AP558A - New erythromycin derivatives, their preparation process and their use as medicaments. - Google Patents
New erythromycin derivatives, their preparation process and their use as medicaments. Download PDFInfo
- Publication number
- AP558A AP558A APAP/P/1995/000744A AP9500744A AP558A AP 558 A AP558 A AP 558A AP 9500744 A AP9500744 A AP 9500744A AP 558 A AP558 A AP 558A
- Authority
- AP
- ARIPO
- Prior art keywords
- butanamine
- methyl
- dideoxy
- oxy
- formula
- Prior art date
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- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 title claims description 114
- 238000002360 preparation method Methods 0.000 title claims description 36
- 239000003814 drug Substances 0.000 title claims description 13
- 229960003276 erythromycin Drugs 0.000 claims description 57
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 49
- 150000001875 compounds Chemical class 0.000 claims description 42
- -1 heterocyclic radical Chemical class 0.000 claims description 35
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- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 24
- 150000003254 radicals Chemical class 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 13
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 claims description 10
- 150000007513 acids Chemical class 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 claims description 4
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- HWFXUWJTXXPEBY-UHFFFAOYSA-N butan-1-amine;1h-1,2,4-triazole Chemical compound CCCCN.C=1N=CNN=1 HWFXUWJTXXPEBY-UHFFFAOYSA-N 0.000 claims description 2
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- 206010006451 bronchitis Diseases 0.000 description 1
- UWFBTKYJJUYNRU-UHFFFAOYSA-N butan-1-amine;7-methoxyquinoline Chemical compound CCCCN.C1=CC=NC2=CC(OC)=CC=C21 UWFBTKYJJUYNRU-UHFFFAOYSA-N 0.000 description 1
- TYAIVPLLOTXIGV-UHFFFAOYSA-N butan-2-amine;1h-imidazo[4,5-b]pyridine Chemical compound CCC(C)N.C1=CC=C2NC=NC2=N1 TYAIVPLLOTXIGV-UHFFFAOYSA-N 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HFPGRVHMFSJMOL-UHFFFAOYSA-N dibromomethane Chemical compound Br[CH]Br HFPGRVHMFSJMOL-UHFFFAOYSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 208000019258 ear infection Diseases 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- VOEPIFVLNUODAC-UHFFFAOYSA-N ethyl 2-pyridin-2-yl-1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C1=CSC(C=2N=CC=CC=2)=N1 VOEPIFVLNUODAC-UHFFFAOYSA-N 0.000 description 1
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 229940081066 picolinic acid Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- HYKQYVSNFPWGKQ-UHFFFAOYSA-N pyridine-2-carbothioamide Chemical compound NC(=S)C1=CC=CC=N1 HYKQYVSNFPWGKQ-UHFFFAOYSA-N 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- DCGLONGLPGISNX-UHFFFAOYSA-N trimethyl(prop-1-ynyl)silane Chemical compound CC#C[Si](C)(C)C DCGLONGLPGISNX-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- 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
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- 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
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Pulmonology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Indole Compounds (AREA)
- Pyrrole Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
The subject of the
Description
The present invention relates to new erythromycin derivatives, their preparation process and their use as medicaments.
A subject of the invention is the compounds of formula (I):
in which R represents a -(CH2)nAr radical, in which n represents the number 3, 4 or 5 and Ar represents a heterocyclic radical, optionally carrying one or more substituents, chosen from the following group of radicals:
Ου
Z
AP/P/ 9 5/007
/
AP.00556 or R represents the radical —{CH }
and Z represents a hydrogen atom or an acid remainder, as well as their addition salts with acids.
As an example of addition salts of the present 5 derivatives with mineral or organic acids, there can be mentioned the salts formed with the following acids: acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric and especially stearic, ethylsuccinic and laurylsulphuric acids.
The heterocyclic radical can be substituted by one or more radicals chosen from the group constituted by free, salified, esterified and amidified carboxyl radicals, hydroxyl radicals, halogen atoms, NO2 radicals, C=N radicals, linear, branched or cyclic alkyl radicals, linear or branched alkenyl or alkynyl radicals, the following radicals: O-alkyl, O-alkenyl and O-alkynyl, S-alkyl, S-alkenyl or S-alkynyl and N-alkyl, N-alkenyl and N-alkynyl, containing up to 12 carbon atoms optionally substituted by one or more halogen atoms, xRi the N radical,'Rx and R2, identical or different, representing a hydrogen atom or an alkyl radical containing 25 up to 12 carbon atoms, the
-C-R3 radical, R3 representing an alkyl radical containing up to 12 carbon atoms, or an optionally substituted carbocyclic or heterocyclic aryl radical, carbocyclic aryl, O-aryl or S-aryl radicals or heterocyclic aryl, O-aryl or Saryl radicals containing one or more heteroatoms, optionally substituted by one or more of the substituents mentioned
above.
When the heterocyclic radical contains several rings (linked together, or condensed) the substituent or substituents can be found on one and/or the other of the heterocyclic or carbocyclic rings, it is thus for example that if a heterocyclic nucleus is linked to or condensed with an aryl radical, the heterocyclic nucleus and the aryl nucleus can both carry one or more substituents.
The aryl radical envisaged is preferably a phenyl or 10 naphthyl radical,
- the alkyl, alkenyl or alkynyl radical is preferably one of the following radicals: methyl, ethyl, propyl, isopropyl, nbutyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, propargyl, cyclobutyl, cyclopentyl or cyclohexyl,
- the halogen is preferably fluorine, chlorine or bromine,
- the alkyl radical substituted by a halogen atom is preferably one of the following radicals: CHC12, CHBr2, CHF2, cci2, cBr3, cf3, ch2cf3, ch2ch2cci3, ch2ch2cf3,
- the carboxylic acid remainder is preferably the acetyl, propionyl, butyryl, isobutyryl, n-valeryl, isovaleryl, tertvaleryl and pivalyl remainder.
A more particular subject of the invention is the compounds of formula (I), in which Z represents a hydrogen atom and the compounds of formula (I) in which n represents the number 4.
A quite particular subject of the invention is the compounds of formula (I) in which Ar represents a radical:
Ϊ i L U u / s 6 /d/dV optionally substituted, as well as the compounds of formula (I) in which Ar represents the radical:
AP.00558
optionally substituted, as well as the compounds of formula (I) in which Ar represents the radical:
optionally substituted and non particularly the compounds of formula (I) in which Ar represents the radical:
optionally substituted.
A more particular subject of the invention is the compounds of formula (I) whose preparation is given hereafter in the experimental part. Among the preferred compounds of the invention, there can be mentioned the compounds:
- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4-(4-phenyl IH-imidazol-l-yl) butyl) imino)) erythromycin,
- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(3H-imidazo(4,5-b)pyridin-3-yl) butyl) imino)) erythromycin,
- 11,12-dideoxy 3-de((2,6-dideoxy-3-c-methy1-3-o-methy1alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(lH-imidazo(4,5-b)pyridin-l-yl) butyl) imino)) erythromycin,
- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methy1-3-O-methy1alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(4-(4-chlorophenyl) lH-imidazol-l-yl) butyl) imino)) erythromycin,
- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(4-(2-methoxypheny1) ΙΗ-imidazol-l-yl) butyl) imino)) erythromycin, ( - 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methyl15 alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(4-(4-fluorophenyl) ΙΗ-imidazol-l-yl) butyl) imino)) erythromycin,
- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxy20 carbonyl ((4-(7-methoxy 4-quinoleinyl) butyl) imino)) erythromyc in,
- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methy1-3-O-methy1alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(2-(2-pyridinyl) 4-thiazolyl) butyl) imino)) erythromycin,
O - 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methy1-3-O-methy1alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(3-(3-pyridinyl) 1H-1,2,4-triazol-l-yl) butyl) imino)) erythromycin, and more particularly the
- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methy1-3-O-methy1alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(4-(3-pyridinyl) ΙΗ-imidazol-l-yl) butyl) imino)) erythromycin.
The products of general formula (I) possess a very good antibiotic activity on gram ® bacteria such as staphylococci, streptococci, pneumococci.
The compounds of the invention can therefore be used as
AP.00558 medicaments in the treatment of infections caused by sensitive germs and in particular in that of staphylococcia, such as staphylococcal speticemia, malignant staphylococcia of the face or skin, pyodermititis, septic or suppurating sores, boils, anthrax, phlegmons, erysipelas and acne, staphylococcia such as primary or post-influenzal acute anginas, bronchopneumonia, pulmonary suppurations, streptococcal infections such as acute anginas, otitis, sinusitis, scarlet fever, pneumococcal infections such as pneumonia, bronchitis; brucellosis, diphtheria, gonococcal infection.
The products of the present invention are also active against infections caused by germs such as Haemophilus influenzae, Rickettsia, Mycoplasma pneumoniae, Chlamydia,
Legionella, Ureaplasma, Toxoplasma or by germs of the
Mycobaterium, Listeria, Meningococci and Campylobacter type. ‘
Therefore a subject of the present invention is also, as c medicaments and in particular antibiotic medicaments, the products of formula (I) as defined above, as well as their addition salts with pharmaceutically acceptable mineral or organic acids.
A more particular subject of the invention is, as medicaments and in particular as antibiotic medicaments, the </ preferred products of formula (I) defined previously namely the products of Examples 1, 2, 3 and 29 to 35, as well as their pharmaceutically acceptable salts.
Also a subject of the invention is the pharmaceutical compositions containing as active ingredient at least one of the medicaments defined above.
These compositions can be administered by buccal, rectal or parenteral route or by local route as a topical application on the skin and mucous membranes, but the preferred administration route is the buccal route.
They can be solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine, such as for example plain or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient or ingredients can be incorporated with excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.
These compositions can also be presented in the form of a powder intended to be dissolved extemporaneously in a suitable vehicle, for example apyrogenic sterile water.
The dose administered is variable according to the illness treated, the patient in question, the administration ι route and the product considered. It can be, for example, ( comprised between 50 mg and 300 mg per day by oral route, for an adult, for the product of Example 1 or Example 2.
Also a subject of the invention is a preparation process for the compounds of formula (I), characterized in that a compound of formula (II):
o <_
(II) >>/00/56 /d/tfv in which Z' represents an acid remainder, is subjected to the action of a compound of formula (III):
RNH2 (III) in which R is defined as previously, in order to obtain the compound of formula (IA):
AP.00558
c>
c in which R and Z' keep their previous meaning, then if appropriate the compound of formula (IA) is subjected to the action of an agent releasing the hydroxyl function in position 2' and/or if appropriate, to the action of an acid in order to form the salt,
- the reaction of the compound of formula (II) with the compound of formula (III) takes place in a solvent such as for example acetonitrile, dimethylformamide or also tetrahydrofuran, dimethoxy ethane or dimethylsulphoxide,
- the hydrolysis of the ester function in position 2' is carried out using methanol or aqueous hydrochloric acid,
- the salification is carried out using acids according to standard processes.
The compounds of formula (II) used as starting products are described and claimed in the European Patent Application 0 596 802.
The compounds of formula RNH2 are generally knovn products, however the precise compounds used for the preparation of the products of the examples are new and are themselves a subject of the invention, their preparation is given below.
The compounds of formula RNH2 can be prepared for example according to the processes described by J. Med. Chem. (1982) vol. 25 p. 947 and subsequent, Tetrahedron Letters vol. 32, No. 14, p. 1699-1702, (1991); J. Org. Chem. 54 (18)
AF/P/ 9 5/0(74
4298, 301 (1989); J. Org. Chem. 28 (101) 2589-91 (1963) or the German Patent 3,406,416; J. Org. Chem. 6-895-901 (1941) or Synth. Commun 17 (14) 1741-8 (1987).
A quite particular subject of the invention is the 5 amines III as defined above whose preparation is given in detail hereafter.
The invention has more particularly for subject:
- 4-phenyl-lH-imidazole 1-butanamine,
- 3H-imidazo(4,5-b)-pyridine 3-butanamine,
- ΙΗ-imidazo(4,5-b)-pyridine 3-butanamine,
- 2-phenyl-4-quinolinebutanamine,
- lH-benzotriazole 1-butanamine,
- 2H-benzotriazole 2-butanamine,
- 1-methyl ΙΗ-imidazo(4,5-c)-pyridine 2-butanamine,
- 3-m6thyl 3H-imidazo(4,5-c)-pyridine 2-butanamine,
- 5-chloro ΙΗ-benzimidazole 1-butanamine, • *
- 7-methoxy 4-quinolenebutanamine,
- lH-imidazo(4,5-c) pyridine 1-butanamine,
- 9H-purine 9-butanamine, ur,
- 1-methyl 1H-indole 4-butanamine,
- 3-phenyl lH-l,2,4-triazole 1-butanamine (hydrochloride),
- 5-phenyl ΙΗ-tetrazole 1-butanamine (hydrochloride),
- 2-benzothiazolebutanamine,
- 4-(thieno(2,3-b) pyridine 4-yl butanamine,
- 5,6-dimethyl ΙΗ-benzimidazole 1-butanamine,
- 3-quinoleine butanamine,
- 2-quinoleine butanamine,
- 5H-imidazo [4,5-c] pyridine 5-butanamine,
- 1-methyl ΙΗ-benzimidazol 2-butanamine,
- 6-chloro ΙΗ-benzimidazol 2-butanamine,
- 2-methyl ΙΗ-benzimidazol 2-butanamine,
- 4-(4-chlorophenyl) ΙΗ-imidazol 1-butanamine,
- 2-(3-pyridinyl) thiazol 5-butanamine,
- 7-methoxyquinoleine 4-butanamine,
- 4-(4-fluorophenyl) ΙΗ-imidazol 1-butanamine,
- 4-(2-methoxyphenyl) ΙΗ-imidazol 1-butanamine,
- 3-(3-pyridinyl) 1H 1,2,4-triazol 1-butanamine,
- 4-(3-pyridinyl) ΙΗ-imidazol l-butanamine,
AP.00558
- 2-(2-pyridinyl) thiazol 4-butanamine,
- 2-phenylthiazol 4-butanamine,
- 4-(4-methoxyphenyl) ΙΗ-imidazol 1-butanamine,
- isoquinoleine 4-butanamine,
- quinazoline 4-butanamine,
- 4,5-diphenyl ΙΗ-imidazol 1-butanamine,
- 4-(3-methoxyphenyl) ΙΗ-imidazol 1-butanamine,
- 4-(4-(trifluoromethoxy) phenyl) ΙΗ-imidazol 1-butanamine,
- 1,2,3,6-tetrahydro 1,3-dimethyl 2,6-dioxo 7H-purine 710 butanamine,
- 2-(4-pyridinyl) thiazol 4-butanamine,
- ΙΗ-indol 1-butanamine,
- 2-(3-pyridinyl) thiazol 4-butanamine, f as well as their addition salts with acids.
The following examples illustrate the invention.
EXAMPLE 1: 11,12-dideoxy 3-de((2,β-dideoxy-3-C-methy1-3-0ethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
I2,ll-(oxycarbonyl ((4-(4-phenyl lH-imidazol-i-yl) butyl) imino)) erythromycin
A mixture of 0.705 g of 11-ddoxy 10,ll-did6hydro 3de(2,6-did6oxy 3-C-m6thyl 3-O-m6thyl alpha-L-ribohexopyranosyl) oxy) 12-0-((ΙΗ-imidazol-l-yl) carbonyl) 6-O-m6thyl 3-oxo drythromycine 2'-acdtate obtained as indicated in example 1C of the European Patent application 0 596 802, 3 ml of acetonitrile with 10% water and 1.08 g of 4-(4-phenyl 1HC imidazol-l-yl) butanamine is taken to 63eC. The reaction ( mixture is maintained at this temperature for 5 hours. It is left to return to ambient temperature, the reaction mixture is poured into a solution of sodium acid phosphate, extraction is carried out with ethyl acetate. The organic phases are washed with water, dried, filtered and concentrated. 1.5 g of a product is obtained to which 210 ml of methanol is added. The whole is maintained under agitation for 16 hours, under a nitrogen atmosphere and at ambient temperature. After concentration, 1.4 g of product is obtained which is purified by chromatography on silica, eluant CH2C12 - MeOH - NH40H (93-7-0.4). After concentration 0.305 g of the crude desired product is obtained, which is
AP/P/ 9 5 / 0 0 7 4 4 recrystallized from isopropyl ether, followed by washing and drying at 50°C under reduced pressure. In this way 0.267 g of the desired product is obtained, melting at 222eC-231°C.
NMR CD Cl-j ppm alphaD =+18° (c = 0.9 CHC13)
0.84 (t) : CH3-CH2 ; 1.01 (d)-1.17 (d)-1.24 (d) :
the CH3-CH's ; 1.30 (d)-1.38 (d)-1.34 to 1.47 : 6 and 12-Me ;
2.27 (s) : N(Me)2 ; 2.45 (-) : Hz3 ; 2.61 (m) : Hg ;
2.63 (s) : 6-OMe ; 3.04 (-) : H4 ; 3.13 (q) : H10 ; 3.18 (dd): H'2 ; 3.53 (-) : H'5 ; 3.56 (s) : H1X ; 3.67 (-)-3.75
I (-) : the -C-NCH2's ; : 3.87 (q) : H2 ; 3.99 (t) : CH2NC ;
4.23 (d) : H5 ; 4.27 (d) : ; 4.94 (dd) : H13 ; 7.26 (s) : -a
H”5 ; 7.5 (s) : H2 ; 7.20 : H in para position ; 7.35 : H r in meta position ; 7.76 : H in ortho position.
PREPARATION 1: 4-(4-phenyl lH-imidazol l-yl) butanamine
Stage A: 2-(4-(4-phenyl ΙΗ-imidazol l-yl) butyl ΙΗ-iso ιχ-, indole-1,3(2H)dione
A solution containing 5.05 g of 4-phenyl ΙΗ-imidazole in 25 cm3 of DMF is introduced dropwise over one hour 30 minutes into a mixture of 7 cm3 of DMF dried on siliporite and 2.02 g of sodium hydride. Then 10.86 g of 2-(4-bromobutyl) lH-iso25 indole l,3(2H)dione N-4-bromobutylphthalimide in solution in 25 cm3 of DMF is introduced. The solution obtained is taken to 70’C for about one hour 30 minutes. It is left to return to ambient temperature, the solution obtained is concentrated, taken up in water, extracted with ethyl acetate. The organic phases are washed with water, dried, filtered and concentrated. 15 g of product is obtained which is recrystallized from ethyl acetate. The product obtained is separated off, washed with ethyl acetate and dried under reduced pressure at 50°C. 5.5 g of desired product is obtained, melting at 130 - 132°C.
NMR CDC13 ppm
1.75 (m) (2H)-1.86 (m) (2H) : central CH2 zs ; 3.74 (t) : 2H ;
4.03 : 2H ; 7.22 (t) : 2H H4 ; 7.26 (m) : IH H'3 ; 7.36 (t) :
AP. Ο Ο 5 5 8
2Η Η3 and Hg ί 7.56 (d) : H'g ; approx. 7.73 (m) : 4H ; approx. 7.86 (m) : H2 and Hg.
Stage B: 4-(4-phenyl ΙΗ-imidazol-l-yl) butanamine
A mixture of 3.45 g of the product obtained in Stage A,
100 ml of ethanol and 0.97 ml of hydrazine hydrate is maintained under reflux for 8 hours. The reaction mixture is concentrated, about 50 ml of 2N soda is added, extraction is carried out with ethyl acetate. The organic phases are washed with 2N soda, then with sodium chloride. After drying, filtering and concentrating, 2.21 g of desired product is obtained.
NMR CDC13 ppm
1.47 (m)-1.87 (m) : central CH2's ; 2.73 (t)-3.97 : -CH2-NH2; 7.20 (d) : H'3 ; 7.50 (d) : H'g ; 7.37 (wt) 2H : H3 Hg ; 7.24 (it) 1H : H4 ; 7.77 (m) 2H : H2 and H6.
EXAMPLE 2; 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11—(oxycarbonyl ((4-(3H-imidazo(4,5-b) pyridin-3-yl) butyl) imino)) erythromycin
708.2 mg of ll-d6oxy 10,ll-did6hydro 3-de(2,6-diddoxy 3C-mdthyl 3-0-m6thyl alpha-L-ribohexopyranosyl) oxy) 12-0((lH-imidazol-l-yl) carbonyl) 6-0-mdthyl 3-oxo ferythromycine 2'-ac6tate obtained as indicated in example 1C of the European Patent application 0 596 802, and 958 mg of (3H25 imidazo(4,5-b) pyridin-3-butanamine are dissolved in 2.82 cm3 of acetonitrile and 0.28 cm3 of water. The reaction mixture is taken to 80°C. It is left to return to ambient temperature and poured into a solution of sodium acid phosphate. Extraction is carried out with methylene chloride followed by washing with water. The aqueous phases are collected and extraction is carried out again. After drying, filtering and rinsing, 826 mg of product is obtained. The product obtained is dissolved in 16.5 cm3 of methanol. The reaction solution is maintained under agitation at ambient temperature for 20 hours. 789 g of crude desired product is obtained which is purified by chromatography, eluting with a mixture of methylene chloride, methanol and ammonium hydroxide (94-16-0.4). 327 mg of desired product is
AP/P/ 95/0074 « obtained, melting at 200°C.
alphaD = +13° c = 1% CHC13
NMR CDC13 400 MHZ ppm
0.85 (t) : CH3-CH2 ; 1.01 (d)-1.16 (d)-1.25 (d)-1.30 (d)-1.26 (d) : the CH3-CH's ; 1.35 and 1.47 : 6 and 12 Me ; approx.
1.63 and approx. 1.98 : the central CH2's of the chain ; 2.27 (s) : N(CH3)2 ; 2.46 (m) : H'3 ; approx. 2.59 (m) : Ηθ ; 2.61 (s) : 6-OMe ; 3.07 (m) : H4 ; 3.12 (wq) : H10 ; 3.18 (dd) :
H'2 ; 3.54 (m) : H'5 ; 3.57 (s) : Hlx ; 3.6 to 3.8 : CH2NC ;
|
O
3.85 (q) : H2 ; 4.24 (d) : H5 ; 4.29 (d) : H/1 ; approx. 4.35 (m) : CH2NC= ; 4.93 (dd) : H13 ; 7.21 (dd) : Hg aromatic ;
( 8.04 (dd) : H7 aromatic ; 8.11 (s) : H2 aromatic ; 8.38 (dd):
H5 aromatic.
EXAMPLE 3: 11,12-dideoxy 3-d·((2,6-dideoxy-3-C-methy1-3-0methyl-alpha-L-ribohexopyranoayl) oxy) 6-O-methyl 3-oxo
12,ll-(oxycarbonyl ((4-(lH-imidazo(4,5-b) pyridin-l-yl) butyl) imino)) erythromycin
708.3 mg of ll-d6oxy 10, ll-did6hydro 3-de(2,6-did6oxy 3C-mdthyl 3-O-m6thyl alpha-L-ribohexopyranosyl) oxy) 12-0((ΙΗ-imidazol-l-yl) carbonyl) 6-O-m6thyl 3-oxo 6rythromycine 2'-acdtate obtained as indicated in example 1C of the European Patent application 0 596 802, is added to a solution.
containing 953 mg of (lH-imidazo(4,5-b) pyridine 3e butanamine, 2.82 cm3 of acetonitrile and 0.28 cm3 of water.
(- The reaction mixture is taken to 55°C, maintained at this temperature for 44 hours and 0.5 cm3 of acetonitrile is added. The mixture is maintained at 55°C for a further 20 hours. It is allowed to return to ambient temperature and poured into a saturated solution of sodium acid phosphate.
The aqueous phase is extracted with methylene chloride and the chloromethylene phases are washed with water. Drying over sodium sulphate is carried out, followed by filtration and evaporation. 806 mg of product is obtained to which 16.1 cm3 of methanol is added. The reaction mixture is maintained at ambient temperature for 24 hours and evaporated to dryness. 656 mg of a product is obtained which is
AP.00558 chromatographed on silica, eluting with a CH2Cl2-MeOH-NH3 mixture (94-6-0.4).
The crude desired product is obtained which is purified by chromatography on silica, eluting with a CHCl3-MeOH-NH4OH mixture (94-6-0.4). The residue is dissolved in an ethyl acetate - isoproyl ether mixture, followed by filtration and evaporation to dryness. In this way the desired product is collected. M.p. « 203°C.
alphaD - 17.6· c = 1% CHC13.
0.81 (t) : CH3-CH2 ; 1.00 (d)-1.17 (d)-1.25 (d)-1.31 (d)-1.38 (d) : the CH3-CH's ; 1.35 (s)-1.47 (s) : 6 and 12-CH3 ; 1.68 (m) and 1.93 (m) : the central CH2's of the chain ; 2.27 (s): N(CH3)2 ; 2.61 (s) : 6-OCH3 ; 2.45 (m) : H'3 ; approx. 2.60 (m in masked part) : Hg ; 3.07 (m) : H4 ; approx. 3.15 (wq) :
H10 ; 3.18 (dd) : H'2 ; 3.56 (s) : Ηχι ; 3.53 (m) : H'5 ;
3.60 to 3.80 (m) : CO-N-CH2 ; 3.87 (q) : H2 ; approx. 4.25 (m) : CH2-N-C« ; 4.24 (d) : H5 ; 4.28 (d) : ; 4.91 (dd) :
H13 ; 7.21 (dd, J = 5 and 8) : Hg ; 7.80 (dd, J = 8 and 1.5):
aromatic H7's ; 8.56 (dd, J = 5 and 1.5) : H5 ; 8.15 (s) :
H2 + CH2C12.
PREPARATION 2: Preparation of the amines used as starting products of Examples 2 and 3:
3H-imidazo(4,5-b)pyridine 3-butanamine and lH-imidazo(4,5-b) pyridine 1-butenamine
Stage A:
10.3 g of potassium carbonate is added to a solution of 5.95 g of 4-azabenzimidazole and 15.5 g of N-4 bromobutylphthalimide in 30 cm3 of dimethylformamide. The mixture is agitated for 20 hours at ambient temperature. The insoluble part is filtered off, rinsed with methylene chloride. The organic phase is washed with water, then dried with magnesium sulphate and evaporated, the oily residue obtained is washed with petroleum ether then with isopropyl ether. In this way
16.3 g of a yellow solid is obtained which is purified by chromatography on silica, eluting with a methylene chloride acetone mixture to give 4.9 g of product (A), M.p. = 143eC, and 3.9 g of product (B), M.p. = 172°C.
Stage BI: 3H-imidazo(4,5-b) pyridine-3-butanamine (starting product of Example 2)
A mixture of 32.86 g of product (A) prepared in the previous stage, 697 cm3 of ethanol and 20 cm3 of hydrazine is taken to reflux for 19 hours. The mixture is allowed to return to ambient temperature, filtered, rinsed and evaporated to dryness. The residue is taken up in methylene chloride, filtered, rinsed and evaporated to dryness. 18.87 g of desired product is obtained.
NMR CDC13 - 250 MHz
1.52 (m)-2.00 (m) : 2 central CH2's ; 1.63 (wide s) : 2 mobile H's ; 2.76 (t) : CH2-CH2-NH2 ; 4.33 (t) :
=C-N-CH2-CH2; 7.24 (dd, J = 8 and 5) : H6 ;
I ( c=o
8.08 (dd, J « 8 and 1.5) : H7 ; 8.40 (dd, J = 5 and 1.5) :
H5 ; 8.08 (s) : H2.
Stage B2: lH-imidazo(4,5-b) pyridine 1-butanamine (starting product of Example 3)
A mixture of 32 g of product (B) of Preparation 3, 640 cm3 of ethanol and 24.8 cm3 of hydrazine is taken to reflux for 21 hours. The mixture is allowed to return to ambient temperature. Filtration is carried out, followed by rinsing with ethanol and evaporating under reduced pressure. The residue is taken up in methylene chloride, followed by filtration, rinsing and evaporating to dryness. 19.5 g of O desired product is obtained.
C NMR CDC13
1.45 (m)-1.96 (m) : 2 central CH2's ; 2.74 (t) : CH2-NH2 ; approx. 1.45 (m) : mobile ; 4.23 (t) : C-N-CH2-CH2 ;
|
C
7.24 (dd, J = 8 and 5) : Hg ; 7.75 (dd, J = 8 and 1.5) : H? ;
8.58 (dd, J = 5 and 1.5) : H5 ; 8.13 (s) : H2 + EtOH.
Operating as previously, the following products were obtained:
EXAMPLE 4: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexoyranosyl) oxy) 6-O-methyl 3-oxo 12,11(oxycarbonyl) ((4-(thieno(2,3-b) pyridxn-4-yl) butyl) imino))
AP/P/ 95/00744
AP .0 0 5 5 8 erythromycin
178°C.
M.p. = alphaD
176 - 178°C.
= +17°C c = 0.9% in CHC1
EXAMPLE 5: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O5 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(3-phenyl lH-l,2,4-triazol-l-yl) butyl) imino)) erythromycin
M.p. = 208 - 210*C.
alphaD - +17· c = 1% in CHC13
EXAMPLE 6: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methy1-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(1-methyl-lH-imidazo(4,5-c)pyridin-2yl) butyl) imino)) erythromycinalphaD = +19° C = 1% CHC13 EXAMPLE 7: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-015 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(3-methyl-3H-imidazo(4,5-c)pyridin-2yl) butyl) imino)) erythromycin alphaD = +16° CHC13 = 1%
EXAMPLE 8: 11,12-dideoxy 3-de( (2,6-dideoxy-3-c-methyl-3-o20 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(7-methoxy-4-guinolinyl) butyl) imino)) erythromycin alphaD - +15.8· c = 1% CHC13
EXAMPLE 9: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O25 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(5-phenyl-lH-tetrazol-l-yl) butyl) imino)) erythromycin
M.p. = 132 - 134’C. alphaD « +25· c = 1% CHC13
EXAMPLE 10: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(2-benzothiazolyl) butyl) imino)) erythromycin
M.p. = 179 - 181eC alphaD = +18° c = 1% CHC13
EXAMPLE 11: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(2-(3-pyridinyl) 4-thiazolyl) butyl) imino)) erythromycin
M.p. = 150 - 152°C alphaD = +17° c = 0.9% CHC13
EXAMPLE 12: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-aethyl-3-O5 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(2-(3-pyridinyl) 5-thiazolyl) butyl) imino)) erythromycin
M.p. = 155 - 159’C alphaD = +12’ c = η CHC13
EXAMPLE 13ϊ 11,12-dideoxy 3-de((2,6-didaoxy-3-C-methyl-3-Omathyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12.11- (oxycarbonyl ((4-(9H-purin-9-yl) butyl) imino)) erythromycin
EXAMPLE 14? 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O15 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12.11- (oxycarbonyl-((4-(ΙΗ-imidazo(4,5-c) pyridin-l-yl) butyl) imino)) erythromycin
Rf = 0.42 CHC13 + 8% of MeOH with 8% of NH^OH
EXAMPLE 15: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methy1-3-O20 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12.11- (oxycarbonyl ((S-(lH-benzimidazol-l-yl) pentyl) imino)) arythromyc in
Prepared starting from 2-(4-bromophenyl) lH-iso-indole 1,3(2H)-dione.
EXAMPLE 16: 11,12-dideoxy 3-de((2,6-dideoxy-3-c-methyl-3-of' methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((5-chloro-lH-benzimidazol-l-yl) butyl) imino)) erythromycin M.p. = 145-148’C.
EXAMPLE 17: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 12,11(oxycarbonyl ((4-(ΙΗ-indol-l-yl) butyl) imino)) erythromycin EXAMPLE 18: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 12,1135 (oxycarbonyl ((4-(l-methyl-lH-indol-4-yl) butyl) imino)) erythromycin alphaD = 20%, c = 1% CHC13
EXAMPLE 19: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-019 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12.11- (oxycarbonyl ((4-(2-phenyl-4-quinolinyl) butyl) imino)) erythromycin
M.p. » 195-197°C.
EXAMPLE 20: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12.11- (oxycarbonyl ((4-(ΙΗ-benzotriazol-i-yl) butyl) imino)) erythromycin
M.p. - 200-202’C.
EXAMPLE 21: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12.11- (oxycarbonyl ((4-(2H-benzotriazol-2-yl) butyl) imino)) erythromycin p M.p. - 164-166’C.
EXAMPLE 22: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,ll-(oxycarbonyl ((4-(5,6-dimethyl lH-benzimidazol-l-yl) butyl) imino)) erythromycin
M.p. - 174-176’C.
EXAMPLE 23: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,ll-(oxyearbonyl ((4-(3-quinolinyl) butyl) imino)) erythromyc in
M.p. = 195-197’C.
EXAMPLE 24: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0AP/P/ 9 5 / 0 0 7 A 4 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(2-quinolinyl) butyl) imino)) erythromycin M.p. = 179-181’C.
EXAMPLE 25: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(2-methyl lH-benzimidazol-l-yl) butyl) imino)) erythromycin
M.p. = 128-132’C.
EXAMPLE 26: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(6-chloro ΙΗ-benzimidazol-l-yl) butyl) imino)) erythromycin
M.p. = 192-194°C.
EXAMPLE 27: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo
12,11-(oxycarbonyl ((4-(1-methyl lH-benzimidazol-2-yl) butyl) imino)) erythromycin
EXAMPLE 28: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(SH-imidazo(4,5-c)pyridin-5-yl) imino)) erythromycin alphap = 12.2 c- 1% CHCl-j
EXAMPLE 29: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(4-(4-chlorophenyl) lH-imidazol-l-yl) butyl) imino)) erythromycin
1 g of 11-deoxy 10,11-didehydro 3-de(2,6-dideoxy 3-Cmethyl 3-0-methyl alpha-L-ribohexopyranosyl) oxy) 12-0-((1Himidazol-l-yl) carbonyl) 6-O-methyl 3-oxo erythromycin 2'-acetate prepared as indicated in Example 1C of the European Patent Application EP 0,596,802 is heated for 7 hours at 75eC in 4 cm3 of acetonitrile with 10% water with
1.4 g of 4-(4-(4-chlorophenyl) ΙΗ-imidazol) butanamine. The reaction medium is left to return to ambient temperature, diluted with water, extraction is carried out with ethyl acetate, followed by drying, the solvent is evaporated off and 2.3 g of product acetylated in position 2' is obtained.
ml of methanol is added and the mixture is maintained under agitation for 16 hours, the solvent is evaporated off, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 95-5-0.4), followed by concentration and the residue is crystallized from ether. The crystallized product is dried under reduced pressure at 80°C and 381 mg of expected product is recovered. M.p. = 192-194°C.
NMR CDC13 ppm
0.83 (t): £H3-CH2; 1.00 (d)-1.16 (d)-1.24 (d)-1.30 (d)-1.38 (d): the CH3-CH's; 1.33 (s)-1.47 (s): 6 and 12 Me; 2.26 (s): N(Me)2; 2.44 (m): H'3; 2.61 (s): 6-OMe; 2.60 (m): Hg; 3.00 to 3.21: H4, H10 and H'2; 3.55 (m) : H'5; 3.56 (s) : H1;L; 3.60 to 3.80 2H-3.99 (t) 2H: CH2NC=; 3.87 (q): H2; 4.23 (d): H5; 4.28
AP/P/ 9 5/00
AP.00558 oo (d): H'p 4.93 (dd): H13; 7.26 (d): Hg imidazole; 7.50 (d):
H2 imidazole; 7.32-7.70: aromatics; 3.51: OH.
Preparation of 4-(4-chlorophenyl) lH-imidazole 1-butanamin· used at the start of Example 29.
Stage A: 4-(4-chlorophenyl) lH-imidazole.
23.34 g of -bromo 4-chloro acetophenone in 150 ml of formamide is taken to reflux for one hour; the reaction medium is left to cool down, alkalinized with a soda solution, extraction is carried out with dichloromethane, the extracts are washed with water, dried, the solvent is evaporated off, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 8-2-0.04) and 13.4 g of expected product is obtained. M.p. = 146-148°C.
Stage B: 2-(4-(4-(4-chlorophenyl) lH-imidazol 1-yl) lH-iso indol-1,3(2H)-dione.
The operation is carried out as in Stage A of the preparation of Example 1 using 12.2 g of the product obtained in Stage A, 4.96 g of sodium hydride and 23.83 g of
N-4-bromobutyl phthalamide. 9.7 g of expected product is 20 obtained.
Stage C; 4-(4-chlorophenyl) ΙΗ-imidazol 1-butanamine.
The operation is carried out as in Stage B of the preparation of Example l using 14.2 g of product obtained as in Stage B above and 3.6 ml of hydrazine hydrate in 200 ml of ethanol. 12 g of crude product is obtained which is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 8-2-0.04) and the product is obtained, which is used as it is for the synthesis.
NMR (CDC13) ppm
1.22 (ws) : mobile 2H's; 1.47 (m)-1.88 (m): 2 central CH2's; 2.74 (m): CH2-£H2-N; 3.98 (m) : =C-N-CH2-CH2;
·>
*
-C=
7.19 (d, J=1.5)-7.50 (d, J=1.5): H2 and H5; 7.33 and 7.70:
aromatics.
EXAMPLE 30: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl, oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(4-(2-methoxyphenyl) lH-imidazol-l-yl) butyl) imino)) erythromycin
706 mg of the starting compound of Example 29 (obtained as indicated in Example 1C of the European Patent Application
EP 0,596,802) in 3 ml of acetonitrile and 908 mg of 4-(4-(25 methoxyphenyl) lH-imidazol-l-yl) butanamine are heated at 80 °C for 8 hours. The reaction medium is left to return to ambient temperature, poured into a solution of sodium hydrogen phosphate (0.5M), extraction is carried out with ethyl acetate, the extracts are washed with water, dried, the solvent is evaporated off, 1.6 g of product acetylated in position 2' is obtained. 50 ml of methanol is added, agitation is carried out for 16 hours, the solvent is evaporated off, the residue is chromatographed on silica ( (eluant: AcOEt-TEA at 4%) and crystallization from ether is carried out. 194 mg of expected product is obtained.
M.p. = 143-145°C.
NMR CDCl-j ppm
0.85 (t): £H3-CH2; 1.01 (d)-1.16 (d)-1.24 (d)-1.30 (d)-1.37 (d): the £H3-CH's; 1.34 (s)-1.47 (s): 6 and 12 Me; 2.26 (s):
N(Me)2; 2.44 (m): H'3; 2.60 (m): H8; 2.64 (s): 6-OMe; 3.08 (m): H4; 3.12 (wq): H10; 3.17 (dd): H'2; 3.54 (m): H'5; 3.57 (s): Ηχχ; 3.66 (m)-3.74 (m): CH2NC;
AP/P/ 95/00744
O
3.85 (q): H2; 3.95 (s): f-OMe; 3.99 (wq): CH2-N-C=; 4.24 (d): C H5; 4.27 (d): Η'χ; 4.93 (dd): Ηχ3; 6.97 (wd): Hg; 7.51 (s):
C the imidazole H's; 7.02: phenyl Hg; 7.19 (ddd) phenyl H4 and
H5; 8.19 (dd): H2.
Preparation of 4-(2-methoxyphenyl) lH-imidazol-i-butanamine used at the start of Example 30.
Stage A: 4-(2-methoxyphenyl) lH-imidazole.
9.36 g of 2-bromo 2'-methoxyacetophenone in 50 ml of formamide is heated under reflux, the reaction medium is left to return to ambient temperature, washed with a 2N hydrochloric acid solution, followed by filtration, alkalinizing to pH 8-9 using 2N soda, extraction with dichloromethane, washing with water, drying, evaporating the solvent and chromatographing the residue on silica (eluant:
AP. Ο Ο 5 5 8
CH2Cl2-MeOH-NH4OH 95-5-0.4) and 6.15 g of expected product is obtained.
Stage B: 2-(4-(4-(2-methoxyphenyl) ΙΗ-imidazol 1-yl) butyl
ΙΗ-iso indol-1,3(2H)-dione.
The operation is carried out as in Stage A of the preparation of Example 1 using 6 g of the product obtained in Stage A, 1.99 g of sodium hydride and 9.93 g of
N-4-bromobutyl phthalimide. 6.15 g of expected product is obtained.
Stage C: 4-(2-methoxyphenyl) ΙΗ-imidazol 1-butanamine (fumarate).
The operation is carried out as in Stage B of the preparation of Example 1 using 5.65 g of the product obtained (' as in Stage B above and 1.45 ml of hydrazine hydrate in 75 ml of ethanol. 3.8 g of crude product is obtained which is dissolved in 4 ml of tetrahydrofuran then 1.87 g of fumaric acid in solution in 20 ml of methanol is added. 10 ml of ether is added, the crystals formed are separated off, dried at 80°C under reduced pressure and 3.77 g of the fumarate of the expected product is recovered. M.p. = 160-162°C.
NMR (CDCl-j) ppm
1.48 (m) 2H-1.87 (m) 2H: the central CH2's; 3.46: NH2; 2.73 (t): CH2N; 3.94 (s): Φ-OMe; 3.97 (t): CH2N-C; 6.94 (dd): H6;
«
7.04 (dt)-7.21 (ddd) : H5 and H4; 7.51: H'2 and H'5; 8.19 O (dd): H2.
C EXAMPLE 31: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo
I2,li-(oxycarbonyl ((4-(4-(4-fluorophenyl) lH-imidazol-l-yl) butyl) imino)) erythromycin
2.11 g of the starting compound of Example 29 (obtained as indicated in Example 1C of the European Patent Application
EP 0,596,802) in 9 ml of acetonitrile and 2.8 g of
4-(4-(4-fluorophenyl) ΙΗ-imidazol-l-yl) butanamine are heated at 60”C for 4 hours 30 minutes. The reaction medium is left to return to ambient temperature, poured into water, extraction is carried out with ethyl acetate, the extracts are washed with water, dried, the solvent is evaporated off,
AP/P/ 95/0074*
5.2 g of product acetylated in position 2' is obtained. 20 ml of methanol is added to it, agitation is carried out for 3 hours 30 minutes, the solvent is evaporated off, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH
95-5-0.3) and crystallization from ether is carried out.
1.34 g of expected product is obtained. M.p. = 190-192’C.
| NMR CDCl-j ppm | ||||||
| 1.33 (s)-1.47 | (s) : 6 and 12 Me; | 2.27 | (s) : | N(Me) | 2; 2.61 | (s) : |
| 6-OMe; 3.0 to | 3.18: H4 and Hlo; | 3.56 | (s) : | Hll' | 3.59 to | 3.81: |
| 10 CH2-N-C; 3.98 | (t): CH2-N-C; |
I I o
approx. 7.05 - approx. 7.73: fluorophenyl; 7.21 (d): H5 imidazole; 7.49 (d): imidazole H2. <
Preparation of 4-(4-fluorophenyl) lH-imidazol-l-butanamine c used at the start of Example 31.
IT
Stage A: 4-(4-fluorophenyl) ΙΗ-imidazole.
10.85 g of 4-fluorophenacyl bromide in 60 ml of formamide is heated under reflux for 2 hours, the reaction 5C medium is left to return to ambient temperature, acidified to pH 2 using N hydrochloric acid, followed by filtration, neutralizing by the addition of ammonium hydroxide, extraction with dichloromethane, washing with water, drying, evaporating the solvent, chromatographing the residue on silica (eluant: CH2Cl2-MeOH-NH4OH 95-5-0.4) and 5.8 g of expected product is obtained. M.p. - 130-132°C.
Stage B: 2-(4-(4-(4-fluorophenyl) ΙΗ-imidazol 1-yl) butyl ΙΗ-iso indol-1,3(2H)-dione.
The operation is carried out as in Stage A of the preparation of Example 1 using 10 g of the product obtained in Stage A, 1.95 g of sodium hydride and 11.80 g of N-4bromobutyl phthalamide. 7.53 g of expected product is obtained. M.p. = 138-140’C.
Stage C: 4-(4-fluorophenyl) ΙΗ-imidazol 1-butanamine.
The operation is carried out as in Stage B of the preparation of Example 1 using 3.64 g of product obtained as in Stage B above and 1 ml of hydrazine hydrate in 80 ml of ethanol. 2.4 g of crude product is obtained which is
AP. Ο Ο 5 5 8 chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH
8-2-0.03) and the product is obtained which is used as it is for the synthesis.
NMR (CDC13) ppm
1.48 (m)-1.81 (m) : the central CH2's; 2.74 (t) : N-CJJ3; 3.98 (t): >N-Cfi2-CH2; 7.06 (t): >CH-F; 7.22 (m) : >CH-C-;
I
7.49 (s): imidazole H2; 7.15 (s) : imidazole H5.
EXAMPLE 32: 11,12-dideoxy
3-d·((2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4-(7-methoxy (4-guinolinyl) butyl) imino)) erythromycin
706 mg of the starting compound of Example 29 (obtained f as indicated in Example 1C of the European Patent Application
EP 0,596,802) in 4 ml of acetonitrile and 1.43 g of
4-(4-7-methoxy 4-guinolinyl) butanamine are heated at 50eC for 53 hours. The reaction medium is left to return to ambient temperature, poured into a solution of sodium hydrogen phosphate (0.5M), extraction is carried out with dichloromethane, the extracts are washed with water, dried, the solvent is evaporated off, 1.09 g of product acetylated in position 2' is obtained. 10 ml of methanol is added to it, agitation is carried out for 16 hours, the solvent is evaporated off, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH 95-5) and crystallization from ether is ’ carried out. 295 mg of expected product is obtained.
( M.p. = approx. 110°C.
NMR CDCI3 ppm
3.06 (m): -(CH2)2-CH<? 3.70 (m) : -N-CH2-; 3.95 (s): -OCH3;
7.12 (d)-7.19 (dd)-7.42 (d)-7.94 (d)-8.70 (d): pyridine. Preparation of 7-methoxy quinoline 4-butanamine used at the start of Example 32.
Stage A: triphenyl phosphonium salt of N-(3-bromopropyl) phthalimide.
13.4 g of N-bromopropylphthalimide and 13.15 g of triphenylphosphine in suspension in 75 ml of xylene are heated under reflux for 44 hours. The reaction medium is left to return to ambient temperature, the precipitate is co separated off, washed with ethyl ether and dried under reduced pressure at 60°C. 24.88 g of expected product is recovered. M.p. = 220-222°C.
Stage Β: Z-(2-(4-(7-methoxyquinolinyl) 3-butenyl lH-iso5 indol-1,3(2H)-dione.
g of 7-methoxy 4-quinolinylcarboxaldehyde is added to a suspension of 12.47 g of the triphenylphosphonium salt of 3-bromopropyl phthalimide in 200 ml of tetrahydrofuran.
The reaction medium is cooled down to -50’C, 2.72 g of potassium terbutylate is added, the temperature is allowed to rise slowly to -6eC, followed by filtration, the filtrate is concentrated, the residue is taken up in ethyl acetate, washed with water, dried, the solvent is evaporated off and 9.26 g of crude product is recovered which is chromatographed on silica (eluant: CHCl3-AcOEt 80-20 then 70-30). 3.575 g of expected product is recovered.
Stage C: 2-(4-(7-methoxy 4-quinolinyl) butyl) lH-isoindol 1,3(2H)-dione.
3.50 g of the product obtained in Stage B is dissolved in 50 ml of methanol, 0.36 g of palladium on activated charcoal is added and the mixture is hydrogenated for 3 hours under 600 mbars. Filtration is carried out, the solvent is evaporated off and 3.48 g of expected product is collected.
Stage D: 7-methoxy quinolin-4-butanamine.
3.46 g of the product obtained in Stage C is dissolved hot in 70 ml of ethanol, 1.86 ml of hydrazine hydrate is added, the reaction medium is taken to reflux for 17 hours, the precipitate is eliminated by filtration, the solvent is evaporated off, the residue is taken up in 70 ml of dichloromethane, filtration is carried out, the solvent is evaporated off and 2.19 g of expected product is collected. NMR (CDC13) ppm
1.6 (m)-1.79 (m): central CH2's; 2.75 (t): >-CH2-(CH2)3; 3.05 (t): CH2-NH2; 3.95 (s): O-CH3; 7.10 (d, J=4.5)-7.21 (dd)-7.92 (d)-8.71 (d, J=4.5): quinoline.
EXAMPLE 33: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alptaa-L-ribohexopyranosyl) oxy) 6-o-methyl 3-oxo
AP/P/ 95/00;
AP. Ο Ο 5 5 8
12,11-(oxycarbonyl ((4-(2-(2-pyridinyl) 4-thiazolyl) butyl) latino)) erythromycin
705 mg of the starting compound of Example 29 (obtained as indicated in Example 1C of the European Patent Application
EP 0,596,802) in 3 ml of acetonitrile and 0.705 g of
4-(2-(2-pyridinyl 4-thiazolyl) butanamine are heated at 60ec for 5 hours. The reaction medium is left to return to ambient temperature, poured into water, extraction is carried out with ethyl acetate, the extracts are washed with water, dried, the solvent is evaporated off, 1.8 g of product acetylated in position 2' is obtained. 15 ml of methanol is added to it, the resultant medium is heated under reflux for 2 hours, the solvent is evaporated off, the residue is
T chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 95-5-0.3 then AcOEt-TEA 9-1) and crystallization from ether is carried out. 194 mg of expected product is obtained.
M.p. - 157-159*C.
NMR (CDC13) ppm
1.33 and 1.47: 6 and 12 Me; 2.26 (s): N(CH3)2? 2.86 (t):
CH2-C; 3.12 (wq) : Hlo; 3.60 (s) : Hllz· 3.66 (m): CH2-N-C;
S
O
7.03 (s): thiazole H5; 7.27 (ddd): pyridine H5; 7.77 (dt): pyridine H4; 8.18 (dd) pyridine H3; 8.53 (ddd): pyridine H6.
Preparation of 2-(2-pyridinyl) thiazol 4-butanamine used at \ the start of Example 33.
t Stage A: 2-aminocarbonyl pyridine.
ml of a diazomethane solution (0.4 M/l) is added dropwise to a solution containing 2 g of picolinic acid, 20 ml of dichloromethane and 5 ml of methanol. After agitation for 30 minutes at ambient temperature, the solvent is evaporated off under reduced pressure, the residue is chromatographed on silica (petroleum ether (60-80)-AcOEt 5-5) and 1.48 g of methyl ester is recovered. 1.42 g of the ester is heated at 5O°C for 4 hours in 5 ml of ammonium hydroxide, the reaction medium is left to return to ambient temperature, extraction is carried out with ether, the extracts are washed with water, dried, the solvent is evaporated off and 1.05 g of expected product is recovered. M.p. = 105°C.
Stage B; 2-pyridine carbothioamide.
g of phosphorus pentasulphide is added slowly to 46.8 g of the amide obtained in Stage A in 700 ml of tetrahydrofuran. Agitation is carried out for 4 hours at ambient temperature, the reaction medium is poured into water, extracted with ether, the extracts are dried and the solvent is evaporated off under reduced pressure. After chromatography on silica (eluant: CH2Cl2-AcOEt 8-2), 10 g of expected product is collected. M.p. = 137°C.
Stage C: ethyl 2-(2-pyridinyl) 4-thiazole carboxylate.
16.3 ml of ethyl bromopyruvate is added dropwise to 15.9 g of the product prepared as in Stage B in 250 ml of ethanol and the whole is heated under reflux for 5 hours. The solvent is evaporated off under reduced pressure, the residue is chromatographed on silica (eluant: hexane-AcOEt 1-1) and
10.2 g of expected product is obtained. M.p. - 69.1°C. ir
Stage D: 2-(2-pyridinyl) 4-thiazole methanol. ° ml of methanol is added slowly to a mixture @ containing 9.3 g of the ester prepared in Stage C and 4.1 g £ of sodium borohydride in 100 ml of tetrahydrofuran and the * whole is heated under reflux for 2 hours. The reaction medium is left to return to ambient temperature, poured into water, neutralized using N hydrochloric acid, extraction is carried out with dichloromethane, the organic phase is dried and the solvent is evaporated off under reduced pressure, the residue is chromatographed on silica (eluant: AcOEt-CH2Cl2 1-1) and 5.8 g of expected product is obtained.
M.p. = 100°C.
Stage E: 2-(2-pyridinyl) 4-thiazole carboxaldehyde.
5.8 g of the product obtained in Stage D in 60 ml of toluene is heated under reflux for 2 hours in the presence of 13 g of manganese oxide, filtration is carried out and the solvent is evaporated off under reduced pressure. 5 g of expected product is obtained. M.p. = 131°C.
Stage F: (Z) 2-(4-(2-(2-pyridinyl) 4-thiazolyl) 3-butenyl) ΙΗ-isoindole 1,3(2H)-dione.
The operation is carried out as in Stage A of
ΑΡ . 0 0 5 5 8
Iv Ο Ο
Preparation 32 using 5.70 g of the aldehyde prepared as in Stage E above and 15.9 g of the triphenylphosphonium salt of
3- bromopropyl phosphonium and 3.70 g of potassium terbutylate. 8.73 g of expected product is obtained.
M.p. - 139-141’C.
Stage G: (2-(4-(2-(2-pyridinyl) 4-thiazolyl) butyl) lH-isoindol 1,3(2H)-dione.
The operation is carried out as in Stage B of Preparation 32 starting with 7.22 g of the product prepared in Stage F above, and 1.5 g of palladium on activated charcoal, hydrogenating for 2 hours under 1800 mbars. 6.33 g of expected product is obtained. M.p. - 119-121°C.
Stage H: 2-(2-pyridinyl) thiazol-4-butanamine.
The operation is carried out as in Stage C of
Preparation 32 using 5.45 g of the product obtained in Stage G above and 1.6 ml of hydrazine hydrate and heating under reflux for 6 hours. The solvent is evaporated off, the residue is taken up in ethyl acetate, washed with water, dried, the solvent is evaporated off, the residue is chromatographed on silica (eluant: CH2cl2-MeOH-NH4OH 9-1-0.03) and 1.65 g of expected product is obtained.
NMR (CDC13) ppm
1.50 (m)-1.82 (m): central CH2's; 2.76 (t)-2.85 (t): CH2-C= and CH2-NH2; 7.85 (s): thiazole H5; 7.31 (m): H'5; 7.78 (dt): 25 H'4; 8.18 (dt): H'3; 8.61 (ddd): H'6; 1.40 (s): NH2·
EXAMPLE 34: 11,12-dideoxy 3-da((2,6-dideoxy-3-C-methyl-3-0~ methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,ll-(oxycarbonyl ((4-(4-(3-pyridinyl) lH-imidazol-l-yl) butyl) imino)) erythromycin
1 g of the starting compound of Example 29 (obtained as indicated in Example 1C of the European Patent Application EP 0,596,802) in 4 ml of acetonitrile and 936 mg of
4- (4-(3-pyridinyl lH-imidazol-1- yl) butanamine are heated at 70*C for 20 hours. The reaction medium is left to return to ambient temperature, poured into water, extraction is carried out with ethyl acetate, the extracts are washed with water, dried, the solvent is evaporated off, 1.34 g of product acetylated in position 2' is obtained. 40 ml of methanol is added to it, agitation is carried out for 2 hours, the solvent is evaporated off, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 95-5-0.4) and crystallization from ether is carried out. 310 mg of 5 expected product is obtained. M.p. = 187-188°C.
NMR (CDC13) ppm
0.83 (t): CH3-CH2; 1.01 (d)-1.17 (d)-1.25 (d)-1.31 (d)-1.38 (d): the CH3-CHzs; 1.34 (s)-1.47 (s): 6 and 12 Me; 2.27 (s) : N(Me)2; 2.45 (m): H'3; 2.62 (s): 6-OMe; 2.60 (m): H8; 2.85 to 3.25: H4 and H10, H'2; 3.52 (m) : H'5; 3.56 (s) : H^; 3.60 to 3.85 (m): CH2NC; 4.23 (d): H5;
I
C' 4.27 (d): H'jj 4.93 (dd): H13; 7.29 (ddd): pyridine H5; 8.08 ( (dt): pyridine H4; 8.45 (dd): pyridine Hg; 8.97 (dd):
pyridine H2; 7.35 (d) and 7.53 (d): imidazole H2 and H5.
Preparation of 4-(3-pyridinyl) lH-iaidazol-l-butanamine used at the start of Example 34.
Stage A: 2-(4-(3-pyridinyl) ΙΗ-imidazol l-yl) butyl lH-iso indol-1,3(2H)-dione.
The operation is carried out as in Stage A of the preparation of Example 1 using 290 mg of 3-pyridinyl ΙΗ-imidazole prepared as indicated in J. Chem. Soc. 753-5 (1938), 115 mg of sodium hydride and 633 mg of N-bromobutyl phthalimide. 277 mg of expected product is obtained.
M.p. - 150-152’C.
o Stage B: 4-(3-pyridinyl) ΙΗ-imidazol 1-butanamine.
O The operation is carried out as in Stage B of the preparation of Example 1 using 1.66 g of the product obtained as in Stage A above and 0.46 ml of hydrazine hydrate in 30 ml of ethanol. 936 mg of product is obtained, which is used as it is for the synthesis.
NMR (CDC13) ppm
1.49 (m)-1.89 (m): the central CH2's; 2.75 (t): CH2-CH2-N;
I
4.01 (t): =C-N-CH2-CH2;
I =c7.29 (d, J=l)-7.55 (d, J=l): H2 and H5; 7.30 (partly masked):
AP/P/ 95/00744
AP.00558
H'5; 8.09 (dt, J—8 and 2): H'4; 8.47 (dd, J=5 and 2): H'g;
8.96 (d, J=2): H'2; 1-49 (ws) : approx, mobile 2H's.
EXAMPLE 35: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(3-(3-pyridinyl) 1H-1,2,4-triazol-iyl) butyl) imino)} erythromycin g of the starting compound of Example 29 (obtained as indicated in Example 1C of the European Patent Application EP 0,596,802) in 4 ml of acetonitrile and 1.21 g of
4-(3-(3-pyridinyl lH-l,2,4-triazol-l-yl) butanamine are heated at 75°C for 8 hours. The reaction medium is left to return to ambient temperature, poured into water, extraction r is carried out with ethyl acetate, the extracts are washed ( with water, dried, the solvent is evaporated off, 2 g of product acetylated in position 2' is obtained. 40 ml of methanol is added to it, agitation is carried out for 16 hours, the solvent is evaporated off, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 90-10-0.04) and crystallization from ether is carried out.
292 mg of expected product is obtained. M.p. = 190-192°C.
NMR (CDC13) ppm
0.84 (t): £H3-CH2; 1.01 (d): OMe; 1.16 (d): 8Me; 1.25 (d) :
5Me; 1.30 (d): 4Me; 1.34 (d): 2Me; 1.33 (s) and 1.47 (s): 6 and 12 Me; 1.67 (m)-1.99 (m): the central CH2's; 2.26 (s):
N(Me)2; 2.44 (m): H'3; 2.58 (m): Ηθ; 2.61 (s): 6-OMe; 3.06 C? (m): H4; 3.12 (q) : H10; 3.17 (dd): H'2; 3.52 (m): H'5; 3.56 o (s): Hu; 3.64 to 3.75 (-): CH2NC;
«
3.85 (q): H2; approx. 4.25: H'v Hg and CH2NC;
II
4.91 (dd): H13; 8.15 (s): triazole H; 7.35 (dd): pyridine H5; 8.34 (dt): pyridine H4; 8.62 (dd): pyridine Hg; 9.31 (wd) : pyridine H2.
Preparation of 3-(3-pyridinyl) 1H-1,2,4-triazol-l-butanamine used at the start of Example 35.
Stage A: 2-(4-(3-(3-pyridinyl) 1H-1,2,4-triazol-l-yl) butyl ΙΗ-isoindol-l,3(2H)-dione.
f ri 0 0 / bi /4/e(V nn
The operation is carried out as in Stage A of the preparation of Example 1 using 2.1 g of 3-pyridinyl 1H-1,2,4-triazole prepared as indicated in J. Org. Chem. (44)
No. 33, 4160-4164 (1979), 1.02 g of sodium hydride and 4.13 g of N-4-bromobutyl phthalimide. 2.4 g of expected product is obtained. M.p. = 150-152eC.
Stage B: 3-(3-pyridinyl) lH-l,2,4-triazol-l-butanamine (fumarate).
The operation is carried out as in Stage B of the 10 preparation of Example 1 using 3.46 g of the product obtained as in Stage A above and 1 ml of hydrazine hydrate in 50 ml of ethanol. 2.1 g of crude product is obtained which is converted into the fumarate as indicated in Preparation 30 and 1.13 g of the fumarate of the expected product is obtained. M.p. = approx. 190-192®C.
NMR (CDC13) ppm
1.50 (m)-2.01 (m): the central CH2's; 2.76 (t): NH2-£H2-;
4.24: =N-N-£H2; 7.37 (ddd): H5; 8.35 (dt): H4; 8.63 (dd): H6; 9.32 (dd): H2; 8.12 (s): triazole =CH.
Operating as previously using the appropriate amines, the following products were prepared:
EXAMPLE 36: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methy1-3-0methyl-alpha-L-ribohexopyranosyl) oxy, 6-0-methyl 3-oxo
12,ll-(oxycarbonyl ((4-(3-guinolinyl) butyl) imino)) £ erythromycin -* r
M.p. = 190-192°C.
EXAMPLE 37: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl, oxy) 6-0-methyl 3-oxo
12,ll-(oxycarbonyl ((4-(4-(4-methoxyphenyl) lH-imidazol-l-yl) butyl) imino)) erythromycin M.p. = 152-154°C.
EXAMPLE 38: 11,12-dideoxy 3-de((2,6-dideoxy-3-c-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo
12,ll-(oxycarbonyl ((4-(2-phenyl 4-thiazolyl) butyl) imino)) erythromycin
M.p. = 141-143°C.
EXAMPLE 39: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0Or methyl-alpha-L-ribohexopyranosyl, oxy) 6-0-methyl 3-oxo
AP.00558
12,11-(oxycarbonyl ((4-(4-(3-methoxyphenyl) lH-imidazol-l-yl) butyl) imino)) erythromycin M.p. = 144-146’C.
EXAMPLE 40: 11,12-dideoxy 3-de( (2,6-dideoxy-3-C-methyl-3-05 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,11-(oxycarbonyl ((4-(4,5-diphenyl) lH-imidazol-l-yl) butyl) imino)) erythromycin M.p. = 180-182’C.
EXAMPLE 41: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O10 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12.11- (oxycarbonyl ((4-(4-quinazolinyl) butyl) imino)) erythromycin
M.p. = 212-214’C.
EXAMPLE 42: il,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O15 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12.11- (oxycarbonyl ((4-(2-(4-pyridinyl) 4-thiazolyl) butyl) imino)) erythromycin
M.p. = 192-194’C.
EXAMPLE 43: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-aethyl-3-O20 aethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12.11- (oxycarbonyl ((4-(1,2,3,6-tetrahydro-l,3-dimethyl 2,6-dioxo 7H-purin-7-yl) butyl) imino)} erythromycin
M.p. = 251-253’C. ί
EXAMPLE 44: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-aethyl-3-O25 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
M.p. - 168-170’C.
The amines used as starting products are prepared 30 according to the following methods:
A - When the chain is attached to a carbon for example one can start with the corresponding aldehydes:
N ϊ i t 11 9
The amines used for the preparation of the products of Examples 4, 8, 11, 12, 18, 19, 23 and 24 were prepared in this way.
B - When the chain is attached to a nitrogen, the amines can be prepared in the following way:
c
C 10 AP/P/ 9 5 / 0 0 7 4 4
AP.00558
The amines used for the preparation of the products of
Examples 1, 2, 3, 5, 9, 13, 14, 15, 16, 17, 20, 21, 22, 25, and 28 vere prepared in this way.
C - Certain amines are prepared in a particular way:
the heterocycle is constructed and the chain is introduced at the same time (Example 6, 7, 10 and 27).
EXAMPLES OF PHARMACEUTICAL COMPOSITIONS
Compounds vere prepared containing:
Product of Example 1 ............................. 150 mg
Excipient s.q.f.................................. 1 g
Detail of the excipient: starch, talc, magnesium stearate
Product of Example 2 ............................. 150 mg
Excipient q.s.f.................................. 1 g
Detail of the excipient: starch, talc, magnesium stearate
Product of Example 3 ............................. 150 mg
Excipient s.q.f. ................................. 1 g
Detail of the excipient: starch, talc, magnesium stearate PHARMACOLOGICAL STUDY OP THE PRODPCTS OF THE INVENTION
Method of dilutions in liquid medium
A series of tubes is prepared into which an equal quantity of sterile nutritive medium is divided. Increasing quantities of the product to be studied is distributed into each tube, then each tube is seeded with a bacterial strain. After incubation for twenty-four hours in a heating chamber at 37’C, the growth inhibition is evaluated by transillumination which permits the minimal inhibiting concentrations (M.I.C.) to be determined expressed in micrograms/cm3.
The following results were obtained:
| 1 | Ci | Ci | Ci | |||
| ιη | 1 | ο | ο | ο | ||
| η | 1 | 00 | * | * | * | |
| 1 | ο | Ό | ο | ο | ο | |
| X | 1 | * | - 1 | VI | VI | VI |
| Μ | 1 1 | ο | ο |
| Μ· | 1 | ο | Ci | CJ | |||
| η | 1 | ο | ο | ο | |||
| • | 1 | Ί1 | co | μ· | V | ||
| X | 1 | ο | ο | ο | ο | ο | ο |
| Η | 1 | * | * | VI | VI | VI | |
| 1 | ο | ο | ο |
<π η
| ΟΙ | ι 1 | Ci | Ci | ΟΙ | ||||
| η | 1 | co | ιη | co | ο | ο | ο | |
| • | 1 | ο | rd | ο | * | * | ||
| X | 1 | * | ο | ο | ο | |||
| Η | 1 | ο | ο | ο | VI | VI | VI | |
| 1 1 | ||||||||
| rd | 1 1 | ΟΙ | ο | Ci | ||||
| η | 1 | •Μ· | co | ο | ο | ο | ||
| • | 1 | Ο | ο | μ· | * | Γ— | ||
| X | 1 | * | ο | ο | ο | |||
| Η | 1 | ο | ο | ο | VI | VI | VI | ι3 |
C3
ΚΟ η
| σι ι | Ci | Ci | Ci | ||||
| Ci | ι | μ· | ιη | μ· | Ο | ο | ο |
| • | ι | ο | <Η | ο | * | * | |
| X | ι | Ο | ο | ο | |||
| ω | ι | ο | ο | ο | VI | VI | VI |
Ci
| η | 1 | co | ιη | ιη | ο | ο | ο | |||||||||
| • | 1 | ο | ι—1 | γΗ | * | *. | ||||||||||
| X | 1 | Η | ο | •Ο | ο | |||||||||||
| Η | 1 1 | ο | Ο | ο | VI | |||||||||||
| 1 1 | Ci | |||||||||||||||
| Ci | 1 | μ· | ιη | Ο | Ci | Ci | ||||||||||
| • | 1 | ο | rd | ο | X | ο | Ο | |||||||||
| X | 1 | κ | ο | * | * | |||||||||||
| Η | 1 | ο | Ο | ο | VI | ο | ο | |||||||||
| 1 1 | VI | VI | ||||||||||||||
| γΗ | 1 1 | Ί· | 00 | co | μ· | Ci | μ | |||||||||
| • | 1 | ο | ο | ο | Ο | ο | ο | |||||||||
| χ | 1 | * | ||||||||||||||
| ω | 1 | ο | ο | ο | ο | ο | ο | |||||||||
| 1 1 | VI | |||||||||||||||
| 1 1 | Η | »μ | rH | r1 | ||||||||||||
| 1 | ΟΙ | 0) | ιη | 10 | 0 | Ε | υ | |||||||||
| 1 | 3 | Μ· | 3 | ΟΙ | 3 | (0 | Ο | (0 | X | (0 | 3 | |||||
| 1 | υ | U | 0 | ο | 0 | 3 | >μ | 3 | rH | 3 | Ci | |||||
| 1 | υ | 3 | υ | 0 | υ οι | 0 | < | υ | η | υ | Q | |||||
| 1 | 0 | Η | 0 | γΗ | 0 -Η | υ | Ci | υ | φ | Ci | 0 | Ci | ||||
| 1 | ο | γ4 | 0 | ιΜ | 0 Ό | 0 | Ο | 0 | φ | ο | 0 | ο | ||||
| 01 | 1 | 0 | Ο | 0 | ο | ο Ή | Μ | υ | (0 | υ | •Η | 0 | (0 | |||
| U | 1 | γΗ | γΜ | Ή Ε | ri | 0 | φ | < | 0 | μι | 0 | 0 | -μ | Ο | ||
| υ | 1 | (0 | >. | to | > μ | •-Ι | μ | C | μ | υ | μ | rM | ||||
| 3 | 1 | A | 3 | A | 3 | Α Φ | ο | £Χ | φ | IX | IX | (0 | ex | (X | (0 | IX |
| Ό | 1 | (X | Φ | α | φ | 0. Ό | ο | φ | θ' | 3 | φ | rM | 3 | Φ | 0 | 3 |
| 0 | 1 | 10 | μ | <0 | μ | φ ·μ | ΟΙ | μ | 0 | Ο | μ | 10 | 0 | μ | φ | 0 |
| Μ | 1 | -μ | 3 | μ | 3 | -μ ex | «μ | μ | >1 | μ | μ | cr | μ | μ | Φ | μ |
| (X | 1 | Μ | (0 | W | Φ | VI <υ | ο | VI | (X | σ> | W | (0 | cn | Μ | <μ | CP |
AP . Ο Ο 5 5 8
| CM | CM | CM | co | CM | ||
| 1 | CM | o | o | O | o | o |
| in ι | O | «b | Wk | *» | ||
| Cl 1 | o | o | o | o | o | |
| • | | o | VI | VI | VI | VI | |
| X I | VI | |||||
| Μ 1 |
| 1 | CM | |||||
| xT 1 | O | CM | CM | xr | (M | |
| Cl 1 | n | O | o | o | o | |
| • 1 | % | o | * | * | ||
| X 1 | o | VI | o | o | o | o |
| ω ι | VI | VI | VI |
ci ci •
X w
CM
| CM 1 | CM | o | CM | CM | in | |
| Cl 1 | O | o | O | o | r4 | |
| • 1 | * | o | * | K | ||
| X 1 | o | VI | o | o | o | o |
| Μ 1 1 | VI | VI | VI | |||
| 1 1 | CM | |||||
| r-l 1 | CM | o | CM | CM | co | in |
| Cl 1 | o | o | o | o | H | |
| • I | o | *» | * | «> | k | |
| X 1 | o | VI | o | o | o | o |
| W 1 a | VI | VI | VI |
o ci
X w
CM
| σι ι | CM | o | CM | CM | xr | ||||||||||
| CM 1 | o | O | O | o | |||||||||||
| • | | o | •b | ι | * | |||||||||||
| X 1 | o | VI | o | o | o | ||||||||||
| «*** | W 1 | VI | VI | VI | |||||||||||
| Ό | 1 | ||||||||||||||
| V | 1 | M1 | |||||||||||||
| 3 | 1 | xr | o | CM | xr | xr | in | ||||||||
| C | Cl 1 | o | O | o | Ο | r-l | |||||||||
| •H | • I | o | * | «k | |||||||||||
| P | X 1 | o | o | .o | ο | o | |||||||||
| c | W 1 | VI | |||||||||||||
| 0 | 1 | ||||||||||||||
| u | 1 | ||||||||||||||
| 1 | CM | ||||||||||||||
| CM 1 | CM | O | CM | in | co | xr | |||||||||
| a | • | | o | «k | O | r-l | ο | o | ||||||||
| c | X 1 | o | * | b | |||||||||||
| •H | Μ 1 | o | VI | o | o | ο | o | ||||||||
| A | 1 | VI | VI | ||||||||||||
| k | 1 | ||||||||||||||
| P | 1 | ||||||||||||||
| 10 | r-l 1 | CM | xi | CM | CM | co | xr | ||||||||
| 1 | O | O | o | O | ο | o | |||||||||
| rM | X 1 | *k | b | Wb | |||||||||||
| A | W 1 | o | o | o | o | ο | o | ||||||||
| Ή | 1 | VI | VI | VI | |||||||||||
| k | 1 | in | |||||||||||||
| Φ | 1 | a | Η | ||||||||||||
| P | 1 | rH | (0 | in | ΙΟ | r-l | w | ||||||||
| υ | 1 | El | « | rH | r-l | o | |||||||||
| A | 1 | (0 | S | io | 0 | to | cq | (0 | » | (0 | w | (0 | Cl | ||
| Ά | 1 | 3 | Cl | 3 | o | 3 | o | 3 | 0 | 3 | A | 3 | o | ||
| 1 | 0 | Q | 0 | 0 | 0 | P | υ | Ρ | υ | ffl | 0 | ||||
| + | 1 | 0 | CM | o | CM | υ | •H | υ | •Η | 0 | Φ | CM | 0 | Φ | |
| 3E | 1 | 0 | o | 0 | O | 0 | ε | 0 | ε | ο | A | O | 0 | A | |
| 2 | (0 1 | o | o | o | CM | 0 | CM | υ | •Η | 0 | •r| | ||||
| K | P 1 | 0 | e | Q | 0 | 0 | 0 | O | ο | Ο | ο | Ρ | β | 0 | c |
| 0 | υ ι | •P | 3 | P | P | Ρ | Ρ | υ | P | 0 | |||||
| 3 1 | ex | •H | CX | IX | ex | CX | (0 | ex | 10 | (X | A | ex | Or | ε | |
| Ό 1 | Φ | 0 | 3 | Φ | 3 | φ | •H | φ | Ή | φ | r-t | 3 | Φ | 3 | |
| 0 1 | k | Φ | O | k | 0 | k | P | k | Ρ | k | A | 0 | k | Φ | |
| k 1 | P | A | k | P | k | P | •H | Ρ | •Η | Ρ | CP | k | P | C | |
| a. ι | w | <w | cp | M | CP | co | ε | W | ε | W | A | CP | CO | CX |
Claims (2)
- - 1,2,3,6-tetrahydro 1,3-dimethyl 2,6-dioxo 7H-purine 75 butanamine,- 2-(4-pyridinyl) thiazol 4-butanamine,- ΙΗ-indol l-butanamine,- 1-methyl ΙΗ-benzimidazol 2-butanamine,- 6-chloro ΙΗ-benzimidazol 2-butanamine,- 2-methyl ΙΗ-benzimidazol 2-butanamine,- 4-(4-chlorophenyl) ΙΗ-imidazol 1-butanamine,- 2-(3-pyridinyl) thiazol 5-butanamine,- 7-methoxyquinoleine 4-butanamine,- 4-(4-fluorophenyl) ΙΗ-imidazol 1-butanamine,- 4-(2-methoxyphenyl) ΙΗ-imidazol 1-butanamine,- 3-(3-pyridinyl) 1H 1,2,4-triazol 1-butanamine,- 4-(3-pyridinyl) ΙΗ-imidazol 1-butanamine,- 2-(2-pyridinyl) thiazol 4-butanamine,- 2-phenylthiazol 4-butanamine,- 4-(4-methoxyphenyl) ΙΗ-imidazol 1-butanamine,- isoquinoleine 4-butanamine,- quinazoline 4-butanamine, ftp . Ο Ο 5 5 6S'- 4,5-diphenyl lH-imidazol l-butanamine,- 4-(3-methoxyphenyl) lH-imidazol l-butanamine,- 4-(4-(trifluoromethoxy) phenyl) lH-imidazol l-butanamine,- 1-methyl ΙΗ-indole 4-butanamine,- 3-phenyl lH-l,2,4-triazole 1-butanamine (hydrochloride),- 5-phenyl ΙΗ-tetrazole 1-butanamine (hydrochloride),- 2-benzothiazolebutanamine,- 4-(thieno(2,3-b) pyridine 4-yl butanamine,- 5,6-dimethyl ΙΗ-benzimidazole 1-butanamine,- 3-quinoleine butanamine,- 2-quinoleine butanamine,- 5H-imidazo [4,5-c] pyridine 5-butanamine,- 1-methyl lH-imidazo(4,5-c)-pyridine 2-butanamine,- 3-methyl 3H-imidazo(4,5-c)-pyridine 2-butanamine,- 5-chloro ΙΗ-benzimidazole 1-butanamine,- 7-methoxy 4-quinolenebutanamine,- lH-imidazo(4,5-c) pyridine 1-butanamine,- 9H-purine 9-butanamine,1) The compounds of formula (I):in which R represents a -(CH2)nAr radical, in which n represents the number 3, 4 or 5 and Ar represents a15 heterocyclic radical, optionally carrying one or more tsubstituents, chosen from the following group of radicals: c tr cf·' *20AP.00558 ζAD/D/ or R represents the radical and Z represents a hydrogen atom or an acid remainder, as well as their addition salts with acids.2) The compounds of formula (I), as defined in claim l, in which Z represents a hydrogen atom.3) The compounds of formula (I), as defined in claim 1 or 2, in which n represents the number 4.4) The compounds of formula (I), as defined in claim 1, 2 or 3, in which Ar represents a radical:I opt iona1ly substituted.5) The compounds of formula (I), as defined in claim 1, 2 or 3, in which Ar represents the radical:I optionally substituted.6.- The compounds of formula (I), as defined in claims 1, 2 or 3, in which Ar represents the radical :N or optionally substituted.7.- The compounds of formula (I), as defined in claim 1, 2 or 3, in which Ar represents the radical :ΑΡ . Ο Ο 5 5 8Q nJ optionaly substituted.8) The compounds of formula (I),10 as defined in claim 1, the names of vhich follow:- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxy carbonyl ((4-(4-phenyl ΙΗ-imidazol-l-yl) butyl) imino)) erythromycin,15 - 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxy carbonyl ((4-(3H-imidazo(4,5-b)pyridin-3-yl) butyl) imino)) erythromycin,- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O-methyl20 alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxy carbonyl ((4-(ΙΗ-imidazo(4,5-b)pyridin-l-yl) butyl) imino)) erythromycin,- 11,12-dideoxy 3-de((2,6-dideoxy-3-c-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxy25 carbonyl ((4-(4-(4-chlorophenyl) ΙΗ-imidazol-l-yl) butyl) imino)) erythromycin,- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4-(4-(2-ιηάthoxyphenyl) ΙΗ-imidazol-l-yl) butyl)30 imino)) erythromycin,- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4-(4-(4-fluorophenyl) ΙΗ-imidazol-l-yl) butyl) imino)) erythromycin,35 - 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(7-methoxy 4-quinoleinyl) butyl) imino)) ery thr omy c i n,S'- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11-(oxycarbonyl ((4-(2-(2-pyridinyl) 4-thiazolyl) butyl) imino)) erythromycin,5 - 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11-(oxycarbonyl ((4-(3-(3-pyridinyl) 1H-1,2,4-triazol-l-yl) butyl) imino)) erythromyc in.9. - The compound of formula (I), as10 defined in claim, the name of whicn follows:- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11-(oxycarbonyl ((4-(4-(3-pyridinyl) lH-imidazol-l-yl) butyl) imino)) erythromycin.10. - As medicaments, the compounds of formula (I) as defined in any one of claims 1 to 7, as well as their addition salts with pharmaceutically acceptable acids.11. - As medicaments, the compounds defined in claim 8, as20 well as their addition salts with pharmaceutically acceptable acids.12. - As medicaments, the compound defined in claim 9 as well as its pharmaceutically acceptable addition salts with acids.13. - Pharmaceutical compositions containing as active25 principle at least one medicament according to any one of claims 10 to 12.14. - Preparation process for the compounds of formula (I), as defined in claim 1, characterized in that a compound of formula (II) :(II)AP. 0 0 5 5 8 in which Z' represents an acid action of a compound of formula remainder, (HI) :is subjected to the rnh2 (HI) in which R is defined as in claim 1, in order to obtain the compound of formula (IA):oo in which R and Z' keep their previous meaning, then if appropriate the compound of formula (IA) is subjected to the35 action of an agent releasing the hydroxyl function in position 2' and/or if appropriate, to the action of an acid in order to form the salt.15.- The compounds of formula (III) as defined in claim 14.16.- The compounds of formula (III) as defined in claim 15, the names of which follow:- 4-phenyl-lH-imidazole 1-butanamine,- 3H-imidazo(4,5-b)-pyridine 3-butanamine,- lH-imidazo(4,5-b)-pyridine 3-butanamine,- 2-phenyl-4-quinolinebutanamine,- ΙΗ-benzotriazole 1-butanamine,- 2H-benzotriazole 2-butanamine,
- - 2-(3-pyridinyl) thiazol 4-butanamine, as well as their addition salts with acids.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9405368A FR2719587B1 (en) | 1994-05-03 | 1994-05-03 | New erythromycin derivatives, their preparation process and their use as drugs. |
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| Publication Number | Publication Date |
|---|---|
| AP9500744A0 AP9500744A0 (en) | 1995-07-31 |
| AP558A true AP558A (en) | 1996-11-07 |
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| APAP/P/1995/000744A AP558A (en) | 1994-05-03 | 1995-05-02 | New erythromycin derivatives, their preparation process and their use as medicaments. |
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| WO1997001539A1 (en) * | 1995-06-27 | 1997-01-16 | Takeda Chemical Industries, Ltd. | 4-acylamino(halogeno) alkyl-quinoline derivatives, their preparation and their use as melatonin agonists |
| FR2742757B1 (en) | 1995-12-22 | 1998-01-30 | Roussel Uclaf | NOVEL ERYTHROMYCIN DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS |
| ATE296308T1 (en) * | 1996-09-04 | 2005-06-15 | Abbott Lab | 6-O-SUBSTITUTED KETOLIDES WITH ANTIBACTERIAL ACTION |
| UA51730C2 (en) * | 1996-09-04 | 2002-12-16 | Ебботт Лабораторіз | 6-0-substituted ketolides having antibacterial activity |
| FR2757168B1 (en) * | 1996-12-12 | 1999-06-11 | Hoechst Marion Roussel Inc | NOVEL ERYTHROMYCIN DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS |
| FR2760017B1 (en) * | 1997-02-27 | 1999-04-30 | Hoechst Marion Roussel Inc | NOVEL ERYTROMYCIN DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS |
| US5780605A (en) * | 1997-09-08 | 1998-07-14 | Abbott Laboratories | 6,9-bridged erythromycin derivatives |
| FR2771008B1 (en) * | 1997-11-17 | 2000-04-28 | Hoechst Marion Roussel Inc | USE OF KETOLIDES FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS FOR PREVENTING ARTERIAL THROMBOTIC COMPLICATIONS LINKED TO ATHEROSCLEROSIS |
| JP4573925B2 (en) * | 1998-07-09 | 2010-11-04 | アベンティス・ファーマ・ソシエテ・アノニム | Novel erythromycin derivative, its production method and its use as a drug |
| FR2781484B1 (en) * | 1998-07-21 | 2001-08-10 | Hoechst Marion Roussel Inc | NOVEL 6-DEOXY ERYTHROMYCIN DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS |
| ES2243066T3 (en) * | 1998-09-22 | 2005-11-16 | Pfizer Products Inc. | CARBAMATE AND CETOLID CARBAZATE ANTIBIOTICS. |
| FR2785612A1 (en) * | 1998-11-10 | 2000-05-12 | Hoechst Marion Roussel Inc | NOVEL DERIVATIVES OF ERYTHROMYCIN, PROCESS FOR PREPARING THEM AND THEIR APPLICATION AS MEDICAMENTS |
| FR2786188B1 (en) * | 1998-11-24 | 2002-10-31 | Hoechst Marion Roussel Inc | NOVEL ERYTHROMYCIN DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS |
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