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1. (WO2017093157) PIPERIDINE, PYRROLIDINE AND 2-OXO-1,3-OXAZINANE DERIVATIVES AS INHIBITORS OF BACTERIAL EFFLUX-PUMPS FOR THE TREATMENT OF MICROBIAL INFECTIONS
Latest bibliographic data on file with the International Bureau

Pub. No.: WO/2017/093157 International Application No.: PCT/EP2016/078938
Publication Date: 08.06.2017 International Filing Date: 28.11.2016
IPC:
C07D 405/12 (2006.01) ,C07D 265/10 (2006.01) ,C07D 207/09 (2006.01) ,C07D 207/14 (2006.01) ,C07D 211/58 (2006.01) ,A61K 31/4468 (2006.01) ,A61K 31/40 (2006.01) ,A61K 31/4025 (2006.01) ,A61K 31/535 (2006.01) ,A61P 31/04 (2006.01)
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
405
Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
02
containing two hetero rings
12
linked by a chain containing hetero atoms as chain links
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
265
Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
04
1,3-Oxazines; Hydrogenated 1,3-oxazines
06
not condensed with other rings
08
having one double bond between ring members or between a ring member and a non-ring member
10
with oxygen atoms directly attached to ring carbon atoms
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
207
Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
02
with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
04
having no double bonds between ring members or between ring members and non-ring members
08
with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
09
Radicals substituted by nitrogen atoms not forming part of a nitro radical
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
207
Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
02
with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
04
having no double bonds between ring members or between ring members and non-ring members
10
with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
14
Nitrogen atoms not forming part of a nitro radical
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
211
Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
04
with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
06
having no double bonds between ring members or between ring members and non-ring members
36
with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
56
Nitrogen atoms
58
attached in position 4
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
395
having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
435
having six-membered rings with one nitrogen as the only ring hetero atom
44
Non-condensed pyridines; Hydrogenated derivatives thereof
445
Non-condensed piperidines, e.g. piperocaine
4468
having a nitrogen atom directly attached in position 4, e.g. clebopride, fentanyl
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
395
having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
40
having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
395
having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
40
having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
4025
not condensed and containing further heterocyclic rings, e.g. cromakalim
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
395
having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
535
having six-membered rings with at least one nitrogen and at least one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
P
SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
31
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
04
Antibacterial agents
Applicants:
BASILEA PHARMACEUTICA INTERNATIONAL AG [CH/CH]; Grenzacherstrasse 487 4058 Basel, CH
Inventors:
GAUCHER, Bérangère; CH
DREIER, Jürg; CH
Agent:
THWAITE, Jonathan; CH
Priority Data:
15197049.830.11.2015EP
Title (EN) PIPERIDINE, PYRROLIDINE AND 2-OXO-1,3-OXAZINANE DERIVATIVES AS INHIBITORS OF BACTERIAL EFFLUX-PUMPS FOR THE TREATMENT OF MICROBIAL INFECTIONS
(FR) DÉRIVÉS DE PIPÉRIDINE, DE PYRROLIDINE ET DE 2-OXO-1,3-OXAZINANE EN TANT QU'INHIBITEURS DE POMPES À EFFLUX BACTÉRIENNES POUR LE TRAITEMENT D'INFECTIONS MICROBIENNES
Abstract:
(EN) The present invention relates to compounds of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof wherein ASC is Ring A represents a 4- to 6-membered saturated ring containing carbon atoms as ring members in addition to the nitrogen atom, wherein a -CH 2 -CH 2 - moiety adjacent to the nitrogen atom is optionally replaced by a -C(=O)-O- moiety to form a carbamate; X represents a bond or -CH 2 -; AR1 and AR2 represent phenyl; R1, R2 and R3 represent independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy; R4 represents hydrogen, halogen, C 1 -C 6 alkyl optionally substituted by 1 to 5 R10a, C 2 -C 6 alkenyl optionally substituted by 1 to 5 R10a, C 1 -C 6 alkylene-R10b, C 2 -C 6 alkenylene-R10b, C(O)OR11a, CHO, C(O)N(R12)R13 or O-R14; R5, R6 and R7 represent independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy; R8 represents methyl or is absent, and when R8 is present the respective nitrogen atom carries a positive charge; R9a and R9b represent independently hydrogen or methyl; R10a represents independently at each occurrence halogen, hydroxyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy; R10b represents C 3 -C 8 cycloalkyl, C(O)OR11a, CHO, C(O)N(R12)R13, N(R12)R13, Cycle-P or Cycle-Q; R11a and R11b represent independently at each occurrence hydrogen or C 1 -C 6 alkyl; R12 and R13 represent independently at each occurrence hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R14 represents C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 1 -C 6 alkylene-Cycle-P, C 1 -C 6 alkylene-Cycle-Q; Cycle-P represents independently at each occurrence a saturated or partially unsaturated C 5 -C 6 carbocyclic ring optionally substituted by 1 to 3 R15 or a saturated or partially unsaturated 5- or 6-membered heterocyclic ring optionally substituted by 1 to 3 R15 containing carbon atoms as ring members and one or two ring members independently selected from N(R11b) and O; Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 R16 or a 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from O, S and N, optionally substituted by 1 to 3 R16; R15 and R16 represent independently at each occurrence halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy; L1 represents -CH=CH-, -CH 2 -O-, -(CH 2 ) 2 -O-, -0-CH 2 -, -CH 2 -S-, -(CH 2 ) 2 -S-, -S-CH 2 -, -C(CH 3 ) 2 -, -(CH 2 ) 2 -or -CH=CH-CH 2 -; L2 represents C 1 -C 7 alkylene, wherein one or more -CH 2 - moieties in the alkylene moiety are optionally replaced independently by -C(=O)-, wherein within L2 there are no adjacent -C(=O)- moieties and wherein the terminal moiety of L2 is not -C(=O)-; and discloses their use in methods of treating a subject with a microbial infection or susceptible to a microbial infection in combination with an antimicrobial agent.
(FR) La présente invention concerne des composés de formule I ou leurs sels, solvates ou hydrates pharmaceutiquement acceptables, ASC étant telle que le cycle A représente un cycle saturé de 4 à 6 chaînons contenant des atomes de carbones en tant que chaînons cycliques en plus de l'atome d'azote, une fraction -CH 2 -CH 2 – adjacente à l'atome d'azote étant éventuellement remplacée par une fraction -C(=O)-O- pour former un carbamate; X représente une liaison ou -CH 2 -; AR1 et AR2 représentent phényle; R1, R2 et R3 représentent indépendamment hydrogène, halogène, alkyle en C 1 -C 6, halogénure d'alkyle en C 1 -C 6, alcoxy en C 1 -C 6 ou halogéno-alcoxy en C 1 -C 6; R4 représente hydrogène, halogène, alkyle en C 1 -C 6 éventuellement substitué par 1 à 5 R10a, alcényle en C 2 -C 6 éventuellement substitué par 1 à 5 R10a, alkylène-R10b en C 1 -C 6, alcénylène-R10b en C 2 -C 6, C(O)OR11a, CHO, C(O)N(R12)R13 ou O-R14; R5, R6 et R7 représentent indépendamment hydrogène, halogène, alkyle en C 1 -C 6, halogénure d'alkyle en C 1 -C 6, alcoxy en C 1 -C 6 ou halogéno-alcoxy en C 1 -C 6; R8 représente méthyle ou est absent, et lorsque R8 est présent, l'atome d'azote respectif porte une charge positive; R9a et R9b représentent indépendamment hydrogène ou méthyle; R10a représente indépendamment à chaque occurrence halogène, hydroxyle, alcoxy en C 1 -C 6 ou halogéno-alcoxy en C 1 -C 6; R10b représente cycloakyle en C 3 -C 8, C(O)OR11a, CHO, C(O)N(R12)R13, N(R12)R13, un cycle P ou un cycle Q; R11a et R11b représentent indépendamment à chaque occurrence hydrogène ou alkyle en C 1 -C 6; R12 et R13 représentent indépendamment à chaque occurrence hydrogène, alkyle en C 1 -C 4, halogénure d'alkyle en C 1 -C 4 ou alcoxy en C 1 -C 4, alkyle en -C 1 -C 4; R14 représente alkyle en C 1 -C 6, halogénure d'alkyle en C 1 -C 6, alcényle en C 2 -C 6, halogéno-alcényle en C 2 -C 6, un cycle P d'alkylène en C 1 -C 6, un cycle Q d'alkylène en C 1 -C 6; le cycle P représente indépendamment à chaque occurrence un cycle carboxylique saturé ou partiellement insaturé en C 5 -C 6 éventuellement substitué par 1 à 3 R15 ou un cycle hétérocyclique saturé ou partiellement insaturé de 5 à 6 chaînons éventuellement substitué par 1 à 3 R15 contenant des atomes de carbones en tant que chaînons cycliques et un ou deux chaînons cycliques étant indépendamment choisis parmi N(R11b) et O; le cycle Q représente indépendamment à chaque occurrence phényle éventuellement substitué par 1 à 3 R16 ou un cycle hétéroaryle de 5 à 6 chaînons contenant de un à quatre hétéroatomes indépendamment choisis parmi O, S et N, éventuellement substitués par 1 à 3 R16; R15 et R16 représentent indépendamment à chaque occurrence halogène, alkyle en C 1 -C 4, halogénure d'alkyle en C 1 -C 4, alcoxy en C 1 -C 4 ou halogéno-alcoxy en C 1 -C 4; L1 représente -CH=CH-, -CH 2 -O-, -(CH 2 ) 2 -O-, -0-CH 2 -, -CH 2 -S-, -(CH 2 ) 2 -S-, -S-CH 2 -, -C(CH 3 ) 2 -, -(CH 2 ) 2 - ou -CH=CH-CH 2 -; L2 représente alkylène en C 1 -C 7, une ou plusieurs fractions -CH 2 – dans la fraction alkylène étant éventuellement remplacées indépendamment par -C(=O)-. L2 ne contient pas de fractions -C(=O)- adjacentes et la fraction terminale de L2 n'est pas -C(=O)-. L'invention concerne en outre leur utilisation dans des procédés de traitement d'un sujet souffrant d'une infection microbienne ou susceptible de souffrir d'une infection microbienne en association avec un agent antimicrobien.
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African Regional Intellectual Property Organization (ARIPO) (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW)
Eurasian Patent Organization (AM, AZ, BY, KG, KZ, RU, TJ, TM)
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Publication Language: English (EN)
Filing Language: English (EN)