol) and the reaction mixture was stirred at room temperature for 18 hours. MeOH (3 mL) was added and the reaction mixture was stirred at room temperature for 1 hours. Sat, NaHC03 was added the reaction mixture was extracted with CH2CI2 (X3) The combined organic layers were washed with H20 (X2) and brine (X1), dried over Na2S04, and evaporated in vacuo to give the title compound as a white solid.
MS. m/z 884 (M+H). Example 9
2'-0-Acetyl-13-cyclobutyl-5-0-deεosaminyl-6-0-methylerythronolide A, 11,12-carbonate To a solution of 2",4"-di-0-acetyl-13-cyclobutyl-6-0-methylerythromycin A, 11 ,12- carbonate obtained from example 8 in EtOH (3.5 mL) was added 2N HCI (6 mL) and the reaction mixture was stirred at room temperature for 3 days The solution was made basic with sat NaHC03, and most EtOH was evaporated, and the aqueous solution was extracted with CH2CI2 (X3). The combined organic layers were washed with H20 (X2) and brine (X1), dried over NaaS04, and evaporated in vacuo. The crude product was purified by preparative TLC (1% NH3*H2O-10% MeOH-89% CH2C!2) to give the title compound (134 mg) as a white solid, MS- m/z 684 (M+H). Example 10
2'-0-Acetyl-13-cyclobutyl-5-0-desosaminyl-6-0-methyl-3-αxo-erythronolide A, 11,12- carbonate To a solution of 2'-0-aeefyl-13-cyclobutyl-5-0-desosamιnyl-6-0-methylerythronolιde A, 11 ,12-carbonate (134 mg, 0 20 mmol) in CH2CI2 (2.0 mL) were DMSO (348 uL, 4,9 mmol), PyTFA (293.6 mg, 1 52 mmol) and EDAC (291 mg, 1 62 mmol) and the reaction mixture was stirred at room temperature for 2 days The solution was made basic with sat NaH0O3, and the aqueous solution was extracted with CH2CI2 (X3). The combined organic layers were washed with H20 (X2) and brine (X1), dried over Na2S04, and evaporated in vacuo to give the title compound (134 mg) as a white solid MS- m/z 682 (M+H)
Example 11 2'-0-Acetyl-10,11 -aπhydro-13-cyclobutyl-5-0-desosaminyl-6-0-methy l-3-oxo- erythronolide A To a solution of 2'-0-ace-yl-l3-cyclobutyl-5-0-desosaminyl-6-0-methyl-3- oxoerythronolide A, 11 ,12-carbonate (134 mg, 0.20 mmol) in CβH6 (5 mL) was DBU (378 uL, 2.53 mmol and the reaction mixture was heated at 90°C for 2 hours, Sat. NaH2P04 was added, and the aqueous solution was extracted with EtOAc (X5). The combined organic layers were washed with H20 (X2) and brine (X1 ), dried over Na2S04, and evaporated in vacuo to give the title compound (122 mg) as a white solid. MS: m/z 638 (M+H).
Example 12 2'-0-Acetyl-10, 11-anhydro-13-cyclobutyl-5-0-desosamιnyl-12-0-imidazolylcarboπyl-6-0- methyl-3-oxoerythronolide A To a solution of 2'-O-acetyl-10,11-anhydro-13-cyclobutyl-5-O-desosaminyl-6-O-methyl-3- oxoerythronolide A (61 mg, 0.10 mmol) in THF (1.2 mL) were added NaH (95% purity, 5mg, 0.20 mmol) and CDI (49 mg, 0.30 mmol) and the reaction mixture was stirred at room temperature for 15 hours Sat. NaHC03 was added, and the aqueous solution was extracted with CH2CI2 (X5) The combined organic layers were washed with H20 (X2) and brine (X1), dried over Na2S04, and evaporated in vacuo to give the title compound as a white solid. MS m/z 732 (M+H)
Example 13
13-Cyclobuty 1-11 -deoxy-5-0-desosamιnyl-11 -hydrazo-6-O-methy l-3-oxoerythronolιde A,
11,12-carbamate To a solution of 2'-O-Acetyl-10,11-anhydro-13-cyclobutyl-5-0-desosamιnyl-12-0- ιmιdazolylcarbonyl-6-θ-methyl-3-oxoerythronollde A obtained from example 12 In MeCN (1 o mL) was added anhydrous NH2NH2 (42 uL, 1 34 mmol) and CD1 (49 mg, 0 30 mmol) and the reaction mixture was heated at 90°C for 15 hours MeCN was evaporated in vacuo and the crude product was purified by preparative TLC (1% NH3'H2O-10% MeOH-89% CH2CI2) to give the title compound (134 mg) as a white solid MS m/z 654 (M+H)
Example 14 13-Cyclobutyl-11 -deoxy-5-0-desosamιnyl-6-0-methyl-3-oxo-11 -(3-quιnolιn-4-yl- propylιdene)hydrazoerythronolιde A, 1 1 ,12-carbamate To a solution of 13-cyclθbutyl-11-deoxy-5-0-desosamιπyl-11-hydrazσ-6-0-methyl-3- oxoerythronolide A 11 , 12-carbamate obtained from example 13 in toluene (1 0 L) was added 3-(4-quιnolιnyl)propιonaldehyde (27 mg, 0 14 mmol) and the reaction mixture is heated at 90*C for 15 hours EtOH is evaporated in vacuo to give the title compound as a white solid MS m/z 821 (M+H)
Example 16 13-Cyclobutyl-11-deoxy-5-0-desosamιnyl-6-0-methyl-3-oxo-11-(3-quιnolιn-4-yl- ρropyl)hydrazoerythronolιde A, 11 ,12-carbamate To a solution of 13-Cyclobutyl-11-deαxy-5-0-desosamιnyl»6-0-methyl-3-oxo-11-(3- quιπolιn-4-yl-propylιdene)hydrazoerythronolιde A, 11 ,12-carbamate obtained from example 14 in MeOH (1 0 mL) at room temperature was added NaBH3CN (60 mg, 0 96 mmol) and HOAc (88 uL, 1 53 mmol), and the resulting solution was stirred at room temperature for 14 hours The solution is made basic with sat NaHC03, and the aqueous solution was extracted with CH2CI2 (X3) The combined organic layers are washed with H20 (X2) and brine (X1), dried over Na2S04, and evaporated m vacuo The crude product was purified by preparative TLC (1% NH3 «H2O-10% MeOH-89% CH2CI2) to give the title compound as a white solid 'H NMR (CDCI3, 400 MHz) d 1 04 (3H, d, J = 6 8 Hz) 1 15 (3H, d , J - 7 2 Hz), 1 22 (3H, d, J = 64 Hz), 1 29 (3H, d, J = 64 Hz), 1 31 (3H, s), 1 33 (3H, d, = 6 8 Hz) 1 43 (3H, s), 2 26 (6H, s), 2 63 (3H, s), 3.67 (1 H, s), 3 83 (1H, q, J - 6 8 Hz)
13C NMR (CDCI3, 100 MHz) d 14 30 14 42, 15 05, 15 39, 18 54, 18 91, 19 86 21 18, 2488, 26 57, 2829, 2861 29 57, 35 09, 39.51, 39 58, 4024 4463, 47 26, 4841, 50 13, 51 07 58.19, 65.92, 69.55, 70.27, 78.09, 78 16, 79 08, 81 42, 103 79, 121 03, 123 87, 126 27, 127 62, 128.90, 130.04, 148.32, 150.21 , 156.15, 169 78, 203.88, and 217.99. MS: m/z 823 (M+H).
Example 16 13-Cyclobutyl-11-deoxy-5-0-desosaminyl-11-6-0-methyl-3-oxo-11-(4-(4-(3-pyridinyl)-1 H- lmldazol-1-yl)butyl)amlπoerythronollde A, 11 ,12-carbamate
To a solution of 2'-O-Acety|-10,11-aπhydro-13-cyclobutyl-5-O-desosamiπyl-12-O- imidazolylcarbonyl-6-0-methyl-3-oxoerythronolide A obtained from example 12 in MeCN (1.0 mL) is added 4-(4-(3-pyridiπyl)-1H-imidazol-1-yl)butylamine and the reaction mixture was heated at 90°C for 15 hours MeCN was evaporated in vacuo, sat. NaHC03 was added, and the aqueous solution is extracted with CH2CI2 (X4). The combined organic layers are washed with H20 (X2) and brine (X1), dried over Na2S04, and evaporated in vacuo. The crude product is purified by preparative TLC (1% NH3-H2O-10% MeOH-89% CH2CI2) to give the title compound as a white solid,
'H NMR (CDCI3, 400 MHz) δ' 0.95 (3H, d, J = 6 8 Hz), 1 13 (3H. d , J = 7 2 Hz), 1.21 (3H, d, J - 6.0 Hz), 1.27 (3H, d, J = 7.6 Hz), 1.30 (3H, s), 1.33 (3H, d, J = 6.8 Hz), 1.42 (3H, s), 2.24 (6H, s), 2.59 (3H, s), 3,48 (1H, s), 3.83 (1H, q, J = 6.8 Hz).
13C NMR (CDCI3, 100 MHz) δ: 13.89, 14.30, 15.15, 15,88, 18.37, 18.91, 19.74, 21 17, 24.30, 24.95, 26.53, 28,13, 28.62, 35.26, 38,89, 39,52, 40.23, 42.41 , 44.89, 46.82, 47.60, 49.78, 51.24, 60.35, 65.83, 69,61 , 70.29, 78,20, 78.24, 79,50, 82.88, 103.88, 115 50, 123.49, 130.26, 131.98, 137.78, 139.08, 146.38, 147.57, 157.32, 169.88, 203.67 and 216.36. MS: m/z 838 (M+H).

Claims

A compound of the formula
Figure imgf000078_0001
or a pharmaceutically acceptable salt thereof, wherein-
R is an alpha-branched C3-CB alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C5-Ca cycloalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-Cβ cycloalkyl or C5-C8 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more CrC4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with at least one substituent selected from CrC alkyl. C,-C alkoxy and C,-C alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyi, and cyano; or R may be with a formula (a) as shown below
Figure imgf000078_0002
wherein X1 is O. S or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d < 5, or R is CH2R24, wherein R24 is H, 0,-Caalkyl, C2-C8aikenyl, CrCβalkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms; or a Ca-Cβcycloalkyl or C5-C8cycloalkenyl either or which may be optionally substituted by methyl or one or more C.-Coalkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms; or a group of the formula SR23 wherein RM is 0,-Cgalkyl, Cz-C8alkenyl, C2- C8alkyny|, C3-C8cycloalkyl, C5-C8cycloalkeny|, phenyl or substituted phenyl wherein the substituent is C1-C4alkyl, CrC4alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C1-C„alkyl groups or halo atoms; and R is H or acyl of an organic acid of up to 18 carbon atoms 2. A compound of the formula
Figure imgf000079_0001
or a pharmaceutically acceptable salt thereof, wherein-
R is an alpha-branched C3-Cfl alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group wherein the alkyl group Is an alpha-branched C2-C5 alkyl group, a C3-C8 cycloalkyl or C5-C8 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C C4 alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with at least one substituent selected from CrCΛ alkyl, C C4 alkoxy and C,-C4 alkylthio groups, halogen atoms, hydroxyl groups, tnfluoromethyl, and cyano; or R may be with a formula (a) as shown below
Figure imgf000080_0001
wherein X1 is O, S or -CH2-, a, b, c, and d are each independently seleoted from an integer ranging from 0 to 2 and a + b + c + d 5;
X is -(CR5RS)S- or -NR5-, wherein g is 0 or 1; wherein when X is -NR5-, X and R3 optionally may be taken together to form -N=CR7RB, or when X is -NR5-, x and Ra optionally may be taken together to form a heterocyclic of the formula
Figure imgf000080_0002
wherein n is selected from an integer ranging from 1 to 3, p is selected from an integer ranging from 1 to 3, q is 0 or 1, and R9 is selected from CH2, 0, S, 0=0, C=S, S02, -CH=CH-, - CH(OH)CH(OH)-, and NH; or when X is -NR5-, X and R together form a heterocyclic as defined above having substituents selected from the group consisting of -C(O)0R10, -OR10, C,-C1ή alkanoyl. halo, nitro. cyano, R10, 4-10 membered heterocyclic, C3-C10 aryl, -C(0)NRlύR12, -NH0(O)R10, - NHC(O)NR10R11, -NR10R1', -SR1D, -S(0)R,α -S02R10 and -S02NR1°R"; or R is CH2R24, wherein H2 is H, CrCaalkyl, C2-Cflalkenyl, C2-CBalkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms; or a C3-CBcycloalkyl or C5-C8cycloalkenyl either or which may be optionally substituted by methyl or one or more CrC4a|ky| groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C1-C4alkyl groups or halo atoms; or a group of the formula SR23 wherein R23 is
Figure imgf000080_0003
CrC8alkenyl, C2- C8alkynyl, C3-C8cycloalkyl, C5-C8cyeloalkenyl, phenyl or substituted phenyl wherein the substituent is C1-C4alkyl, CrC4a|koχy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C1-C4alkyl groups or halo atoms; R1ϋ and R11 are each independently selected from H, 0,-0^ alkyl; or R3 is selected from H, C(=0)Z, C(=0)OZ, (CRsR6)mZ , C(=0)R7, C(=0)OR7, -7Θ-
(CR5R6) R7, wherein m Is an Integer ranging from 0 to 6;
Z is a 4-10 membered heterocyclic or C6-C10 aryl, wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -C(0)OR1D, -OR10, C,-Cι0 alkanoyl, halo, nitro, cyano, R1°. 4-10 membered heterocyclic, C6-C10 aryl, -C(0)NR10R11, -NHC(0)R10, -NHC(O)NR10R -NR10Rπ, -SR10 - S(O)R1Q -SO2R,0 and -SO2NR1Q R11;
R4 is H or acyl of an organic carboxylic acid of up to 18 carbon atoms; R5 and R6 are each independently selected from H,
Figure imgf000081_0001
alkyl, halogen: and Rs and R6 may each independently vary when m is greater than 1; and
R7 and RB are each Independently selected from H, CrC18 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)OR10, -
OR10, CrC10 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, C6-C1D aryl, -
NR1DR11 , -C(O)NRl0R' -NHC(0)R , -NHCfONR^R11, -SR10, -S(0)Rια, -S02R10 and
SO,NR ilQuRiι
3. A compound of the formula
Figure imgf000081_0002
or a pharmaceutically acceptable salt thereof, wherein:
R is an alpha-branched C--Cβ alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C3-C8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-CB cycloalkyl or C3-Ca cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more CrC4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocychc ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4 alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with at least one substituent selected from C C4 alkyl, CrC4 alkoxy and CrC4 alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano; or R may be with a formula (a) as shown below:
Figure imgf000082_0001
wherein X1 is O, S or -CH2-, a, b, c, and d are each independently selected from an Integer ranging from 0 to 2 and a + b + c + d ^δ;
X is -(CR5R6)a- or -NR5-, wherein g is 0 or 1, wherein when X is -NR5-, X and R3 optionally may be taken together to form -N=CR7RB, or when X is -NR5-, X and R3 optionally may be taken together to form a heterocyclic of the formula
Figure imgf000082_0002
wherein n is selected from an integer ranging from 1 to 3, p is selected from an integer ranging from 1 to 3, q is 0 or 1 , and Rβ is selected from CH2, O, S, C=0, C=S, S02, -CH=CH-, -CH(OH)CH(OH)-, and NH, or when X is -NR5-, X and R3 together form a heterocyclic as defined above having substituents selected from the group consisting of -C(0)OR1°, -OR10, C,-Cι0 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, CB-C10 aryl, -C(O)NR10R , -NHC(0)R1D, -NHC(O)NR10R11, -N V, -SR10, -S(0)R1°, -S02R10 and -SO2NR,0R11; or R is CH2R34, wherein R34 is H, C1-C8alkyl, C2-C8alkenyl, C2-Cβalkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms; or a C3-Cβcycloalkyl or C5-CBcycloalkenyl either or which may be optionally substituted by methyl or one or more C,-C4alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more CrC4alkyl groups or halo atoms; or a group of the formula SR23 wherein R23 is Chalky!, C2-Caalkenyl, C2- C8alkynyl, C3-Cβcycloalkyl, C5-C8cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C1-C4alkyl, CrC4alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic nng which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more CrC4alkyl groups or halo atoms; R1D and R11 are each independently selected from H, C|-C1D alkyl; or R3 is selected from H, C(=0)Z, C(=0)OZ, (CR5R6)mZ , C(=0)R7, 0(-O)ORr, (CR5Rβ)rr,R7 wherein m is selected from an integer ranging from 0 to 6; Z is a 4-10 membered heterocyclic or C6-C10 aryl; wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -C(0)OR1°, -OR10, C^C^ alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, Cβ-C10 aryl, -C(O)NR10Rn, -NH0(O)R10, -NHC(O)NR 0R11, -NR 0R11, -SR10, -S(0)R ύ -S02R1Q and -S02NR10 R'1, R4 is H or acyl of an organic carboxylic acid of up to 18 carbon atoms,
R5 and R6 are each independently selected from H, C,-C9 alkyl, halogen and Rε and Rs may each independently vary when m is greater than 1 , where the bond between C9 and the nitrogen to which C9 is linked is a single bond, R1 and R2 together with the nitrogen atom to which they are linked optionally may together form -N=CR7RB, or R1 and R2 together with the nitrogen atom to which they are linked optionally may together form a heterocyclic of the formula
Figure imgf000083_0001
wherein n is selected from an integer ranging from 1 to 3, p is selected from an integer ranging from 1 to 3, q is 0 or 1, and Rβ ιs selected from CH2, O, S, C=0, C=S, S02l -CH=CH-, -CH(OH)CH(OH)-, and NH, or X and R3 together form a heterocyclic as defined above having substituents selected from the group consisting of -C(0)OR10, -OR10, C,-C10 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, C8-C10 aryl, -C(O)NR10R11, -NHC(0)R1D, -NHC(O)NR10R11, -NR^R11, -SR10, -S(0)R10, -S02R10 and -S02NR10 R11, and
R1, R2, R7, and Rβ are each independently selected from H, C,-C12 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O. S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)OR10, -OR10, CrC10 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, Cβ-C,0 aryl, -C(O)NR10R11, -NHC(0)R10, -NHC(O)NRl0R11, -NR^R11, -SR10. -S(0)R10, -S02R10 and -SO2NR10R11, where the bond between 09 and the nitrogen to which C9 is linked is a double bond, R1 is not existent, and R2 is OR7, wherein R7 is defined as above 4. A compound of the formula
Figure imgf000084_0001
or a pharmaceutically acceptable salt thereof, wherein:
R is an alpha-branched C3-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or Cg-Cg cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C1-C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C1-C4 alkyl groups or halo atoms, or R is phenyl which may be optionally substituted with at least one substituent selected from C1-C4 alkyl, C1-C4 alkoxy and C1-C4 alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano, or R may be with a formula (a) as shown below
Figure imgf000084_0002
wherein X1 is O, S or -CH2-, a, b, c, end d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d 5; or R is CH2R24, wherein R24 is H, C C8alky|, C2-Cβalkeπyl, C2-Caalkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms; or a C3-C8cycloalkyi or C3-C8cycloalkenyl either or which may be optionally substituted by methyl or one or more d-C4alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C1-C4alkyl groups or halo atoms; or a group of the formula SR" wherein RΏ IS C,-Cβalkyl, C2-CBalkenyl, C2- C„alkynyl, C3-CBcycloalkyl, C5-Cβcycloalkenyl, phenyl or substituted phenyl wherein the substituent is C,-C4alkyl, CτC4alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C.,-C4alkyl groups or halo atoms;
R3, R2, R7, and R8 are Independently selected from H, CrciB alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -0(O)OR10, -OR10, C C10 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, C_-C,0 aryl, -C(0)NR1pR11, -NHC(0)R10, -NHC(O)NR 0R11, -NR1QR1 -SR' -SfOJR1 -SO.R1 and
-SQ2NR 11-Ur| R,1η1ι .; and
R10 and R11 are each independently selected from H, C,-C10 alkyl; and R4 is H or acyl of an organic carboxylic acid of up to 18 carbon atoms, 5, A compound of the formula
Figure imgf000085_0001
or a pharmaceutically acceptable salt thereof, wherein
R Is an alpha-branched c3-c8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a CS-CΛ cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-Cβ cycloalkyl or Cs-Ca cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and hich may optionally be substituted by one or more C,-C4 alkyl groups or halo atoms, or R is phenyl which may be optionally substituted with at least one substituent selected from C,-C4 alkyl, C,-C4 alkoxy and CrC4 alkylthio groups, halogen atoms, hydroxyl groups, tπfluoromethyl, and cyano, or R may be with a formula (a) as shown below
Figure imgf000086_0001
wherein X1 is O, S or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d < 5, or R is CH2R24, wherein R24 is H, CrCsalkyl, C2-C8alkenyl, C2-C„alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms, or a C3-C8cycloalkyl or C5-C8cycloalkenyl either or which may be optionally substituted by methyl or one or more C C4alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C C4alkyl groups or halo atoms, or a group of the formula SR23 wherein R23 is C,-C,alkyl. C2-CBalkenyl, C3- CBalkynyl, C3-Cβcycloalkyl, C5-C8cycloalkenyl, phenyl or substituted phenyl wherein the substituent is CrC4alkyl, C1-C4alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more 0,-C^alkyl groups or halo atoms, R10 and R11 are independently selected from H, C,-C10 alkyl,
R3 is selected from H, C(=0)Z, C(*0)OZ, (CRsR6)mZ, C(=0)R7, C(=0)OR7, (CR5R6) R7 wherein m is selected from an integer ranging from 0 to 6,
2 is a 4-10 membered heterocyclic or CB-C10 aryl, wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -C(0)OR10, -OR10, C^C^ alkanoyl, halo, nitro, cyano, R1D, 4-10 membered heterocychc, C6-C1D aryl, -C(O)NR10Rn, -NH0(O)R10, -NHC(O)NR10R11, -NR^R11, -SR'0 -S(0)R10 -S02R10 and -S02NR10 R11,
R5 and R6 are independently selected from H. C,-C6 alkyl. halogen, and R5 and R9 may each vary independently when m is greater than 1, R2, R7, and R8 are each independently selected from H, 0,-0,8 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)OR1° -OR10, c,-c10 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, Cβ-C10 aryl, -C(O)NR10R11, -NHC(0)R10, -NHC(O)NRl0R11, -NR10R11, -SR10, -S(0)R10, -S02R10 and -SO2NR10R11; and
R4 is H or acyl of an organic carboxylic acid of up to 18 carbon atoms.
6. A compound according to claim 1 selected from the group consisting of: the compound of claim 1 wherein R is Me and R4 is H, the compound of claim 1 wherein R is n-butyl and R4 is H; the compound of claim 1 wherein R is MeS and R4 is H; the compound of claim 1 wherein R is EtS and Ra is H, the compound of claim 1 wherein R is cyclopropyl and R4 is H; the compound of claim 1 wherein R is cyclobutyl and R4 is H; the compound of claim 1 wherein R is cyclopentyl and R4 is H, and the compound of claim 1 wherein R is cyclohexyl and R4 is H.
7, A compound according to claim 2 selected from the group consisting of: the compound of claim 2 wherein R is Me, R4 is H, X iβ NH and R3 is 3-quiπoliπ-4-yl- propyl; the compound of claim 2 wherein R is Me, R4 is H, X is CH2 and R3 is 3-quinolin-4-yl- propyl; the compound or claim 2 wherein R = Me, R4 is H, x is NH and Rs is 3-(4-phenyl- ιmidazol-1 -y l)-pr opy I; the compound of claim 2 wherein R is Me, R4 is H; X is CH2 and R3 is 3-(4-phenyl- ιmidazol-1-yl)-propyl; the compound of claim 2 wherein R is Me, R4 is H, X is NH and R3 is 3-(4-(3-pyridιnyl)-
1 H-ιmida2θl-1-y-)propyl, the compound of claim 2 wherein R is Me, R4 is H, X is CH2 and R3 is 3-(4-(3-pyridinyl)- 1H-ιmιdazol-1-yl)propyl; the compound of claim 2 wherein R is n-butyl, R4 is H, X is NH and R3 is 3-quinolin-4-yl- propyl; the compound of claim 2 wherein R is n-butyl, R4 is H, X is CHa and R3 is 3-quinolin-4-yl- propyl; the compound of claim 2 wherein R is n-butyl, R4 is H, X is NH and R3 is 3-(4-phenyl- ιmιdazol-1-yl)-propyl; the compound of claim 2 wherein R is n-butyl, R4 is H, X is CH2 and R3 is 3-(4-phenyl- ιmιdazo|-1-y|)-propyl, the compound of claim 2 wherein R is n-butyl, R4 is H, X is NH and R3 is 3-(4-(3- ρyrιdιnyi)-l H-ιmidazoi-ι-yi)propyl; the compound of claim 2 wherein R is n-butyl, R4 is H, X is CH2 and R3 is 3-(4-(3- pyridinylM H-imidazol-1 -yl)propyl; the compound of claim 2 wherein R is MeS, R4 is H, X is NH and R3 is 3-quιnolin-4-yl- propyl; the compound of claim 2 wherein R is MeS, R4 is H, X is CH2 and R3 Is 3-qulnolln-4-yl- propyl; the compound of claim 2 wherein R is MeS, R4 is H, X is NH and R3 is 3-(4-phenyl- ιmιdazol-1-y|)-propyl; the compound of claim 2 wherein R Is MeS, RΛ is H, X is CH2 and R3 is 3-(4-phenyl- ιmιdazol-1-y|)-propyl; the compound of claim 2 wherein R is MeS, R4 is H, X is NH and R3 is 3-(4-(3-pyridinyl)- 1 H-imιdazol-1-yl)propyI; the compound of claim 2 wherein R is MeS, R4 is H, X is CH2 and R3 is 3-(4-(3-pyridinyl)- 1 H-imidazol-1-yl)proρyl; the compound of claim 2 wherein R is EtS, R4 is H, X is NH and R3 is 3-quinolin-4-yl- propyl; the compound of claim 2 wherein R is EtS, R4 is H, X is CH2 and R3 is 3-quιnolin-4-yl- propyl; the compound of claim 2 wherein R i≤ EtS, R4 is H, X is NH and R3 is 3-(4-phenyl- ιmιdazol-1-yl)-propyl, the compound of claim 2 wherein R is EtS, R4 is H, X is CH2 and R3 is 3-(4-phenyl- ιmιdazol-l-yl)-propyl; the compound of claim 2 wherein R is EtS, R4 is H, X is NH and R3 is 3-(4-(3-pyridiπyl)- 1 H-imidazol-1-yl)propy!; the compound of claim 2 wherein R is EtS, R4 is H, X is CH2 and R3 is 3-(4-(3-pyπdιnyl)-
1 H-ιmιdazol-1-yl)propy|; the compound of claim 2 wherein R is cyclopropyl, R4 is H, X is NH and R3 is 3-q inolιn- 4-yl-ρropyl; the compound of claim 2 wherein R is cyclopropyl, R4 is H, X is CH2 and R3 is 3-quιnolin- 4-yl-propyl; the compound of claim 2 wherein R Is cyclopropyl, R4 Is H, X Is NH and R3 is 3-(4- pheny|-ιmιdazol-1-yl)-proρyl; the compound of claim 2 wherein R is cyclopropyl, R4 is H, X is CH2 and R3 is 3-(4- phenyl-imιdazol-1 -y l)-proρy I; the compound of claim 2 wherein R is cyclopropyl, R" is H, X is NH and R° is 3-(4-(3- py πdinyl)-1 H-imidazol-1 -yl)propyl; the compound of claim 2 wherein R is cyclopropyl, R4 is H, X is CH2 and R3 is 3-(4-(3- pyridιnyl)-1 H-imidazol-1 -yl)propyl; the compound of claim 2 wherein R is cyclobutyl, R4 is H, X is NH and R3 is 3-quinolin-4- yl-propyl; the compound of claim 2 wherein R is cyclobutyl, R4 is H, X is CH2 and R3 is 3~quinolιn-4- yl-propyl; the compound of claim 2 wherein R is cyclobutyl, R4 is H, X is NH and R3 is 3-(4-pheπyl- imidazoi-i-yi)-ρropyi; the compound of claim 2 wherein R is cyclobutyl, R4 is H, X is CH2 and R3 ιε 3-(4-phenyl- ιmιdazol-1-yl)-propyl; the compound of claim 2 wherein R is cyclobutyl, R4 is H, X is NH and R3 is 3-(4-(3- pyπdinyl)-1H-imidazol-1-yl)propyl; the compound of claim 2 wherein R is cyclobutyl, R4 is H, X is CH2 and R3 is 3-(4-(3- pyridιnyl)-1H-imidazol-1-yl)propyl; the compound of claim 2 wherein R is cyclopentyl, R4 is H, X is NH and R3 is 3-quinolin- 4-yl-propyl; the compound of claim 2 wherein R is cyclopentyl, R4 is H, X is CH2 and R3 is 3-quιnolιn- 4-yl-propyl; the compound of claim 2 wherein R is cyclopentyl, R4 is H, X is NH and R3 is 3-(4- phenyl-imidazol-1-yl)-propyl, the compound of claim 2 wherein R is cyclopentyl, R4 is H, X is CH2 and R3 is 3-(4- phenyl-ιmidazol-1 -yI)-ρropyl; the compound of claim 2 wherein R is cyclopentyl, R4 is H, X is NH and R3 is 3-(4-(3- pyπdιnyl)-1 H-imidazol-1 -yl)propyl; the compound of claim 2 wherein R is cyclopentyl, R4 is H, X is CH2 and R3 is 3-(4-(3- pyridiny l)-1 H-imidazol-1 -yl)propyl; the compound of claim 2 wherein R is cyclohexyl, R4 is H, X is NH and R3 is 3-quιnolιn--l- yl-propyl; the compound of claim 2 wherein R is cyclohexyl, R4 is H, X is CH2 and R3 is 3-quιnolιn-
4-yl-propyl; the compound of claim 2 wherein R is cyclohexyl, R4 is H, X is NH and R3 is 3-(4-phenyl- ιmιdazol-l-yl)-propyl; the compound of claim 2 wherein R is cyclohexyl, R4 is H, X is CH2 and R3 is 3-(4- -86-
phenyl-ιmιdazo|-1-y|)-propyl, the compound of claim 2 wherein R is cyclohexyl, R4 is H, X is NH and R3 is 3-(4-(3 pyπdιπyl)-1 H-ιmidazol-1-yl)propyl; and the compound of claim 2 wherein R is cyclohexyl, R4 is H, X is CH2 and R3 is 3-(4-(3- py rιdιnyl)-1 H-ιmιdazol-1 -yl)propyl. θ A compound according to claim 3 wherein the bond between C-9 and the nitrogen to which C-9 is connected is a double bond, selected from the group consisting of: the compound of claim 3 wherein R is Me, R4 is H, X is NH, R3 is 3-quιnolιn-4-yl-propyl and R2 is OMe; the compound of claim 3 wherein R is Me, R4 is H, X is NH, R3 is 3-(4-phenyl-ιmιdazo|-1- yl)-propyl and R2 is OMe; the compound of claim 3 wherein R is Me, R4 is H, X is NH, R3 is 3-(4-(3-pyπdιπyl)-1H- ιmιdazol-1-y|)propyl and R2 is OMe; the compound of claim 3 wherein R is n-butyl, R4 is H, X is NH, R3 is 3-quιnolm-4-yl- propyl and R2 13 OMe, the compound of claim 3 wherein R is n-butyl, R4 is H, X is NH, R3 is 3-(4-phenyl- ιmιdazol-1-yl)-propyl and R2 is OMe, the compound of claim 3 wherein R is n-butyl, R4 is H, X is NH, R3 is 3-(4-(3-pyridinyl)- 1 H-lmldazol-i-yl)propyl and Ra Is OMe; the compound of claim 3 wherein R is MeS, R4 is H, X is NH, R3 is 3-quιnolιn-4-yl-proρyl and R2 is OMe; the compound of claim 3 wherein R is MeS, R4 is H, X is NH, R3 is 3-(4-pheπyl-imιdazol- 1-yl)-propyl and R2 is OMe; the compound of claim 3 wherein R is MeS, R4 is H, X is NH, R3 is 3-(4-(3-pyndιnyl)-1 H- ιmιdazol-1-yl)propyl and R2 is OMe, the compound of claim 3 wherein R is EtS, R4 is H, X is NH, R3 is 3-quιnolιπ-4-yl-propyl and R2 is OMe; the compound of claim 3 wherein R is EtS, R4 is H, X is NH, R3 is 3-(4-phenyl-ιmιdazol-1- yl)-ρroρyl and R2 is OMe, the compound of claim 3 wherein R is EtS, R4 is H, X is NH, R3 is 3-(4-(3-pyπdιnyl)-1H- ιmιdazo|-1-y|)propyl and R2 is OMe, the compound of claim 3 wherein R is cyclopropyl, R4 is H, X is NH, Rs is 3-quιπolιn-4-yl- propyl and R2 is OMe, the compound of claim 3 wherein R is cyclopropyl, R4 is H, X is NH, R3 is 3-(4-phenyl- ιmιdazol-1-yl)-propyl and R2 is OMe -Θ9-
the compound of claim 3 wherein R is cyclopropyl, R" is H, X is NH, R' is 3-(4-(3- pyridinyl)-1H-imidazol-1-yl)propyl and R2 is OMe; the compound of claim 3 wherein R is cyclobutyl, R4 is H, X is NH, R3 is 3-quιno|ιn-4-yl- propyl and R2 is OMe; the compound of claim 3 wherein R is cyclobutyl, R4 is H, X is NH, R3 is 3-(4-phenyl- imidazol-1-yl)-prop l and R2 is OMe; the compound of claim 3 wherein R is cyclobutyl, R4 is H, X is NH, R3 is 3-(4-(3- pyrιdιnyl)-1 H-ιmιdazol-1-yl)propyl and R2 is OMe, the compound of claim 3 wherein R is cyclopentyl, R4 is H, X is NH, R3 is 3-quinolιn-4-yl- propyl and R2 is OMe, the compound of claim 3 wherein R is cyclopentyl; R4 is H, X is NH, R3 is 3-(4-pheπyl- imidazol-1-yl)-propyl and R2 is OMe; the compound of claim 3 wherein R is cyclopentyl; R4 is H, X is NH, R3 is 3-(4-(3- pyridiny|)-1H-imidazol-1-yl)propyl and R2 is OMe, the compound of claim 3 wherein R is cyclohexyl, R4 is H, X is NH, R3 is 3-quιnolιn-4-yl- propyl and Rz is OMe the compound of claim 3 wherein R is cyclohexyl, R4 is H, X is NH, R3 is 3-(4-phenyl- imidazol-1-yl)-propyl and R2 is OMe; and the compound of claim 3 wherein R Is cyclohexyl, R4 Is H, X Is NH, R1 Is 3-(4-(3- pyridinyl)-1H-imidazol-1-yl)propyl and R2 is OMe. 9. A compound according to claim 3 wherein the bond between C-9 and the nitrogen to which C-9 is connected is a single bond, selected from the group consisting of: the compound of claim 3 wherein R4 is H, X is NH, R3 is 3-quinolin-4-yl-propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of claim 3 wherein R is Me, R4 is H, X is NH, R3 is 3-(4-phenyl-imidazol-1- yl)-propyl; R1 is H and R2 is Me, Et, or n-Pπ the compound of claim 3 wherein R is Me, R4 is H, X is NH, R3 is 3-(4-(3-pyrιdιnyl)-1H- ιmidazol-1-yl)propyl, R1 is H and R2 is Me, Et, or n-Pr; , the compound of claim 3 wherein R is n-butyl, R4 is H, X is NH, R3 is 3-quinolin-4-yl- propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of claim 3 wherein R is n-butyl, R4 is H, X is NH, R3 is 3-(4-phenyl- imidazol-1-yl)-propyl, R is H and R* is Me, Et, or n-Pr; the compound of claim 3 wherein R is n-butyl, R4 is H, X is NH, R3 is 3-(4-(3-pyridinyl)- 1H-ιmιdazol-1-yl)prαpyl, R1 is H and R2 is Me, Et, or n-Pr, the compound of claim 3 wherein R is MeS, R4 is H, X is NH, R3 is 3-quιπolιn-4-yl-ρropyl, R1 is H and R8 is Me, Et, or n-Pr, the compound of claim 3 wherein R is MeS, R4 is H, X is NH, R3 is 3-(4-phenyl-ιrπidazol- 1-yl)-propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of claim 3 wherein R is MeS, R4 is H, X is NH, R3 is 3-(4-(3-pyridιnyl)-1 H- ιmidazol-1-yl)propyl R1 is H and R2 is Me, Et, or n-Pr; the compound of claim 3 wherein R Is EtS, R4 Is H, X Is NH, R3 Is 3-qulnolln~4-yl-propyl,
R1 is H and R2 is Me, Et, or n-Pr; the compound of claim 3 wherein R is EtS, R4 is H, X is NH, R3 is 3-(4-phenyl-ιmιdazol-1- yl)-proρyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of claim 3 wherein R is EtS, R4 is H, X is NH, R3 is 3-(4-(3-pyrιdιnyl)-1 H- imidazol-1-yl)propyl, R is H and R2 is Me, Et, or n-Pr; the compound of claim 3 wherein R is cyclopropyl, R4 is H, X is NH, R3 is 3-quinolιn-4-yl- propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of claim 3 wherein R is cyclopropyl, R4 is H, X is NH, R3 is 3-(4-phenyl- imidazol-1-yl)-prop l, R1 is H and R2 is Me, Et, or π-Pr; the compound of claim 3 wherein R is cyclopropyl, R4 is H, X is NH, R3 is 3-(4-(3- pyridiπyl)-1H-ιmidazoi-1-yl)propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of claim 3 wherein R is cyclobutyl, R4 is H, X is NH,R3 is 3-quinolin-4-yl- propyl, R1 is H and Ra is Me, Et, or n-Pr; the compound of claim 3 wherein R is cyclobutyl, R4 is H, X is NH, R3 is 3-(4-phenyl- imidazol-1-yl)-propyl, R1 is H and R is Me, Et, or n-Pr; the compound of claim 3 wherein R is cyclobutyl, R4 is H, X is NH,R3 is 3-(4-(3-pyridiπyl)- 1 H-imidazol-1-yl)propyl, R1 is H and R2 is Me, Et, or π-Pr, the compound of claim 3 wherein R is cyclopentyl, R4 is H, X is NH, R3 is 3-quinolιn-4-yl- propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of claim 3 wherein R is cyclopentyl, R4 is H, X is NH, R3 is 3-(4-phenyl- imϊdazol-1-yO-propyl, R1 is H and R2 is Me, Et, or n-Pr, the compound of claim 3 wherein R is cyclopentyl, R4 is H, X is NH, R3 is 3-(4-(3- ρyrιdinyl)-1H-ιmidazol-1-yl)propyl, R1 is H and R2 is Me, Et. or n-Pr. the compound of claim 3 wherein R is cyclohexyl, R4 is H, X is NH, R3 is 3-quinoliπ-4-yl- propyl, R1 is H and R2 is Me, Et, or n-Pr; the compound of claim 3 wherein R is cyclohexyl, R4 is H, X is NH, Ra is 3-(4-phenyl- imidazol-1-y|)-propyl, R1 is H and R2 is Me, Et, or n-Pr, and the compound of claim 3 wherein R is cyclohexyl, R4 is H, X is NH, R3 is 3-(4-(3- pyπdιnyl)-1H-imidazol-1-yl)propyl, R1 is H and R2 is Me, Et, or n-Pr.
10. A compound according to claim 5 selected from the group consisting of the compound of claim 5 wherein R is Me, R4 is H, R3 is 3-quinolin-4-yl-propyl, R7 is H, R8 is H and R2 is H, Me, or Et; the compound of claim 5 wherein R is Me, R4 is H, R3 is 3-(4-phenyl-imidazol-1-yl)- propyl, R7is H, Rβ is H and R2 is H, Me, or Et; the compound of claim 5 wherein R Is Me, R4 Is H, R3 Is 3-(4-(3-pyrldlnyi)-lH-lmldazol-1- yl)ρropy|, R7 is H, Ra is H and R2 is H, Me, or Et; the compound of claim 5 wherein R is n-butyl, R4 is H, R3 is 3-quιnolιn-4-yl-propyl, R7 is H, Rβ is H and R2 is H, Me, or Et; the compound of claim 5 wherein R is n-butyl, R4 is H, R3 is 3-(4-phenyI-ιmidazol-1-yl)- propyl, R7 is H, R8 is H and R2 is H, Me, or Et; the compound of claim 5 wherein R is n-butyl, R4 is H, R3 is 3-(4-(3-pyridinyl)-1 H- imidazol-1-yl)proρyl, R1 is H. R7 is H, Ra is H and R2 is H, Me, or Et, the compound of claim 5 wherein R is MeS, R4 is H, R3 is 3-quιnolιn-4-yl-ρropyl, R7 is H, Ra Is H and R2 is H, Me, or Et, the compound of claim 5 wherein R is MeS, R4 is H, R3 is 3-(4-phenyl-imidazol-1-yl)- propyl, R7 is R8 is H and R2 is H, Me, or Et; the compound of claim 5 wherein R is MeS, R4 is H, R3 is 3-(4-(3-pyridinyl)-1H-imidazo|- 1-yl)propyl, R7ιs H, Rβιs H and Ra is H, Me, or Et, the compound of claim 5 wherein R is EtS, R4 is H, R3 is 3-quinolιn----yl-propyl1 R7 is H, R8 is H and 2 is H, Me, or Et, the compound of claim 5 wherein R is EtS, R4 is H, R3 is 3-(4-phenyl-ιmιdazol-1-yl)- propyl, R7 is H, R8 is H and R2 is H, Me, or Et; the compound of claim 5 wherein R is EtS, R4 is H, R3 is 3-(4-(3-pyπdinyl)-1 H-ιmιdazol-1- yl)ρropyl, R7 is H. R8is H and R2 is H, Me, or Et; the compound of claim 5 wherein R is cyclopropyl, R4 is H, R3 is 3-quinolιn-4-yl-propyl,
R7 is H, R8 is H and R2 is H, Me, or Et; the compound of claim 5 wherein R is cyclopropyl, R4 is H, R3 is 3-(4-phenyl-imjdazol-1- yt)-propyl, R7 is H, Rβ is H and R2 is H, Me, or Et; the compound of claim 5 wherein R is cyclopropyl, R4 is H, R3 is 3-(4-(3-pyridiπyl)-1 H- imidazol-1-yl)propyl, R7 is H, R8 is H and R2 is H, Me, or Et, the compound of claim 5 wherein R is cyclobutyl, R4 is H, R3 is 3-quιnolιn-4-yl-propyl, R7 is H, Rβ is H and R2 is H, Me, or Et, the compound of claim 5 wherein R is cyclobutyl, R4 is H, R3 is 3-(4-phenyl-ιmidazol-1- yl)-propyl, R7is H, R8 is H and R2 is H, Me, or Et, the compound of claim 5 wherein R is cyclobutyl, R4 is H, R3 is 3-(4-(3-pyrιdinyl)-1H- ιmidazo|-1-yl)propyl, R7 is H, Rβ is H and R2 is H, Me, or Et; the compound of claim 5 wherein R is cyclopentyl, R4 is H, R3 is 3-quιnolιn-4-yl-propyl, R7 is H, Rβ is H and R2 is H, Me, or Et; the compound of claim 5 wherein R is cyclopentyl, R4 is H, R3 is 3-(4-phenyl-ιmidazol-1- yl)-propy|, R7 ιs H, R8 is H and R2 is H, Me, or Et, the compound of claim 5 wherein R is cyclopentyl, R4 is H, R3 is 3-(4-(3-ρyrιdιπy|)-1H- imidazol-1-yl)propyl, R7 is H, Rβ is H and R2 is H, Me, or Et, the compound of claim 5 wherein R is cyclohexyl, R4 is H, R3 is 3-quinolin~4-yl-propyl, R7 is H, Rβ is H aπd R* ιs H, Me, or Et, the compound of claim 5 wherein R is cyclohexyl, R4 is H, R3 is 3-(4-ρhenyl-ιmιdazol-1- yl)-propyl, R7 is H, RB is H and R2 is H, Me, or Et, and the compound of claim 5 wherein R is cyclohexyl, R4 is H, R3 is 3-(4-(3-pyridinyl)-1H- imidazol-1-yDpropyl, R7 is H, Ra is H and R2 is H, Me or Et.
11. A pharmaceutical composition for the treatment of a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound Of formulas 2, 3, 4 or 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier
12. A method of treating a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of formula 1_, 2, _3, 4 or 5 or a pharmaceutically acceptable salt thereof.
13. A process for preparing a compound of the formula
Figure imgf000094_0001
or a pharmaceutically acceptable salt thereof, wherein: R is methyl, an alpha-branched C3-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C5-C8 cycloalkyl group wherein the alkyl group is an alpha-branched C3-C3 alkyl group; a C3-CB cycloalkyl or C5-C8 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more CrC4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more CrC4 alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with at least one substituent selected from C,-C4 alkyl, C,-C4 alkoxy and C C4 alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano, or R may be with a formula (a) as shown below
Figure imgf000095_0001
wherein X1 is O, S or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d < 5; and
R4 is H or acyl of an organic acid of up to 18 carbon atoms, which comprises treating a compound of the formula
Figure imgf000095_0002
22
wherein R and R4 are as defined in formula 1_with a hydrolyzing agent.
14 The process of claim 13 wherein the hydrolyzing agent is sodium bisulfite 15 The process of claim 13 wherein R4 is H
16. A process for preparing a compound of the formula
Figure imgf000096_0001
wherein R, R3, R4 and Rs are as defined in formula 2 and X in formula 2 is -NR5 which comprises treating a compound of the formula
Figure imgf000096_0002
wherein R and R4 are as defined in formula 2, with an alkylating agent. 17. The process of claim 16 wherein R4 is H. 18 A process for preparing a compound of the formula
Figure imgf000097_0001
wherein R, R , R4, R and R are as defined in formula 2 and X in formula 2 is -(CR R )g- which comprises treating a compound of the formula
Figure imgf000097_0002
wherein R is as defined in formula 2 with a compound of the formula R3- C(RSR6)B-NH2, wherein g is 0 or 1 and R3, Rs and R6 are as defined in formula 2.
19. A process for preparing a compound of the formula
Figure imgf000098_0001
wherein R and R4 are as defined in formula 2, by treating a compound of the formula
Figure imgf000098_0002
wherein R is as defined in formula 2, with NH2NH2. 20. The process of claim 19 wherein R4 is H
21. A process for preparing a compound of the formula
Figure imgf000099_0001
wherein R is as defined in formula 2 which comprises treating a compound of the formula
Figure imgf000100_0001
wherein R is as defined in formula 2 with carbonyldiimidazole. 22. A process for preparing a compound of the formula
Figure imgf000100_0002
wherein R is as defined in formula 2 which comprises treating a compound of the formula
Figure imgf000100_0003
wherein R is as defined in formula 2 with a base,
23. A process for preparing a compound of the formula
Figure imgf000101_0001
wherein R is as defined in formula 2 which comprises treating a compound of the formula
Figure imgf000101_0002
wherein R is as defined in formula 2 with an oxidizing agent.
24. A process for preparing a compound of the formula
Figure imgf000102_0001
wherein R is as defined in formula 2 which comprises treating a compound of the formula
Figure imgf000102_0002
14 wherein R is as defined in formula 2 with an acid
25, A process for preparing a compound of the formula
Figure imgf000103_0001
14
wherein R is as defined in formula 2 which comprises treating a compound of the formula
Figure imgf000103_0002
wherein R is as defined in formula 2, with trichloromethylisocyanate, ethylene carbonate or caronyyldiimidazole.
26. A process for preparing a compound of the formula
Figure imgf000104_0001
wherein R is as defined in formula 2 which comprises treating a compound of the formula
Figure imgf000104_0002
wherein R is as defined in formula 2 with an acylating agent,
27. The process of claim 26 wherein the acylating agent is acetic anhydride,
28. A compound of the formula
Figure imgf000105_0001
or a pharmaceutically acceptable salt thereof, wherein:
R is an alpha-branched C3-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C5-CB cycloalkyl group wherein the alkyl group Is an alpha-branched C2-c5 alkyl group, a C3-C8 cycloalkyl or C5-C3 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more c,-c4 alkyl groups or halo atoms, or R is phenyl which may be optionally substituted with at least one substituent selected from C,-C4 alkyl, CrC4 alkoxy and C,-C4 alkylthio groups, halogen atoms, hydroxyl groups, tπfluoromethyl, and cyano; or R may be with a formula (a) as shown below
Figure imgf000105_0002
wherein X1 is 0. S or -CHa-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d < 5; or R is CHaR24, wherein R24 is H, 0,-Cβalkyl. C2-C8alkenyl, C2-C8alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms, or a C3-CBcyc|oalkyl or C5-Cacycloalkenyl either or which may be optionally substituted by methyl or one or more CrC4alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more CrC4alkyl groups or halo atoms; or a group of the formula SR23 wherein R23 is C,-CBalkyl, C2-C8alkenyl, Cz- Caalkynyl, C3-C„cycloalkyl, C3-Cβcydoalkenyl, phenyl or substituted phenyl Wherein the substituent is CrC4alkyl, C1-C4alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C1-C4alkyl groups or halo atoms; and
R4 is H or acyl of an organic acid of up to 18 carbon atoms.
29, A compound of the formula
Figure imgf000106_0001
or a pharmaceutically acceptable salt thereof, wherein: R is an alpha-branched C3-C„ alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched Ca-CE alkyl group; a C3-Ca cycloalkyl or C5-C8 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more CrC4 alkyl groups or halo atoms: or R is phenyl which may be optionally substituted with at least one substituent selected from C,-C4 alkyl, C C4 alkoxy and C,-C4 alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano; or R may be with a formula (a) as shown below
Figure imgf000106_0002
w w --/--!-• / PCT/IB98/02100
-105-
wherein X1 is 0, S or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d < 5;
X is -(CRBRβ V)8- or -NRB-, wherein g is 0 or 1; wherein when X is -NR5-, X and R3 optionally may be taken together to form -N=CR R , or when X is -NR5-, X and R3 optionally may be taken together to form a heterocyclic of the formula
Figure imgf000107_0001
wherein n is selected from an integer ranging from 1 to 3, p is selected from an integer ranging from 1 to 3, q is 0 or 1. and Rs is selected from CH.,, O, S, 0=0, C=S, S02, -CH=CH-, - CH(OH)CH(OH)-, and NH; or when X is -NR5-, X and R3 together form a heterocyclic as defined above having substituents selected from the group consisting of -C(θ)θR10, -OR10, CrC1Q alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, C6-C10 aryl, -C(0)NR1°R12, -NHC(0)R1°, - NHC(O)NR10R11, -NR^R11, -SR10, -S(0)R10, -S02R1° and -SO2NR10R11; or R is CH2R24, wherein R24 is H, CrCβalkyl, C2-Caalkenyl, C2-C8alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groupε or by one or more halo atoms; or a Ca-Cacycloalkyl or CB-Cacycloalkenyl either or which may be optionally substituted by methyl or one or more C,-C4alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C,-C alkyl groupβ or halo atoms; or a group of the formula SR23 wherein R23 is CrCβalkyl. C2-Cβalkenyl, C2- C8alkynyl, C3-C8cycloalkyl, C5-C$cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C.,-C4alkyl, C1-C4alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-cohtaining heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms; R10 and R11 are each independently selected from H, CrC,o alkyl; or R3 is selected from H, C(=0)Z, C(=0)OZ, (CR5R6)mZ , C(0)R7, C(=0)OR7, (CR5Rβ)mR7, wherein m is an integer ranging from 0 to 6;
Z Is a 4-10 membered heterocyclic or C6-C10 aryl, wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -0(O)OR10, -OR1ύ, 0,-0,0 alkanoyl, halo, nitro, cyano, R1D, 4-10 membered heterocyclic, Cβ-C10 aryl, -C(O)NR10R11, -NHC(0)R10, -NHCfOJNRV1, -NR10R11, -SR10, - S(0)R10 -S02R10 and -SOzNR10 R11,
R4 is H or acyl of an organic carboxylic acid of up to 18 carbon atoms, Rs and Rβ are each independently selected from H, CrCβ alkyl, halogen and Rs and R6 may each independently vary when m is greater than 1, and
R7 and Rβ are each independently selected from H, C,-Cι8 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -0(O)OR10, - OR10, C,-C,0 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyc c, C6-C,α aryl, -
NR1ήR11, -C(O)NRl0R11, -NHC(0)R10, -NHC(O)NR10Rn, -SR10, -S(0)R10 -S02R10 and
SO2NR10R11
30 A compound of the formula
Figure imgf000108_0001
or a pharmaceutically acceptable salt thereof, wherein R is an alpha-branched C3-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups, a C5-Cβ cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group, a C3-C8 cycloalkyl or C5-CB cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C,-C4 alkyl groups or halo atoms, or a 3 to 6 membered oxygen or sulphur containing heterocychc πng which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more CrC4 alkyl groups or halo atoms, or R is phenyl which may be optionally substituted with at least one substituent selected from C,-C4 alkyl, C,-C4 alkoxy and CrC4 alkylthio groups, halogen atoms, hydroxyl groups, yyl "" 13 ' PCT/IB98/02100
-107-
trifluoromethyl, and cyano, or R may be with a formula (a) as shown below
Figure imgf000109_0001
wherein X1 ιβ O, S or -CH_~, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d < 5,
X is -(CR5Rs V)g- or -NR5-, wherein g is 0 or 1 , wherein when X is -NR3-, X and R3 optionally may be taken together to form -N=CR7Rβ, or when X is -NR5-, X and R3 optionally may be taken together to form a heterocyclic of the formula
Figure imgf000109_0002
wherein n is selected from an integer ranging from 1 to 3, p is selected from an integer ranging from 1 to 3, q is 0 or 1, and R9 is selected from CH2, 0, S, C=0, C=S, S02, -CH=CH-, -CH(OH)CH(OH)-, and NH, or when X is -NR5-, X and R3 together form a heterocyclic as defined above having substituents selected from the group consisting of -C(0)OR1°, -OR10, C,-C,0 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, Cβ-C10 aryl, -C(O)NR10R11, -NHC(0)R10, -NHC(O)NR10R , -NR 0R11, -SR10, -S(0)R1ύ, -S02R10 and -SO2NR10R11; or R is CH2R24, wherein R24 is H, C,-C8alkyl, C2-C8alkenyl, C2-CBalkyhyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyi or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms; or a C3-Cacycloaikyl or C3-Cβcycloalkenyl either or which may be optionally substituted by methyl or one or more C,-C4alkyl groups or halo atoms, or g 3 to 6 membered oxygen or sulphur containing heterocyc c πng which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C1-C4alkyl groups or halo atoms, or a group of the formula SR23 wherein R23 is d-Cβalkyl, C2-CBaikenyl, C2- CBalkynyl, C3-Cβcyc|oalkyl, Cs-Cacycloalkenyl, phenyl or substituted phenyl wherein the substituent is C,-C4alkyl, C^alko y or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms; R10 and R11 are each independently selected from H, C,-C,0 alkyl, or R3 is selected from H, C(=0)Z, C(=0)OZ, (CR6Rβ)mZ , C(=0)R7, C(=0)OR7,
(CR6Ra)mR7 wherein m is selected from an integer ranging from 0 to 6;
Z is a 4-10 membered heterocyclic or Ce-C.0 aryl; wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -0(O)0R10, -OR10, C,-C1D alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, C6-C10 aryl, -CfOJNR^R11, -NHC(0)R10, -NHC(0)NR16R1\ -NR10R11, -SR",
-S(0)R10 -S02R10 and -S02NR1Q R11;
R4 is H or acyl of an organic carboxylic acid of up to 18 carbon atoms; Rs and Rβ are each independently selected from H, C,-Cβ alkyl, halogen- and R5 and R6 may each independently vary when m is greater than 1 ; where the bond between C9 and the nitrogen to which C9 is linked is a single bond, R1 and R2 together with the nitrogen atom to which they are linked optionally may together form -N=CR7R8, or R1 and R2 together with the nitrogen atom to which they are linked optionally may together form a heterocyclic of the formula
Figure imgf000110_0001
wherein n is selected from an integer ranging from 1 to 3, p is selected from an integer ranging from 1 to 3, q is 0 or 1 , and Rs is selected from CH2, O, S, C-O, C-S, S02, -CH=CH-, -CH(OH)CH(OH)-, and NH; or X and R3 together form a heterocyclic as defined above having substituents selected from the group consisting of -C(0)OR10, -OR10, 0,-0,0 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, Cβ-C10 aryl,
Figure imgf000110_0002
-NHC(0)R1D, -NHC(0)NR10R11, -NR^R11, -SR1°, -S(0)R10, -S02R10 and -S02NR10 R11; and
R1, R2, R7, and R8 are each independently selected from H. C,-C1a alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from 0, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)0R10, -OR10, 0,-0,0 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, C6-c10 aryl, -C(O)NR10R11, -NHC(0)R10. -NHCfOJNR^R11, -NR10R11, -SR10, -S(0)R10, -SOzR10 and -SO3NRl0R11, where the bond between 09 and the nitrogen to which C9 is linked is a double bond, R1 is not existent, and R2 is OR7, wherein R7 is defined as above 31. A compound of the formula:
Figure imgf000111_0001
or a pharmaceutically acceptable salt thereof, wherein:
R is an alpha-branched C3-C8 alkyl, alkenyl, alkynyl. alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or C5-C8 cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C1-C4 alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and hich may optionally be substituted by one or more C 1-C4 alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with at least one substituent selected from C1-C4 alkyl, C1-C4 alkoxy and C1-C4 alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano; or R may be with a formula (a) as shown below
Figure imgf000111_0002
wherein X1 is O, S or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d < 5; or R is CH2R2", wherein R*4 is H, C,-C8alkyl, C2-Caalkenyl, C2-Caalkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms; or a C3-C8cycloalkyl or C3-CBcycloalkenyl either or which may be optionally substituted by methyl or one or more CrC4alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms, or a group of the formula SR23 wherein R23 is C,-Caalkyl, C2-CBalkenyl, C2- C„alkynyl, C3-C„cycloalkyl, C6-Cβcycloalkenyl, phenyl or substituted phenyl wherein the substituent is C,-C alkyl, C,-C4alkoχy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocychc ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms,
R3, R2, R7, and R8 are independently selected from H, C,-C18 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)OR10, -OR10, C,-C10 alkanoyl, halo, nitro, cyano, R 0, 4-10 membered heterocychc, C6-C10 aryl,
-C(0)NRιυR11, -NHC(0)R10, -NHC(0)NR ji1-U DRn -NR10R11, -SR 1- -S(0)R 10 -SO,Rlu and -SO2NR10R11, and
R10 and R1 are each independently selected from H, C,-C,0 alkyl, and R" is H or acyl of an organic carboxylic acid of up to 18 carbon atoms 32 A compound of the formula
Figure imgf000112_0001
or a pharmaceutically acceptable salt thereof, wherein
R is an alpha-branched C3-CB alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups, a C5-C8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C3 alkyl group, a C3-C8 cycloalkyl or C5-Ca cycioalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C C4 alkyl groups or halo atoms, or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4 alkyl groups or halo atoms; or R is phenyl which may be optionally substituted with at least one substituent selected from C,-C4 alkyl, C,-C4 alkoxy and C,-C4 alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano, or R may be with a formula (a) as shown below,
Figure imgf000113_0001
wherein X1 is O, S or -CH2-, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a + b + c + d < 5, or R Is CH2R24, wherein R24 is H, CrCββl yl, C2-Caa|kenyl, C2-C„alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms; or a C3-CBcycloalkyl or C5-CBcycloalkenyl either or which may be optionally substituted by methyl or one or more C,-C4alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms, or a group of the formula SR23 wherein R23 is C,-CBalkyl, C2-C8alkβnyl, C2-
Cβalkynyl, C3-Cacycloalkyl, C3-C8cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C,-C4alkyl, C,-C4alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C,-C4alkyl groups or halo atoms;
R10 and R11 are independently selected from H, C,-C,0 alkyl;
R3 is selected from H, C(=0)Z, C(=0)OZ, (CR5Rfi)mZ, C(=0)R7, C(=0)OR7, (CR5R6)mR7 wherein m is selected from an integer ranging from 0 to 6;
Z is a 4-10 membered heterocyclic or Cβ-C,0 aryl, wherein said heterocyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -C(0)OR1D, -OR10, C,-C,0 alkanoyl, halo, nitro, cyano, R1D, 4-1 o membered heterocychc, C6-C10 aryl, -C(O)NR10R11, -NHC(0)R10, -NHC(O)NR10R11, -NR^R11, -SR10, -S(0)R10 -SOaR10 and -S02NR10 R11;
R5 and R6 are independently selected from H, C,-C6 alkyl, halogen- and R5 and Rs may each vary independently when m is greater than 1 ;
R2, R7, and R8 are each independently selected from H, C,-Cιa alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of -C(0)OR10,
-OR10, 0,-0,0 alkanoyl, halo, nitro, cyano, R10, 4-10 membered heterocyclic, Cβ-C10 aryl,
Figure imgf000113_0002
-NH0(O)R10, -NHC(O)NR10R11, -NR10R11, -SR10, -S(0)R10, -S02R10 and d
R4 is H or acyl of an organic carboxylic acid of up to 18 carbon atoms.
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