patents.google.com

US20070185061A1 - Heterocyclic boronic acid compounds - Google Patents

️Thu Aug 09 2007

US20070185061A1 - Heterocyclic boronic acid compounds - Google Patents

Heterocyclic boronic acid compounds Download PDF

Info

Publication number

US20070185061A1

US20070185061A1 US11/556,944 US55694406A US2007185061A1 US 20070185061 A1 US20070185061 A1 US 20070185061A1 US 55694406 A US55694406 A US 55694406A US 2007185061 A1 US2007185061 A1 US 2007185061A1 Authority

United States

Prior art keywords

alkyl

independently

cycloalkyl

phenyl

optionally mono

Prior art date

2003-11-12

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Application number

US11/556,944

Inventor

David Campbell

David Winn

Juan Betancort

Kevin Shreder

Yi Hu

Bei Li

Melissa Wong

Lifu Ma

William Ripka

Min Wu

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Activx Biosciences Inc

Phenomix Corp

Original Assignee

Activx Biosciences Inc

Phenomix Corp

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2003-11-12

Filing date

2006-11-06

Publication date

2007-08-09

2006-11-06 Application filed by Activx Biosciences Inc, Phenomix Corp filed Critical Activx Biosciences Inc

2006-11-06 Priority to US11/556,944 priority Critical patent/US20070185061A1/en

2007-04-09 Assigned to PHENOMIX CORPORATION reassignment PHENOMIX CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ACTIVX BIOSCIENCES, INC.

2007-04-09 Assigned to PHENOMIX CORPORATION reassignment PHENOMIX CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BETANCORT, JUAN MANUEL, CAMPBELL, DAVID ALAN, WINN, DAVID T.

2007-04-09 Assigned to ACTIVX BIOSCIENCES, INC. reassignment ACTIVX BIOSCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WU, MIN, MA, LIFU, RIPKA, WILLIAM, WONG, MELISSA, LI, BEI, HU, YI, SHREDER, KEVIN

2007-08-09 Publication of US20070185061A1 publication Critical patent/US20070185061A1/en

Status Abandoned legal-status Critical Current

Links

-1 Heterocyclic boronic acid compounds Chemical class 0.000 title claims description 87
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 54
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 40
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 37
125000001072 heteroaryl group Chemical group 0.000 claims abstract description 33
229910052736 halogen Inorganic materials 0.000 claims abstract description 22
150000002367 halogens Chemical class 0.000 claims abstract description 22
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 12
125000004400 (C1-C12) alkyl group Chemical group 0.000 claims abstract description 9
229910052799 carbon Inorganic materials 0.000 claims abstract description 6
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 6
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 5
IPZJQDSFZGZEOY-UHFFFAOYSA-N dimethylmethylene Chemical compound C[C]C IPZJQDSFZGZEOY-UHFFFAOYSA-N 0.000 claims abstract description 3
229910052739 hydrogen Inorganic materials 0.000 claims description 41
239000001257 hydrogen Substances 0.000 claims description 41
125000003118 aryl group Chemical group 0.000 claims description 38
125000000217 alkyl group Chemical group 0.000 claims description 31
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 27
125000003342 alkenyl group Chemical group 0.000 claims description 25
125000000304 alkynyl group Chemical group 0.000 claims description 25
125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 18
125000000392 cycloalkenyl group Chemical group 0.000 claims description 18
150000003839 salts Chemical class 0.000 claims description 17
229920006395 saturated elastomer Polymers 0.000 claims description 17
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 16
125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 16
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 16
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
125000003545 alkoxy group Chemical group 0.000 claims description 15
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 14
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 12
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 12
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 10
125000003710 aryl alkyl group Chemical group 0.000 claims description 10
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 10
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
125000003282 alkyl amino group Chemical group 0.000 claims description 9
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
125000004093 cyano group Chemical group *C#N 0.000 claims description 9
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 9
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 9
125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 8
125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 8
IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 8
125000002527 bicyclic carbocyclic group Chemical group 0.000 claims description 8
125000004663 dialkyl amino group Chemical group 0.000 claims description 8
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 8
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 7
125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 7
125000002252 acyl group Chemical group 0.000 claims description 7
150000002431 hydrogen Chemical class 0.000 claims description 7
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 6
125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 6
125000004949 alkyl amino carbonyl amino group Chemical group 0.000 claims description 6
125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 6
125000004414 alkyl thio group Chemical group 0.000 claims description 6
125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 6
125000004122 cyclic group Chemical group 0.000 claims description 6
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
125000001624 naphthyl group Chemical group 0.000 claims description 6
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
OIMWEHOYHJJPJD-UHFFFAOYSA-N pyridine;pyrimidine Chemical compound C1=CC=NC=C1.C1=CN=CN=C1 OIMWEHOYHJJPJD-UHFFFAOYSA-N 0.000 claims description 6
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 5
235000008206 alpha-amino acids Nutrition 0.000 claims description 5
125000003277 amino group Chemical group 0.000 claims description 5
125000001769 aryl amino group Chemical group 0.000 claims description 5
125000005620 boronic acid group Chemical group 0.000 claims description 5
125000004446 heteroarylalkyl group Chemical group 0.000 claims description 5
125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 5
229910052757 nitrogen Inorganic materials 0.000 claims description 5
125000006684 polyhaloalkyl group Polymers 0.000 claims description 5
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
125000005089 alkenylaminocarbonyl group Chemical group 0.000 claims description 4
125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 4
125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 4
125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 4
125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 4
125000005095 alkynylaminocarbonyl group Chemical group 0.000 claims description 4
150000001370 alpha-amino acid derivatives Chemical class 0.000 claims description 4
125000001091 aminosulfinyl group Chemical group [H]N([H])S(*)=O 0.000 claims description 4
239000007864 aqueous solution Substances 0.000 claims description 4
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
150000001602 bicycloalkyls Chemical group 0.000 claims description 4
239000013060 biological fluid Substances 0.000 claims description 4
125000004438 haloalkoxy group Chemical group 0.000 claims description 4
125000000623 heterocyclic group Chemical group 0.000 claims description 4
150000004677 hydrates Chemical class 0.000 claims description 4
125000005350 hydroxycycloalkyl group Chemical group 0.000 claims description 4
125000005476 oxopyrrolidinyl group Chemical group 0.000 claims description 4
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
125000005592 polycycloalkyl group Polymers 0.000 claims description 4
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
125000004076 pyridyl group Chemical group 0.000 claims description 4
239000012453 solvate Substances 0.000 claims description 4
125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims description 4
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
125000002947 alkylene group Chemical group 0.000 claims description 3
125000004429 atom Chemical group 0.000 claims description 3
125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 3
125000005843 halogen group Chemical group 0.000 claims description 3
125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
WWODQSMOSOXYQQ-UHFFFAOYSA-N 1-pentylbicyclo[2.2.2]octan-4-amine Chemical compound C1CC2(N)CCC1(CCCCC)CC2 WWODQSMOSOXYQQ-UHFFFAOYSA-N 0.000 claims description 2
125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 2
125000004423 acyloxy group Chemical group 0.000 claims description 2
125000005162 aryl oxy carbonyl amino group Chemical group 0.000 claims description 2
125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 2
125000005241 heteroarylamino group Chemical group 0.000 claims description 2
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 2
125000003396 thiol group Chemical class [H]S* 0.000 claims 2
150000001875 compounds Chemical class 0.000 abstract description 44
230000002401 inhibitory effect Effects 0.000 abstract description 3
102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 abstract 2
101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 abstract 2
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
239000000243 solution Substances 0.000 description 23
0 CC.[3*]C([4*])(N[5*])C(C)(C)C(=O)N1CCCC1B(C)C Chemical compound CC.[3*]C([4*])(N[5*])C(C)(C)C(=O)N1CCCC1B(C)C 0.000 description 22
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
238000003786 synthesis reaction Methods 0.000 description 17
230000015572 biosynthetic process Effects 0.000 description 16
125000004432 carbon atom Chemical group C* 0.000 description 16
238000005160 1H NMR spectroscopy Methods 0.000 description 12
238000000034 method Methods 0.000 description 12
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
239000007787 solid Substances 0.000 description 11
238000006243 chemical reaction Methods 0.000 description 10
239000000203 mixture Substances 0.000 description 10
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
235000019439 ethyl acetate Nutrition 0.000 description 9
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 7
102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 7
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
239000002253 acid Substances 0.000 description 6
150000002148 esters Chemical class 0.000 description 6
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 6
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
239000002904 solvent Substances 0.000 description 6
239000007858 starting material Substances 0.000 description 6
238000003756 stirring Methods 0.000 description 6
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 5
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 5
235000004279 alanine Nutrition 0.000 description 5
ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 5
239000000460 chlorine Substances 0.000 description 5
239000003921 oil Substances 0.000 description 5
239000000741 silica gel Substances 0.000 description 5
229910002027 silica gel Inorganic materials 0.000 description 5
MOILFCKRQFQVFS-OORONAJNSA-N (1s,3r,4s,5s)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@H]2C(C)(C)[C@@H]1C[C@@H](O)[C@]2(O)C MOILFCKRQFQVFS-OORONAJNSA-N 0.000 description 4
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 4
102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 4
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
229910052801 chlorine Inorganic materials 0.000 description 4
238000004440 column chromatography Methods 0.000 description 4
238000005859 coupling reaction Methods 0.000 description 4
238000010511 deprotection reaction Methods 0.000 description 4
ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
239000003112 inhibitor Substances 0.000 description 4
239000010410 layer Substances 0.000 description 4
230000004048 modification Effects 0.000 description 4
238000012986 modification Methods 0.000 description 4
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
239000002244 precipitate Substances 0.000 description 4
125000006239 protecting group Chemical group 0.000 description 4
238000000746 purification Methods 0.000 description 4
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
MOILFCKRQFQVFS-BDNRQGISSA-N (1r,3s,4r,5r)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@@H]2C(C)(C)[C@H]1C[C@H](O)[C@@]2(O)C MOILFCKRQFQVFS-BDNRQGISSA-N 0.000 description 3
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
229910052794 bromium Inorganic materials 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
230000008878 coupling Effects 0.000 description 3
238000010168 coupling process Methods 0.000 description 3
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
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 3
NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 3
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
201000010099 disease Diseases 0.000 description 3
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
150000002430 hydrocarbons Chemical group 0.000 description 3
WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 3
150000007524 organic acids Chemical class 0.000 description 3
125000001424 substituent group Chemical group 0.000 description 3
WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 3
GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
JWJVSDZKYYXDDN-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]azetidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC1C(O)=O JWJVSDZKYYXDDN-UHFFFAOYSA-N 0.000 description 2
ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
229910015446 B(OCH3)3 Inorganic materials 0.000 description 2
HSFFCWPJIKXPNU-LURJTMIESA-N CNCC(=O)N1CCC[C@H]1B(O)O Chemical compound CNCC(=O)N1CCC[C@H]1B(O)O HSFFCWPJIKXPNU-LURJTMIESA-N 0.000 description 2
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
206010056997 Impaired fasting glucose Diseases 0.000 description 2
COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
239000007832 Na2SO4 Substances 0.000 description 2
KCOZLUNAAHYCCE-KZUDCZAMSA-N O=C(C1CN(S(=O)(=O)C2=CC=C(OC(F)(F)F)C=C2)CCN1)N1CCC[C@H]1B(O)O Chemical compound O=C(C1CN(S(=O)(=O)C2=CC=C(OC(F)(F)F)C=C2)CCN1)N1CCC[C@H]1B(O)O KCOZLUNAAHYCCE-KZUDCZAMSA-N 0.000 description 2
XDZHQSLFDFTPRJ-JCYILVPMSA-N O=C(NC1CCC(NCC(=O)N2CCC[C@H]2B(O)O)CC1)C1CCCCC1 Chemical compound O=C(NC1CCC(NCC(=O)N2CCC[C@H]2B(O)O)CC1)C1CCCCC1 XDZHQSLFDFTPRJ-JCYILVPMSA-N 0.000 description 2
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical compound CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 2
235000001014 amino acid Nutrition 0.000 description 2
229940024606 amino acid Drugs 0.000 description 2
150000001413 amino acids Chemical class 0.000 description 2
239000000908 ammonium hydroxide Substances 0.000 description 2
125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 2
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
239000004305 biphenyl Substances 0.000 description 2
235000010290 biphenyl Nutrition 0.000 description 2
150000001642 boronic acid derivatives Chemical class 0.000 description 2
WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
125000001589 carboacyl group Chemical group 0.000 description 2
YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
150000001768 cations Chemical class 0.000 description 2
239000012230 colorless oil Substances 0.000 description 2
229940125797 compound 12 Drugs 0.000 description 2
229940126142 compound 16 Drugs 0.000 description 2
238000001816 cooling Methods 0.000 description 2
150000005690 diesters Chemical class 0.000 description 2
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
238000010828 elution Methods 0.000 description 2
238000010931 ester hydrolysis Methods 0.000 description 2
238000001704 evaporation Methods 0.000 description 2
229910052731 fluorine Inorganic materials 0.000 description 2
238000009472 formulation Methods 0.000 description 2
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
230000014509 gene expression Effects 0.000 description 2
239000008103 glucose Substances 0.000 description 2
238000010438 heat treatment Methods 0.000 description 2
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
229940088597 hormone Drugs 0.000 description 2
239000005556 hormone Substances 0.000 description 2
150000003840 hydrochlorides Chemical class 0.000 description 2
230000007062 hydrolysis Effects 0.000 description 2
238000006460 hydrolysis reaction Methods 0.000 description 2
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
230000005764 inhibitory process Effects 0.000 description 2
238000005342 ion exchange Methods 0.000 description 2
125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 2
125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
230000007935 neutral effect Effects 0.000 description 2
235000005985 organic acids Nutrition 0.000 description 2
125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
239000008194 pharmaceutical composition Substances 0.000 description 2
COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
235000008729 phenylalanine Nutrition 0.000 description 2
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
108090000765 processed proteins & peptides Proteins 0.000 description 2
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
150000003254 radicals Chemical class 0.000 description 2
239000011541 reaction mixture Substances 0.000 description 2
238000001953 recrystallisation Methods 0.000 description 2
230000002829 reductive effect Effects 0.000 description 2
YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
229910052938 sodium sulfate Inorganic materials 0.000 description 2
229910052717 sulfur Inorganic materials 0.000 description 2
NPDBDJFLKKQMCM-UHFFFAOYSA-N tert-butylglycine Chemical compound CC(C)(C)C(N)C(O)=O NPDBDJFLKKQMCM-UHFFFAOYSA-N 0.000 description 2
150000003573 thiols Chemical class 0.000 description 2
208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
238000003828 vacuum filtration Methods 0.000 description 2
230000000007 visual effect Effects 0.000 description 2
DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
UPXRTVAIJMUAQR-BTYIYWSLSA-N (2s,4s)-4-(9h-fluoren-9-ylmethoxycarbonylamino)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C1[C@@H](C(O)=O)N(C(=O)OC(C)(C)C)C[C@H]1NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 UPXRTVAIJMUAQR-BTYIYWSLSA-N 0.000 description 1
IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
COLOHWPRNRVWPI-UHFFFAOYSA-N 1,1,1-trifluoroethane Chemical compound [CH2]C(F)(F)F COLOHWPRNRVWPI-UHFFFAOYSA-N 0.000 description 1
GWVWUZJOQHWMFB-UHFFFAOYSA-N 1,1,2-triphenylethane-1,2-diol Chemical compound C=1C=CC=CC=1C(O)(C=1C=CC=CC=1)C(O)C1=CC=CC=C1 GWVWUZJOQHWMFB-UHFFFAOYSA-N 0.000 description 1
JHDMMNYIVVWNOF-UHFFFAOYSA-N 1,2-dicyclohexylethane-1,1-diol Chemical compound C1CCCCC1C(O)(O)CC1CCCCC1 JHDMMNYIVVWNOF-UHFFFAOYSA-N 0.000 description 1
YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
125000006017 1-propenyl group Chemical group 0.000 description 1
YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
OBGFNGZXMSFPAR-UHFFFAOYSA-N 2,5-dimethylhexane-3,3-diol Chemical compound CC(C)CC(O)(O)C(C)C OBGFNGZXMSFPAR-UHFFFAOYSA-N 0.000 description 1
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 description 1
125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 1
239000004475 Arginine Substances 0.000 description 1
DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
239000005711 Benzoic acid Substances 0.000 description 1
OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 1
GCXDZZDDWXMVKB-BPCQOVAHSA-N CC(=O)NC1CCC(NCC(=O)N2CCC[C@H]2B(O)O)CC1 Chemical compound CC(=O)NC1CCC(NCC(=O)N2CCC[C@H]2B(O)O)CC1 GCXDZZDDWXMVKB-BPCQOVAHSA-N 0.000 description 1
QJNNHIGKGZLJEW-QMMMGPOBSA-N CC(C)NCC(=O)N1CCC[C@H]1B(O)O Chemical compound CC(C)NCC(=O)N1CCC[C@H]1B(O)O QJNNHIGKGZLJEW-QMMMGPOBSA-N 0.000 description 1
STHNVFPIQXOAON-JWOPXBRZSA-N CC(CN)C(=O)N1CCC[C@H]1B(O)O.O=CO Chemical compound CC(CN)C(=O)N1CCC[C@H]1B(O)O.O=CO STHNVFPIQXOAON-JWOPXBRZSA-N 0.000 description 1
UZWIMKFRQQMCIK-JWOPXBRZSA-N CC(N)CC(=O)N1CCC[C@H]1B(O)O.O=CO Chemical compound CC(N)CC(=O)N1CCC[C@H]1B(O)O.O=CO UZWIMKFRQQMCIK-JWOPXBRZSA-N 0.000 description 1
NNZMNKCKCVRJKE-GKAPJAKFSA-N CCC(C)NCC(=O)N1CCC[C@H]1B(O)O Chemical compound CCC(C)NCC(=O)N1CCC[C@H]1B(O)O NNZMNKCKCVRJKE-GKAPJAKFSA-N 0.000 description 1
125000006519 CCH3 Chemical group 0.000 description 1
BUAAKYSJGLRXTN-UTLUCORTSA-N CC[C@@H](C)[C@H](NC)C(=O)N1CCC[C@H]1B(O)O Chemical compound CC[C@@H](C)[C@H](NC)C(=O)N1CCC[C@H]1B(O)O BUAAKYSJGLRXTN-UTLUCORTSA-N 0.000 description 1
BUAAKYSJGLRXTN-GUBZILKMSA-N CC[C@H](C)[C@H](NC)C(=O)N1CCC[C@H]1B(O)O Chemical compound CC[C@H](C)[C@H](NC)C(=O)N1CCC[C@H]1B(O)O BUAAKYSJGLRXTN-GUBZILKMSA-N 0.000 description 1
HLDORPKEVOTFJC-BQBZGAKWSA-N CN[C@@H](C)C(=O)N1CCC[C@H]1B(O)O Chemical compound CN[C@@H](C)C(=O)N1CCC[C@H]1B(O)O HLDORPKEVOTFJC-BQBZGAKWSA-N 0.000 description 1
YWIUMSCOSVIFRF-MCIGGMRASA-N COC1CCC(NCC(=O)N2CCC[C@H]2B(O)O)CC1 Chemical compound COC1CCC(NCC(=O)N2CCC[C@H]2B(O)O)CC1 YWIUMSCOSVIFRF-MCIGGMRASA-N 0.000 description 1
LIVLXTKPEWPUOI-GJZGRUSLSA-N CS(=O)(=O)C1=CC=C(S(=O)(=O)N2CCN[C@H](C(=O)N3CCC[C@H]3B(O)O)C2)C=C1.Cl Chemical compound CS(=O)(=O)C1=CC=C(S(=O)(=O)N2CCN[C@H](C(=O)N3CCC[C@H]3B(O)O)C2)C=C1.Cl LIVLXTKPEWPUOI-GJZGRUSLSA-N 0.000 description 1
RPDJWRSLPPZRMB-IUCAKERBSA-N CS(=O)(=O)N1CCN[C@H](C(=O)N2CCC[C@H]2B(O)O)C1.Cl Chemical compound CS(=O)(=O)N1CCN[C@H](C(=O)N2CCC[C@H]2B(O)O)C1.Cl RPDJWRSLPPZRMB-IUCAKERBSA-N 0.000 description 1
SUWZUOSHAVPKLF-YPMHNXCESA-N C[C@@H](NCC(=O)N1CCC[C@H]1B(O)O)C1=CC=CC=C1 Chemical compound C[C@@H](NCC(=O)N1CCC[C@H]1B(O)O)C1=CC=CC=C1 SUWZUOSHAVPKLF-YPMHNXCESA-N 0.000 description 1
JWLRZYBOPBNOCJ-YPMHNXCESA-N C[C@@H](NCC(=O)N1CCC[C@H]1B(O)O)C1CCCCC1 Chemical compound C[C@@H](NCC(=O)N1CCC[C@H]1B(O)O)C1CCCCC1 JWLRZYBOPBNOCJ-YPMHNXCESA-N 0.000 description 1
BHFZEVQXINCZGX-ONGXEEELSA-N C[C@H](NC1CCCC1)C(=O)N1CCC[C@H]1B(O)O Chemical compound C[C@H](NC1CCCC1)C(=O)N1CCC[C@H]1B(O)O BHFZEVQXINCZGX-ONGXEEELSA-N 0.000 description 1
SUWZUOSHAVPKLF-AAEUAGOBSA-N C[C@H](NCC(=O)N1CCC[C@H]1B(O)O)C1=CC=CC=C1 Chemical compound C[C@H](NCC(=O)N1CCC[C@H]1B(O)O)C1=CC=CC=C1 SUWZUOSHAVPKLF-AAEUAGOBSA-N 0.000 description 1
JWLRZYBOPBNOCJ-AAEUAGOBSA-N C[C@H](NCC(=O)N1CCC[C@H]1B(O)O)C1CCCCC1 Chemical compound C[C@H](NCC(=O)N1CCC[C@H]1B(O)O)C1CCCCC1 JWLRZYBOPBNOCJ-AAEUAGOBSA-N 0.000 description 1
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
SYMFOKMPHZCHRA-PYMCNQPYSA-N Cl.O=C(C1CN(S(=O)(=O)C2=C(C(F)(F)F)C=CC=C2)CCN1)N1CCC[C@H]1B(O)O Chemical compound Cl.O=C(C1CN(S(=O)(=O)C2=C(C(F)(F)F)C=CC=C2)CCN1)N1CCC[C@H]1B(O)O SYMFOKMPHZCHRA-PYMCNQPYSA-N 0.000 description 1
MGJDBTICDUXROP-VFXSIBAZSA-N Cl.O=C(C1C[C@@H](NS(=O)(=O)C2=CC=CC=C2)CN1)N1CCC[C@H]1B(O)O Chemical compound Cl.O=C(C1C[C@@H](NS(=O)(=O)C2=CC=CC=C2)CN1)N1CCC[C@H]1B(O)O MGJDBTICDUXROP-VFXSIBAZSA-N 0.000 description 1
MGJDBTICDUXROP-UFPXDFCQSA-N Cl.O=C(C1C[C@H](NS(=O)(=O)C2=CC=CC=C2)CN1)N1CCC[C@H]1B(O)O Chemical compound Cl.O=C(C1C[C@H](NS(=O)(=O)C2=CC=CC=C2)CN1)N1CCC[C@H]1B(O)O MGJDBTICDUXROP-UFPXDFCQSA-N 0.000 description 1
ODVAICXIULRAFI-IHRRRGAJSA-N Cl.O=C(N[C@@H]1CN[C@H](C(=O)N2CCC[C@H]2B(O)O)C1)C1=CC=CC=C1 Chemical compound Cl.O=C(N[C@@H]1CN[C@H](C(=O)N2CCC[C@H]2B(O)O)C1)C1=CC=CC=C1 ODVAICXIULRAFI-IHRRRGAJSA-N 0.000 description 1
RTOCWYQXKMDCDH-IHRRRGAJSA-N Cl.O=C(N[C@@H]1CN[C@H](C(=O)N2CCC[C@H]2B(O)O)C1)C1CCCCC1 Chemical compound Cl.O=C(N[C@@H]1CN[C@H](C(=O)N2CCC[C@H]2B(O)O)C1)C1CCCCC1 RTOCWYQXKMDCDH-IHRRRGAJSA-N 0.000 description 1
ODVAICXIULRAFI-RDBSUJKOSA-N Cl.O=C(N[C@H]1CN[C@H](C(=O)N2CCC[C@H]2B(O)O)C1)C1=CC=CC=C1 Chemical compound Cl.O=C(N[C@H]1CN[C@H](C(=O)N2CCC[C@H]2B(O)O)C1)C1=CC=CC=C1 ODVAICXIULRAFI-RDBSUJKOSA-N 0.000 description 1
RTOCWYQXKMDCDH-RDBSUJKOSA-N Cl.O=C(N[C@H]1CN[C@H](C(=O)N2CCC[C@H]2B(O)O)C1)C1CCCCC1 Chemical compound Cl.O=C(N[C@H]1CN[C@H](C(=O)N2CCC[C@H]2B(O)O)C1)C1CCCCC1 RTOCWYQXKMDCDH-RDBSUJKOSA-N 0.000 description 1
LHOYWVNJUAWCJB-JSGCOSHPSA-N Cl.O=C([C@@H]1CN(S(=O)(=O)C2=CC=C(F)C=C2F)CCN1)N1CCC[C@H]1B(O)O Chemical compound Cl.O=C([C@@H]1CN(S(=O)(=O)C2=CC=C(F)C=C2F)CCN1)N1CCC[C@H]1B(O)O LHOYWVNJUAWCJB-JSGCOSHPSA-N 0.000 description 1
UMTSMYNIWMDKIY-KGLIPLIRSA-N Cl.O=C([C@H]1CN(S(=O)(=O)C2=CC=C(C(F)(F)F)C=C2)CCN1)N1CCC[C@H]1B(O)O Chemical compound Cl.O=C([C@H]1CN(S(=O)(=O)C2=CC=C(C(F)(F)F)C=C2)CCN1)N1CCC[C@H]1B(O)O UMTSMYNIWMDKIY-KGLIPLIRSA-N 0.000 description 1
229940126657 Compound 17 Drugs 0.000 description 1
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
108010016626 Dipeptides Proteins 0.000 description 1
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
101800000224 Glucagon-like peptide 1 Proteins 0.000 description 1
WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
239000004471 Glycine Substances 0.000 description 1
206010022489 Insulin Resistance Diseases 0.000 description 1
XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 1
ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
239000004472 Lysine Substances 0.000 description 1
239000012359 Methanesulfonyl chloride Substances 0.000 description 1
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
230000006181 N-acylation Effects 0.000 description 1
125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
KBHCPIJKJQNHPN-UHFFFAOYSA-N N=NP(O)=O Chemical compound N=NP(O)=O KBHCPIJKJQNHPN-UHFFFAOYSA-N 0.000 description 1
JTJLUBCXQABHOV-ILDUYXDCSA-N NC1CCC(NCC(=O)N2CCC[C@H]2B(O)O)CC1 Chemical compound NC1CCC(NCC(=O)N2CCC[C@H]2B(O)O)CC1 JTJLUBCXQABHOV-ILDUYXDCSA-N 0.000 description 1
JNLKMVJULWUTRF-FXQIFTODSA-N N[C@@H]1CN[C@H](C(=O)N2CCC[C@H]2B(O)O)C1 Chemical compound N[C@@H]1CN[C@H](C(=O)N2CCC[C@H]2B(O)O)C1 JNLKMVJULWUTRF-FXQIFTODSA-N 0.000 description 1
JNLKMVJULWUTRF-CSMHCCOUSA-N N[C@H]1CN[C@H](C(=O)N2CCC[C@H]2B(O)O)C1 Chemical compound N[C@H]1CN[C@H](C(=O)N2CCC[C@H]2B(O)O)C1 JNLKMVJULWUTRF-CSMHCCOUSA-N 0.000 description 1
ARDPHCZHNSIHQN-DFQHDRSWSA-N O=C(C1=CC=CC=C1)N1CCN[C@@H](C(=O)N2CCC[C@H]2B(O)O)C1.O=CO Chemical compound O=C(C1=CC=CC=C1)N1CCN[C@@H](C(=O)N2CCC[C@H]2B(O)O)C1.O=CO ARDPHCZHNSIHQN-DFQHDRSWSA-N 0.000 description 1
QAHSOARMOYUZAD-KZUDCZAMSA-N O=C(C1CN(S(=O)(=O)C2=CC=CC=C2)CCN1)N1CCC[C@H]1B(O)O Chemical compound O=C(C1CN(S(=O)(=O)C2=CC=CC=C2)CCN1)N1CCC[C@H]1B(O)O QAHSOARMOYUZAD-KZUDCZAMSA-N 0.000 description 1
YVPWFUJDUDLFQN-DQPZFDDXSA-N O=C(CNC1CCC(NS(=O)(=O)C2=CC=CC=C2)CC1)N1CCC[C@H]1B(O)O Chemical compound O=C(CNC1CCC(NS(=O)(=O)C2=CC=CC=C2)CC1)N1CCC[C@H]1B(O)O YVPWFUJDUDLFQN-DQPZFDDXSA-N 0.000 description 1
SSYIQAHTLAQLMC-ILDUYXDCSA-N O=C(CNC1CCC(O)CC1)N1CCC[C@H]1B(O)O Chemical compound O=C(CNC1CCC(O)CC1)N1CCC[C@H]1B(O)O SSYIQAHTLAQLMC-ILDUYXDCSA-N 0.000 description 1
LTHRKIRUFUTAAV-ABHNRTSZSA-N O=C(CNC1CCC(OCC2=CC=CC=C2)CC1)N1CCC[C@H]1B(O)O Chemical compound O=C(CNC1CCC(OCC2=CC=CC=C2)CC1)N1CCC[C@H]1B(O)O LTHRKIRUFUTAAV-ABHNRTSZSA-N 0.000 description 1
BYSBLNSCHBIOLU-VIFPVBQESA-N O=C(CNC1CCC1)N1CCC[C@H]1B(O)O Chemical compound O=C(CNC1CCC1)N1CCC[C@H]1B(O)O BYSBLNSCHBIOLU-VIFPVBQESA-N 0.000 description 1
LHBJCBLEWINWEE-NSHDSACASA-N O=C(CNC1CCCCC1)N1CCC[C@H]1B(O)O Chemical compound O=C(CNC1CCCCC1)N1CCC[C@H]1B(O)O LHBJCBLEWINWEE-NSHDSACASA-N 0.000 description 1
IDJLNHSTUOWNMK-LBPRGKRZSA-N O=C(CNCC1=CC=CC=C1)N1CCC[C@H]1B(O)O Chemical compound O=C(CNCC1=CC=CC=C1)N1CCC[C@H]1B(O)O IDJLNHSTUOWNMK-LBPRGKRZSA-N 0.000 description 1
HQKFSPHQZWLWFA-LBPRGKRZSA-N O=C(CNCC1CCCCC1)N1CCC[C@H]1B(O)O Chemical compound O=C(CNCC1CCCCC1)N1CCC[C@H]1B(O)O HQKFSPHQZWLWFA-LBPRGKRZSA-N 0.000 description 1
JLXCZEOFTJWZOO-JCYILVPMSA-N O=C(NC1CCC(NCC(=O)N2CCC[C@H]2B(O)O)CC1)C1=CC=CC=C1 Chemical compound O=C(NC1CCC(NCC(=O)N2CCC[C@H]2B(O)O)CC1)C1=CC=CC=C1 JLXCZEOFTJWZOO-JCYILVPMSA-N 0.000 description 1
VLUWAZAPYUVFKS-YUMQZZPRSA-N O=C([C@@H]1CNCCN1)N1CCC[C@H]1B(O)O Chemical compound O=C([C@@H]1CNCCN1)N1CCC[C@H]1B(O)O VLUWAZAPYUVFKS-YUMQZZPRSA-N 0.000 description 1
102100040918 Pro-glucagon Human genes 0.000 description 1
ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
108010022999 Serine Proteases Proteins 0.000 description 1
102000012479 Serine Proteases Human genes 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
239000004473 Threonine Substances 0.000 description 1
QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
235000011054 acetic acid Nutrition 0.000 description 1
238000005903 acid hydrolysis reaction Methods 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
239000004480 active ingredient Substances 0.000 description 1
125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 description 1
239000000443 aerosol Substances 0.000 description 1
230000001476 alcoholic effect Effects 0.000 description 1
150000001298 alcohols Chemical class 0.000 description 1
150000001299 aldehydes Chemical class 0.000 description 1
125000004450 alkenylene group Chemical group 0.000 description 1
125000004183 alkoxy alkyl group Chemical group 0.000 description 1
125000004419 alkynylene group Chemical group 0.000 description 1
150000001371 alpha-amino acids Chemical class 0.000 description 1
BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
150000001408 amides Chemical class 0.000 description 1
150000001412 amines Chemical class 0.000 description 1
239000008346 aqueous phase Substances 0.000 description 1
ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
125000003435 aroyl group Chemical group 0.000 description 1
125000005018 aryl alkenyl group Chemical group 0.000 description 1
125000001691 aryl alkyl amino group Chemical group 0.000 description 1
125000004659 aryl alkyl thio group Chemical group 0.000 description 1
125000005015 aryl alkynyl group Chemical group 0.000 description 1
125000005110 aryl thio group Chemical group 0.000 description 1
125000004104 aryloxy group Chemical group 0.000 description 1
235000009582 asparagine Nutrition 0.000 description 1
229960001230 asparagine Drugs 0.000 description 1
235000003704 aspartic acid Nutrition 0.000 description 1
239000012298 atmosphere Substances 0.000 description 1
125000003828 azulenyl group Chemical group 0.000 description 1
235000010233 benzoic acid Nutrition 0.000 description 1
OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
125000002619 bicyclic group Chemical group 0.000 description 1
230000037396 body weight Effects 0.000 description 1
239000012267 brine Substances 0.000 description 1
125000001246 bromo group Chemical group Br* 0.000 description 1
OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 description 1
KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
239000002775 capsule Substances 0.000 description 1
125000002837 carbocyclic group Chemical group 0.000 description 1
230000015556 catabolic process Effects 0.000 description 1
125000001309 chloro group Chemical group Cl* 0.000 description 1
235000015165 citric acid Nutrition 0.000 description 1
229940125758 compound 15 Drugs 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
125000006254 cycloalkyl carbonyl group Chemical group 0.000 description 1
125000002993 cycloalkylene group Chemical group 0.000 description 1
125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
235000018417 cysteine Nutrition 0.000 description 1
XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
230000003247 decreasing effect Effects 0.000 description 1
238000006731 degradation reaction Methods 0.000 description 1
206010012601 diabetes mellitus Diseases 0.000 description 1
HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
XEBCWEDRGPSHQH-UHFFFAOYSA-N diisopropyl tartrate Chemical compound CC(C)OC(=O)C(O)C(O)C(=O)OC(C)C XEBCWEDRGPSHQH-UHFFFAOYSA-N 0.000 description 1
150000002009 diols Chemical class 0.000 description 1
239000002552 dosage form Substances 0.000 description 1
239000003937 drug carrier Substances 0.000 description 1
239000003480 eluent Substances 0.000 description 1
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
239000000284 extract Substances 0.000 description 1
239000000706 filtrate Substances 0.000 description 1
238000001914 filtration Methods 0.000 description 1
125000001153 fluoro group Chemical group F* 0.000 description 1
235000019253 formic acid Nutrition 0.000 description 1
239000012458 free base Substances 0.000 description 1
238000004108 freeze drying Methods 0.000 description 1
239000001530 fumaric acid Substances 0.000 description 1
235000011087 fumaric acid Nutrition 0.000 description 1
230000002496 gastric effect Effects 0.000 description 1
230000004153 glucose metabolism Effects 0.000 description 1
235000013922 glutamic acid Nutrition 0.000 description 1
239000004220 glutamic acid Substances 0.000 description 1
ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
235000004554 glutamine Nutrition 0.000 description 1
HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
235000014304 histidine Nutrition 0.000 description 1
238000001727 in vivo Methods 0.000 description 1
125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
229910052500 inorganic mineral Chemical class 0.000 description 1
230000003914 insulin secretion Effects 0.000 description 1
230000002473 insulinotropic effect Effects 0.000 description 1
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
125000002346 iodo group Chemical group I* 0.000 description 1
238000002955 isolation Methods 0.000 description 1
AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
229960000310 isoleucine Drugs 0.000 description 1
125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
150000002576 ketones Chemical class 0.000 description 1
239000004310 lactic acid Substances 0.000 description 1
235000014655 lactic acid Nutrition 0.000 description 1
229960003136 leucine Drugs 0.000 description 1
230000000670 limiting effect Effects 0.000 description 1
239000007788 liquid Substances 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
239000001630 malic acid Substances 0.000 description 1
235000011090 malic acid Nutrition 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
238000004949 mass spectrometry Methods 0.000 description 1
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
229930182817 methionine Natural products 0.000 description 1
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
239000011707 mineral Chemical class 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
125000002950 monocyclic group Chemical group 0.000 description 1
239000012452 mother liquor Substances 0.000 description 1
125000004370 n-butenyl group Chemical group [H]\C([H])=C(/[H])C([H])([H])C([H])([H])* 0.000 description 1
239000012299 nitrogen atmosphere Substances 0.000 description 1
239000012044 organic layer Substances 0.000 description 1
239000012074 organic phase Substances 0.000 description 1
125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
235000006408 oxalic acid Nutrition 0.000 description 1
125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 description 1
235000011007 phosphoric acid Nutrition 0.000 description 1
150000003016 phosphoric acids Chemical class 0.000 description 1
125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
230000036470 plasma concentration Effects 0.000 description 1
125000003367 polycyclic group Chemical group 0.000 description 1
229920000166 polytrimethylene carbonate Polymers 0.000 description 1
229910000027 potassium carbonate Inorganic materials 0.000 description 1
238000002360 preparation method Methods 0.000 description 1
GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
239000000047 product Substances 0.000 description 1
235000019260 propionic acid Nutrition 0.000 description 1
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
235000018102 proteins Nutrition 0.000 description 1
102000004169 proteins and genes Human genes 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
229940107700 pyruvic acid Drugs 0.000 description 1
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
230000001105 regulatory effect Effects 0.000 description 1
229960004889 salicylic acid Drugs 0.000 description 1
235000004400 serine Nutrition 0.000 description 1
239000000377 silicon dioxide Substances 0.000 description 1
125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
239000000126 substance Substances 0.000 description 1
239000000758 substrate Substances 0.000 description 1
125000004434 sulfur atom Chemical group 0.000 description 1
235000011149 sulphuric acid Nutrition 0.000 description 1
239000000725 suspension Substances 0.000 description 1
239000012622 synthetic inhibitor Substances 0.000 description 1
239000003826 tablet Substances 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
LPQZERIRKRYGGM-UHFFFAOYSA-N tert-butyl pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1 LPQZERIRKRYGGM-UHFFFAOYSA-N 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
125000004001 thioalkyl group Chemical group 0.000 description 1
235000008521 threonine Nutrition 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
125000000165 tricyclic carbocycle group Chemical group 0.000 description 1
125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
239000004474 valine Substances 0.000 description 1
229960004295 valine Drugs 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

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- 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
- A61P27/02—Ophthalmic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table

Definitions

the present invention relates to boronic acid compounds and their use as inhibitors of post-proline/alanine cleaving amino-dipeptidases.
the invention also relates to methods of employing such inhibitors to treat DPP-related diseases.
the invention has applications in the medicinal chemical, pharmacological, and medical arts.
DPP Dipeptidyl peptidases
IGF impaired fasting glucose
DPP-IV has been implicated in the control of glucose metabolism because its substrates include the insulinotropic hormones, glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), which are inactivated by removal of their two N-terminal amino acids.
GLP-1 glucagon like peptide-1
GIP gastric inhibitory peptide
the present invention provides DPP inhibitors that are effective in treating conditions that may be regulated or normalized by inhibition of DPPs. More particularly, the invention relates to boronic acid-containing heterocycles and their derivatives that inhibit DPP-IV.
the present invention provides compounds of formula I: including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein:
n 1 to 3;
X is CH 2 ; S; O; CF 2 or C(CH 3 ) 2 ;
Z is H; halogen; hydroxyl; (C 1-6 )alkoxy; (C 1-12 )alkyl; (C 3-12 )cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ;
R 7 is halogen; (C 1-10 )alkyl; (C 1-10 )alkoxy; (C 1-10 )alkylamino; (C 1-10 ) dialkylamino; benzyl; benzyloxy; hydroxyl(C 1-6 )alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyamino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;
one of the bonds in the ring containing X is a double bond
R 1 and R 2 independently or together are hydrogen; a boronic acid protecting group; or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; and
CR i R ii may be present or absent
R 3 , R 4 and R 5 are selected from (cc), (dd) or (ee):
Compounds of formula I also include those wherein X is CH 2 ; the ring containing X is saturated; CR i R ii is absent, R 1 , R 2 are hydrogen; and R 3 , R 4 and R 5 have the subgeneric designations given by foregoing cause (cc)b).
R 5 is a (C 1-12 )alkyl or (C 3-12 )cycloalkyl, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, 1-cyclohexylethyl, or adamantyl.
X is CH 2 ; the ring containing X is saturated; CR i R ii is absent, R 1 , R 2 are hydrogen; and R 3 , R 4 and R 5 have the subgeneric designation given by foregoing clause (cc)d).
X is CH 2 ; the ring containing X is saturated; CR i R ii is absent, R 1 , R 2 are hydrogen; and R 3 , R 4 and R 5 have the subgeneric designation given by foregoing clause (cc)e).
X is CH 2 ; the ring containing X is saturated; CR i R ii is absent; R 1 , R 2 , are hydrogen; and R 3 , R 4 and R 5 have the subgeneric designation given by foregoing clause (cc)f).
X is CH 2 ; the ring containing X is saturated; CR i R ii is absent, R 1 , R 2 are hydrogen; R 3 , R 4 and R 5 have the subgeneric designation given by foregoing clause (cc)g.
Compounds of formula I include those wherein X is CH 2 ; the ring containing X is saturated; CR i R ii is absent, R 1 , R 2 are hydrogen; R 3 , R 4 and R 5 have the subgeneric designation given by foregoing clause (cc)h.
X is CH 2 ; the ring containing X is saturated; CR i R ii is absent, R 1 , R 2 are hydrogen; R 3 , R 4 and R 5 have the subgeneric designation given by foregoing clause (cc)j.
X is CH 2 ; the ring containing X is saturated; CR i R ii is absent, R 1 , R 2 are hydrogen; R 3 , R 4 and R 5 have the subgeneric designation given by foregoing clause (cc)k.
a preferred subgeneric formulation of the invention when CR i R ii of Formula I is absent includes compounds of Formula II having the following linear alkyl pyrrolidine formula:
R 3 , R 4 and R 5 are defined as given for groups (cc), (dd) and (ee) as given above for Formula I, and R 1 and R 2 independently or together are —OH, —O ⁇ M + wherein M + is a cation, a hydroxyl bearing a boronic acid protecting group, or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids.
R 5 may be alkyl, cycloalkyl, optionally mono- or independently plurisubstituted as described above.
R 3 and R 4 are both hydrogen.
n 1
R 5 is a group of the formula: where R 21 is hydrogen; (C 1-8 )alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R 2 ; each t is independently 0 to 6; and u is 0 to 3.
R 5 has formula:
Another preferred subgeneric formulation of Formula I when CR i R ii is present includes compounds of formula III:
R 1 and R 2 independently or together are —OH, —O ⁇ M + wherein M + is a cation, a hydroxyl bearing a boronic acid protecting group, or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; and, R 3 , R 4 , R 5 , R i and R ii are the same as are designated for groups (aa) and (bb) of foregoing Formula I.
the invention also relates to methods for preparing the above-described compounds.
the compounds of formula II and III are prepared by reacting a cyclic amine (e.g., pyrrolidine or piperidine), suitably protected with a standard protecting group such as Boc-, Fmoc-, CBz- or the like, with sec-BuLi/TMEDA followed by B(OCH 3 ) 3 , to provide the methyl boronic ester derivative.
Acid hydrolysis of the methyl esters with 2N HCl provides the boronic acid intermediate 1.
Reaction of 1 with (+) pinanediol, deprotection of the amino protecting group, and recrystallization provides the pinanediol ester 2 as an isomerically pure salt.
Intermediate 2 is useful for the synthesis of both series A and series B compounds.
N-acylation of 2 with chloroacetyl chloride provides the ⁇ -chloro amide 3.
Treatment of 3 with Na 2 CO 3 and cyclopentylamine, and hydrolysis of the pinanediol boronic ester provides a compound of formula I, 4.
coupling of intermediate 2 with N-Boc-5-phenyl-Pro using EDAC/HOBT provides amide 5.
Deprotection of the amino group and hydrolysis of the boronic esters provides a compound of formula II, 6.
This synthetic scheme is adaptable for the preparation of all the compounds of the invention, by reacting the appropriate cyclic amine (pyrrollidine, piperidine, and other cyclic amines) with sec-BuLi/B(OCH 3 ) 3 , and coupling the boronic ester intermediate with the desired acid chloride or acid via routes A or B, respectively.
the appropriate cyclic amine may either be commercially available or is easily synthesized through known procedures, for example, those procedures disclosed in U.S. Pat. Nos.
Another aspect of the invention provides a process for preparing the compounds of formula I:
R 1 , R 2 , R 3 , R 4 , R i , R ii , n, X, and Z are as defined herein. Preferred embodiments are those where R 3 and R 4 are hydrogen, L is halogen, including but not limited to Cl, and R 5 —NH 2 is cyclopentylamine.
the compounds of the invention may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids.
salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like.
Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like.
Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are known to the skilled artisan.
the acid addition salts may be obtained as the direct products of compound synthesis.
the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
the compounds of this invention may form solvates with standard low molecular weight solvents, including water to yield hydrates, using methods known to the skilled artisan.
compositions containing a compound of the invention of the invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19th Ed., 1995.
the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
the compounds of the invention are effective for DPP-IV inhibition over a wide dosage range.
dosages from about 0.05 to about 1000 mg, preferably from about 1 to about 500 mg, per day may be used.
a typical dosage is about 10 mg to about 500 mg per day.
the exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
the compounds of the invention are dispensed in unit dosage form comprising from about 0.05 to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
substantially pure in relation to compounds of the invention such as, but not limited to, those of formula VA and VB, it is meant that one isomer or the other, including all enantiomers, diastereoisomers, solvates, hydrates, and pharmaceutically acceptable salts thereof, represents at least 90% by weight of the composition. In some embodiments one isomer represents at least 98% by weight of the composition.
boronic acid protecting group refers to a moiety employed to block or protect the boronic acid functionality while reactions involving other functional sites of the compound are carried out.
the boronic acid OH groups are protected as boronic acid esters derived from alchohols such as (+)-pinanediol; pinacol; 1,2-dicyclohexyl-ethanediol; 1,2-ethanediol; 2,2-diethanolamine; 1,3-propanediol; 2,3-butanediol, diisopropyl tartrate; 1,4-butanediol; diisopropylethanediol; (S,S,)-5,6-decanediol; 1,1,2-triphenyl-1,2-ethanediol; (2R,3R)-1,4-dimethyoxy-1,1,4,4-tetraphenyl-2,3-butanediol;
alcohols having only a single hydroxy group such as methanol, form diesters having the structure —B(OR) 2 in which R is the organic moiety from the alcohol (e.g., —B(OMe) 2 ).
diols such as pinacol form cyclic boronic diesters with —B(OH) 2 in which the organic moiety (e.g., —C(Me) 2 —C(Me) 2 —)is attached to both oxygens.
N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T. W. Greene, P. G. Wuts, “Protective Groups In Organic Synthesis, 3 rd Ed.” (John Wiley & Sons, New York (1999)), which is hereby incorporated by reference.
N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzy
N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
alkyl or “(C 1-12 )alkyl”, alone or in combination, refers to linear or branched chains and may include cyclic portions, having from 1-12 (the use of 1-12 herein implies each of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, such as but not limited to, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, 2,2-dimethylpropyl, and the like.
(C 1-10 )alkyl refers to linear or branched chains and may include cyclic portions, having from 1-10, 1-8, or 1-6 carbon atoms, respectively, such as but not limited to, e.g.
(C 1-4 )alkyl refers to linear or branched chains and may include cyclic portions, having from 1-4 carbon atoms, such as but not limited to, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
(C 2-12 )alkenyl and “(C 2-10 )alkenyl”, alone or in combination, refers to a straight or branched, unsaturated hydrocarbon chain having from 2-12 or 2-10 carbon atoms, respectively, and at least one double bond, such as, but not limited to, vinyl, 1-propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl, n-hexenyl, and the like.
(C 3-12 )cycloalkyl and “(C 3-10 )cycloalkyl” refers to one or more saturated cyclic hydrocarbons having from 3-12 or 3-10 carbon atoms, respectively, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
(C 5-10 )cycloalkenyl refers to a radical of one or more cyclic hydrocarbon having at least one double bond having from 5-10 carbon atoms such as, but not limited to, cyclopentenyl, cyclohexenyl, and the like.
cycloalkylene refers to a “cycloalkyl” group which has single bonds for attachment at two different carbon atoms.
(C 1-6 )alkylaminocarbonyl and “di-(C 1-6 )alkylaminocarbonyl” refer to straight or branched chain hydrocarbon groups having 1 to 6 carbon atoms connected to NC( ⁇ O).
exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like.
(C 1-6 )alkylcarbonyl refers to linear or branched chain and cyclic hydrocarbon groups having 1 to 6 carbon atoms connected to C( ⁇ O).
exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like.
(C 3-8 )cycloalkylcarbonyl refers to cyclic hydrocarbon groups having 3 to 8 carbon atoms connected to C( ⁇ O).
exemplary cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
(C 1-10 )alkoxy refers to “O” connected to alkyl, having linear or branched chains and may include cyclic portions, having from 1-10, 1-8 or 1-6 carbon atoms, respectively.
linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like.
branched alkoxy include but are not limited to isoprpoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like.
cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
aryloxy refers to an aryl group bonded to O.
alkanoyl alone or as part of another group, refers to alkyl linked to a carbonyl group.
alkylene refers to alkyl groups which have single bonds for attachment at two different carbon atoms.
alkenylene refers to alkenyl groups which have single bonds for attachement at two different carbon atoms.
alkynylene refers to alkynyl groups which have single bonds for attachement at two different carbon atoms.
aryl refers to monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring systems having 6 to 14 carbon atoms in the ring portion.
aryl groups include but are not limited to phenyl, naphthyl, biphenyl, anthracenyl, azulenyl, and the like.
Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems including 1,2,3,4-tetrahydro-naphthyl, indanyl and the like.
aryl examples include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), and the like.
arylalkenyl and “arylalkynyl” alone or as part of another group refer to alkenyl and alkynyl groups as described above having an aryl substituent.
halogen and “halo” refers to chloro, fluoro, bromo or iodo.
alkylamino alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.
substituted amino refers to amino substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituents may be further substituted with any of the groups as set out above.
alkylthio alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.
acyl by itself or part of another group refers to an organic radical linked to a carbonyl group; examples of acyl groups include any of the groups attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl, and the like.
Naturally occurring ⁇ -amino acid sidechain refers to the moieties (sidechains) attached to the ⁇ -amino carbon in the following naturally occurring ⁇ -amino acids: glycine, alanine, 2-aminobutyric acid, valine, leucine, isoleucine, tert-leucine, serine, threonine, cysteine, asparagine, aspartic acid, glutamine, glutamic acid, phenylalanine, histidine, tryptophan, tyrosine, phenylglycine, lysine, methionine, and arginine.
the side chains of these amino acids are well known in the art.
the ⁇ -amino acid sidechain of alanine is methyl
the sidechain of phenylalanine is benzyl
the sidechain of tert-leucine is tert-butyl.
polyhaloalkyl refers to an “alkyl” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF 3 CH 2 , CF 3 or CF 3 CF 2 CH 2 .
polyhaloalkoxy refers to an “alkoxy” or “alkyloxy” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF 3 CH 2 O, CF 3 O or CF 3 CF 2 CH 2 O.
polycyclic and “polycycle” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, aryls, heteroaryls and/or cycloheteroalkyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are “fused rings.” Fused rings that are joined through nonadjacent atoms, are also known as “bridged” rings.
Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, trifluoromethyl, cyano, or the like.
substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, si
a flame dried round bottom flask equipped with a magnetic stir bar was charged with N-Boc-pyrrolidine (20 g, 117 mmol, 1 eq) and dry THF (60 mL) under a nitrogen atmosphere.
the clear colorless solution was cooled to ⁇ 78° C. and a solution of s-BuLi (100 mL of a 1.4 M solution in cyclohexane, 140 mmol) was added slowly over a 30 minute period.
the light orange colored solution was stirred at ⁇ 78° C. for 3 hours followed by treatment with B(OMe) 3 (39 mL, 350 mmol) after which the cooling bath was removed and the clear colorless solution slowly warmed to 0° C.
the reaction Upon reaching 0° C., the reaction was quenched with a small amount of water ( ⁇ 2 mL), allowed to warm to room temp then extracted into 2 N NaOH (250 mL) and backwashed with additional EtOAc (150 mL). The aqueous phase was acidified to pH 3 by the addition of 2 N HCl and then extracted with EtOAc (3 ⁇ 120 mL). The organic extracts were combined and dried over Na 2 SO 4 and concentrated to produce the free boronic acid (22.08 g, 103 mmol) as a sticky white solid in 88% yield.
Crystallization and isolation of the desired isomer was performed by dissolving the HCl salt in a minimal amount of dichloromethane (250 mL) with gentle heating to facilitate a homogenous solution followed by continuous stirring for 8 hours to yield a fluffy white precipitate that was collected by vacuum filtration, dried and then dissolved in minimal 2-propanol ( ⁇ 200 mL) with gentle heating until homogenous. The alcoholic solution was stirred over night and the resulting white precipitate was collected by vacuum filtration affording isomerically pure 1 as a white solid. (7.0 g, 27 mmol, 23% yield).
Step 1 (2R)-1-(2-Chloroacetyl)-boroPro-(1S,2S,3R,5S)-pinanediol ester (3A).
Step 2 (2R)-1-(2-Cyclopentylamino-acetyl)-boroPro-(1S,2S,3R,5S)-pinanediol ester (3B).
Step 1 N-Boc-5-phenylPro-(2R)-boroPro-(1S,2S,3R,5S)-pinanediol ester (5):
Step 2 1-(5R-Phenyl-pyrrolidine-2S-carbonyl)-pyrrolidine-(2R)-boronic acid (6):
aqueous layer was separated and applied to a Dowex 50-X2-100 ion exchange column (H + form) and eluted with water until the eluate was neutral. Elution was continued with aqueous ammonium hydroxide (2 wt %) and the appropriate fractions were lyophilized to afford the free boronic acid B1 (76 mg, 0.26 mmol) as an amorphous white solid.
Step 1 (2R)-1-[(2S,4S)-1-tert-Butoxycarbonyl-4-benzyloxycarbonylamino-pyrrolidine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (13)

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Public Health (AREA)
Animal Behavior & Ethology (AREA)
Veterinary Medicine (AREA)
Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Diabetes (AREA)
Immunology (AREA)
Hematology (AREA)
Endocrinology (AREA)
Physical Education & Sports Medicine (AREA)
Obesity (AREA)
Rheumatology (AREA)
Neurology (AREA)
Urology & Nephrology (AREA)
Orthopedic Medicine & Surgery (AREA)
Biomedical Technology (AREA)
Neurosurgery (AREA)
Heart & Thoracic Surgery (AREA)
Emergency Medicine (AREA)
Cardiology (AREA)
Child & Adolescent Psychology (AREA)
Hospice & Palliative Care (AREA)
Psychiatry (AREA)
Ophthalmology & Optometry (AREA)
Pain & Pain Management (AREA)
Oncology (AREA)
Transplantation (AREA)
Vascular Medicine (AREA)
Reproductive Health (AREA)
Epidemiology (AREA)

Abstract

Dipeptidyl peptidase IV (DPP-IV)-inhibiting compounds are provided that have formula I:

wherein n is 1 to 3; X is CH₂; S; O; CF₂or C(CH₃)₂; Z is H; halogen; hydroxyl; (C_1-6)alkoxy; (C_1-12)alkyl; (C_3-12)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁷; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; and CRⁱRⁱⁱ, R¹, R², R³, R⁴and R⁵are as described herein.

Description

This application is a Divisional application under 37 C.F.R. 1.53(b) of U.S. application Ser. No. 10/514,575, filed Nov. 15, 2004, which is a National Stage Filing under 35 U.S.C. 371 of International Application No. PCT/US2004/037820, and published on May 26, 2005 as WO 2005/047297, which claims priority to U.S. Provisional Application Ser. No. 60/519,566, filed Nov. 12, 2003, which is related to U.S. Provisional Application Ser. No. 60/557,011, filed Mar. 25, 2004, and to U.S. Provisional Application Ser. No. 60/592,972, filed Jul. 30, 2004, all of which applications and publication are incorporated herein by reference.
The present invention relates to boronic acid compounds and their use as inhibitors of post-proline/alanine cleaving amino-dipeptidases. The invention also relates to methods of employing such inhibitors to treat DPP-related diseases. Thus, the invention has applications in the medicinal chemical, pharmacological, and medical arts.
Dipeptidyl peptidases (DPP) are a family of serine protease that belongs to a group of post-proline/alanine cleaving amino-dipeptidases. While the physiological role of DPPs have not been fully elucidated, they have been implicated in a number of disease states. For example, DPP-IV catalyzes the release of an N-terminal dipeptide only from proteins with N-terminal penultimate proline or alanine and DPP-IV is believed to play an important role in impaired fasting glucose (IFG) and diabetes. In particular, DPP-IV has been implicated in the control of glucose metabolism because its substrates include the insulinotropic hormones, glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), which are inactivated by removal of their two N-terminal amino acids.
In vivo administration of synthetic inhibitors of DPP-IV prevents N-terminal degradation of GLP-1 and GIP, resulting in higher plasma concentrations of these hormones, increased insulin secretion and, therefore, improved glucose tolerance. Therefore, such inhibitors have been proposed for the treatment of patients with type II diabetes, a disease characterized by decreased glucose tolerance and insulin resistance.
Accordingly, a need exists for compounds that are useful for inhibiting DPPs such as DPP-IV.
The present invention provides DPP inhibitors that are effective in treating conditions that may be regulated or normalized by inhibition of DPPs. More particularly, the invention relates to boronic acid-containing heterocycles and their derivatives that inhibit DPP-IV.
The present invention provides compounds of formula I:

including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein:
n is 1 to 3;
X is CH₂; S; O; CF₂or C(CH₃)₂;
Z is H; halogen; hydroxyl; (C_1-6)alkoxy; (C_1-12)alkyl; (C_3-12)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁷;
R⁷is halogen; (C_1-10)alkyl; (C_1-10)alkoxy; (C_1-10)alkylamino; (C_1-10) dialkylamino; benzyl; benzyloxy; hydroxyl(C_1-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyamino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;
optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and
optionally, one of the bonds in the ring containing X is a double bond;
R¹and R²independently or together are hydrogen; a boronic acid protecting group; or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; and
CRⁱRⁱⁱmay be present or absent, and
when CRⁱRⁱⁱis present, then

- Rⁱ, Rⁱⁱ, R³, R⁴and R⁵are selected from (aa) or (bb):
- (aa) Rⁱ, Rⁱⁱ, R³and R⁴are hydrogen; and R⁵is hydrogen, (C_1-12)alkyl or (C_3-12) cycloalkyl;
- (bb) Rⁱ, Rⁱⁱ, R³, R⁴and R⁵are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl,

or alternatively,
when CRⁱRⁱⁱis absent, then R³, R⁴and R⁵are selected from (cc), (dd) or (ee):

- (cc) R³and R⁴are hydrogen; and
  - R⁵is
    - a) hydrogen, provided that R⁵is not hydrogen when n is 1, X is CH₂, and Z is H;
    - b) (C_1-12)alkyl; (C_2-12)alkenyl; (C_2-12)alkynyl; (C_3-12)cycloalkyl; or (C_3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R⁶, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
    - R⁶is (C_1-6)alkyl; (C_1-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C_1-6)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁷; amino, where the amino group is optionally mono- or independently plurisubstituted with R⁸; —SOR⁸; —SO₂R⁸; —COR⁸; —CO₂R⁸, —CONHR⁸; —CON(R⁸)₂; —OR⁸; or —S—R⁸;
    - R⁷is halogen; (C_1-10)alkyl; (C_1-10)alkoxy; (C_1-10)alkylamino; (C_1-10) dialkylamino; benzyl; benzyloxy; hydroxyl(C_1-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyamino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;
    - R⁸is (C_1-10)alkyl; (C_2-10)alkenyl; (C_2-10)alkynyl; (C_3-10)cycloalkyl; (C_5-10)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁷;
    - c) aryl optionally fused to a (C_3-10)cycloalkyl; or heteroaryl optionally fused to a (C_3-10)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁷;
    - d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH₂)_jadamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH₂)_jadamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C_1-8)alkyl, (C_1-8)alkoxy, (C_1-8)alkanoyloxy, or R⁹R¹⁰N—CO—O—, where R⁹and R¹⁰are independently (C_1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C_1-8)alkyl, (C_1-8)alkoxy, halogen, or trifluoromethyl, or R⁹and R¹⁰together are (C_3-6)alkylene;
    - e) R¹¹(CH₂)_p— where R¹¹is 2-oxopyrrolidinyl; (C_1-6)alkoxy; phenyl; phenoxy; (C_1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (C_1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R¹²; where the phenoxy group is optionally mono- or independently disubstituted with (C_1-4)alkyl, (C_1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono- or independently plurisubstituted with (C_1-8)alkyl; and p is 0 to 3;
    - R¹²is halogen; trifluoromethyl; cyano; nitro; (C_1-6)alkyl; (C_1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C_1-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁷;
    - f) (R¹³)₂CH(CH₂)_q—, where R¹³is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R¹²; and q is 0 to 3;
    - g) a group of the formula:
      
      where R¹⁴and R¹⁵are independently hydrogen; (C_1-8)alkyl; (C_1-6)alkylcarbonyl; (C_3-12)cycloalkyl ring; (C_3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C_1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R¹²; or R¹⁴and R¹⁵together form a (C_3-12)cycloalkyl ring; and r is 2 to 6;
- h) a group of the formula:
  
  where R¹⁶and R¹⁷are each independently hydrogen; (C_1-8)alkyl; (C_1-6)alkylcarbonyl; di-(C_1-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R¹²; or R¹⁶and R¹⁷together form a (C_3-12)cycloalkyl ring; and s is 1 to 6;
- i) a group of the formula:
  
  wherein R¹⁸and R¹⁹are independently hydrogen; (C_1-8)alkyl; (C_1-6)alkylcarbonyl; di-(C_1-6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R²; or wherein R¹⁸and R¹⁹together with the N form an (N, C_3-12) heterocycloalkyl ring containing the nitrogen atom; and each t is independently 0 to 6; and u is 0 to 3;
- j) a group of the formula:
  (phenyl-CH₂—C(CH₃)₂—),
  where the phenyl group is optionally mono- or independently plurisubstituted with R¹²;
  ; or
- k) a group of the formula:
  
  where R²¹is hydrogen; (C_1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R¹²; each t is independently 0 to 6; and u is 0 to 3; and,
  wherein a bond containing a wavy line signifies a point of attachment;
- (dd) R³, R⁴and R⁵are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl or aralkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, arylamino, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl, provided that when n is 1, X is CH₂, the ring containing X is saturated, and Z, R³and R⁵are H, R⁴is not a side chain of a naturally occurring α-amino acid, and provided that when n is 1, X is CH₂, the ring containing X is saturated, and Z and R⁵are H, R³and R⁴are not both methyl; or,
- (ee) R³is hydrogen, and R⁴and R⁵together with the atoms to which they are attached form a 4 to 8 membered heterocyclic ring of 3 to 7 carbons and 1 nitrogen,
  wherein the heterocyclic ring carbon atoms other than the carbon connected to N and R⁴have the formula —(CR²²R²³)_m— wherein m is 2 to 6, and R²²and R²³are independently hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, halo, amino, substituted amino, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, or alkylaminocarbonylamino; and, optionally the heterocyclic ring has an aryl, heteroaryl or a 3 to 7 membered cycloalkyl ring fused thereto, provided that when n is 1, X is CH₂, the ring containing X is saturated, and Z and R³are H, then R⁴and R⁵together are not —(CH₂)₂— or —(CH₂)₃—.

Compounds of formula I also include those wherein X is CH₂; the ring containing X is saturated; CRⁱRⁱⁱis absent, R¹, R²are hydrogen; and R³, R⁴and R⁵have the subgeneric designations given by foregoing cause (cc)b). In some such embodiments, R⁵is a (C_1-12)alkyl or (C_3-12)cycloalkyl, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, 1-cyclohexylethyl, or adamantyl.
In some embodiments of compounds of formula I, X is CH₂; the ring containing X is saturated; CRⁱRⁱⁱis absent, R¹, R²are hydrogen; and R³, R⁴and R⁵have the subgeneric designation given by foregoing clause (cc)d).
In other embodiments of compounds of formula I, X is CH₂; the ring containing X is saturated; CRⁱRⁱⁱis absent, R¹, R²are hydrogen; and R³, R⁴and R⁵have the subgeneric designation given by foregoing clause (cc)e).
In certain embodiments of compounds of formula I, X is CH₂; the ring containing X is saturated; CRⁱRⁱⁱis absent; R¹, R², are hydrogen; and R³, R⁴and R⁵have the subgeneric designation given by foregoing clause (cc)f).
In some embodiments of compounds of formula I, X is CH₂; the ring containing X is saturated; CRⁱRⁱⁱis absent, R¹, R²are hydrogen; R³, R⁴and R⁵have the subgeneric designation given by foregoing clause (cc)g.
Compounds of formula I include those wherein X is CH₂; the ring containing X is saturated; CRⁱRⁱⁱis absent, R¹, R²are hydrogen; R³, R⁴and R⁵have the subgeneric designation given by foregoing clause (cc)h.
Compounds of formula I wherein X is CH₂; the ring containing X is saturated; CRⁱRⁱⁱis absent, R¹, R²are hydrogen; R³, R⁴and R⁵have the subgeneric designation given by foregoing clause (cc)i).
In some embodiments of compounds of formula I, X is CH₂; the ring containing X is saturated; CRⁱRⁱⁱis absent, R¹, R²are hydrogen; R³, R⁴and R⁵have the subgeneric designation given by foregoing clause (cc)j.
In some embodiments of compounds of formula I, X is CH₂; the ring containing X is saturated; CRⁱRⁱⁱis absent, R¹, R²are hydrogen; R³, R⁴and R⁵have the subgeneric designation given by foregoing clause (cc)k.
A preferred subgeneric formulation of the invention when CRⁱRⁱⁱof Formula I is absent includes compounds of Formula II having the following linear alkyl pyrrolidine formula:
In embodiments of Formula II, R³, R⁴and R⁵are defined as given for groups (cc), (dd) and (ee) as given above for Formula I, and R¹and R²independently or together are —OH, —O⁻ M⁺ wherein M⁺ is a cation, a hydroxyl bearing a boronic acid protecting group, or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids.
In such embodiments of Formula II, R⁵may be alkyl, cycloalkyl, optionally mono- or independently plurisubstituted as described above.
In some embodiments of compounds of Formula II, R³and R⁴are both hydrogen.
In other embodiments of Formula II, n is 1.
Included also are compounds of formula II wherein X is CH₂; the ring containing X is saturated; R¹, R², R³and R⁴are hydrogen; and R⁵is a group of the formula:

where R²¹is hydrogen; (C_1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R²; each t is independently 0 to 6; and u is 0 to 3. In some such embodiments, R⁵has formula:
Another preferred subgeneric formulation of Formula I when CRⁱRⁱⁱis present includes compounds of formula III:
wherein R¹and R²independently or together are —OH, —O⁻ M⁺ wherein M⁺ is a cation, a hydroxyl bearing a boronic acid protecting group, or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; and, R³, R⁴, R⁵, Rⁱand Rⁱⁱare the same as are designated for groups (aa) and (bb) of foregoing Formula I.
The invention also relates to methods for preparing the above-described compounds. As shown below and as described in the EXAMPLES, the compounds of formula II and III are prepared by reacting a cyclic amine (e.g., pyrrolidine or piperidine), suitably protected with a standard protecting group such as Boc-, Fmoc-, CBz- or the like, with sec-BuLi/TMEDA followed by B(OCH₃)₃, to provide the methyl boronic ester derivative. Acid hydrolysis of the methyl esters with 2N HCl provides the boronic acid intermediate 1. Reaction of 1 with (+) pinanediol, deprotection of the amino protecting group, and recrystallization provides the pinanediol ester 2 as an isomerically pure salt.
Intermediate 2 is useful for the synthesis of both series A and series B compounds. For example, N-acylation of 2 with chloroacetyl chloride provides the α-chloro amide 3. Treatment of 3 with Na₂CO₃and cyclopentylamine, and hydrolysis of the pinanediol boronic ester, provides a compound of formula I, 4. Alternatively, coupling of intermediate 2 with N-Boc-5-phenyl-Pro using EDAC/HOBT provides amide 5. Deprotection of the amino group and hydrolysis of the boronic esters, provides a compound of formula II, 6.
This synthetic scheme is adaptable for the preparation of all the compounds of the invention, by reacting the appropriate cyclic amine (pyrrollidine, piperidine, and other cyclic amines) with sec-BuLi/B(OCH₃)₃, and coupling the boronic ester intermediate with the desired acid chloride or acid via routes A or B, respectively. The appropriate cyclic amine may either be commercially available or is easily synthesized through known procedures, for example, those procedures disclosed in U.S. Pat. Nos. 6,617,340; 6,432,969; 6,380,398; 6,172,081; 6,166,063; 6,124,305; 6,110,949; 6,107,317; 6,011,155; and 6,395,767, which are hereby incorporated by reference in their entirety.
Thus, another aspect of the invention provides a process for preparing the compounds of formula I:
by coupling a reactive compound of formula:

with an amine of formula: R⁵—NT₂; optionally deprotecting the boronic acid ester; and recovering the resultant compound as a free acid or as an acid addition salt; wherein L is a leaving group. R¹, R², R³, R⁴, Rⁱ, Rⁱⁱ, n, X, and Z are as defined herein. Preferred embodiments are those where R³and R⁴are hydrogen, L is halogen, including but not limited to Cl, and R⁵—NH₂is cyclopentylamine.
The compounds of the invention may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids. Examples of such salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are known to the skilled artisan.
The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
The compounds of this invention may form solvates with standard low molecular weight solvents, including water to yield hydrates, using methods known to the skilled artisan.
It is to be understood that the invention extends to all of the stereoisomeric forms of the claimed compounds, including enantiomers and diastereomers, as well as the racemates.
Pharmaceutical Compositions
Pharmaceutical compositions containing a compound of the invention of the invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19th Ed., 1995. The compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
The compounds of the invention are effective for DPP-IV inhibition over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 1000 mg, preferably from about 1 to about 500 mg, per day may be used. A typical dosage is about 10 mg to about 500 mg per day. In choosing a regimen for patients it may frequently be necessary to begin with a higher dosage and when the condition is under control to reduce the dosage. The exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
Generally, the compounds of the invention are dispensed in unit dosage form comprising from about 0.05 to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
By “substantially pure” in relation to compounds of the invention such as, but not limited to, those of formula VA and VB, it is meant that one isomer or the other, including all enantiomers, diastereoisomers, solvates, hydrates, and pharmaceutically acceptable salts thereof, represents at least 90% by weight of the composition. In some embodiments one isomer represents at least 98% by weight of the composition.
The term “boronic acid protecting group” as used herein refers to a moiety employed to block or protect the boronic acid functionality while reactions involving other functional sites of the compound are carried out. Typically, the boronic acid OH groups are protected as boronic acid esters derived from alchohols such as (+)-pinanediol; pinacol; 1,2-dicyclohexyl-ethanediol; 1,2-ethanediol; 2,2-diethanolamine; 1,3-propanediol; 2,3-butanediol, diisopropyl tartrate; 1,4-butanediol; diisopropylethanediol; (S,S,)-5,6-decanediol; 1,1,2-triphenyl-1,2-ethanediol; (2R,3R)-1,4-dimethyoxy-1,1,4,4-tetraphenyl-2,3-butanediol; methanol; ethanol; isopropanol; catechol; 1-butanol; and the like. As will be understood by those skilled in the art, alcohols having only a single hydroxy group, such as methanol, form diesters having the structure —B(OR)₂in which R is the organic moiety from the alcohol (e.g., —B(OMe)₂). By comparison, diols such as pinacol form cyclic boronic diesters with —B(OH)₂in which the organic moiety (e.g., —C(Me)₂—C(Me)₂—)is attached to both oxygens.
The term “N-protecting group” or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T. W. Greene, P. G. Wuts, “Protective Groups In Organic Synthesis, 3^rdEd.” (John Wiley & Sons, New York (1999)), which is hereby incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-di methyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The term “alkyl” or “(C_1-12)alkyl”, alone or in combination, refers to linear or branched chains and may include cyclic portions, having from 1-12 (the use of 1-12 herein implies each of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, such as but not limited to, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, 2,2-dimethylpropyl, and the like.
The terms “(C_1-10)alkyl”, “(C_1-8)alkyl” and “(C_1-6)alkyl”, alone or in combination, refers to linear or branched chains and may include cyclic portions, having from 1-10, 1-8, or 1-6 carbon atoms, respectively, such as but not limited to, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, 2,2-dimethylpropyl, and the like.
The term “(C_1-4)alkyl”, alone or in combination, refers to linear or branched chains and may include cyclic portions, having from 1-4 carbon atoms, such as but not limited to, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
The terms “(C_2-12)alkenyl” and “(C_2-10)alkenyl”, alone or in combination, refers to a straight or branched, unsaturated hydrocarbon chain having from 2-12 or 2-10 carbon atoms, respectively, and at least one double bond, such as, but not limited to, vinyl, 1-propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl, n-hexenyl, and the like.
The terms “(C_2-12)alkynyl” and “(C_2-10)alkynyl”, alone or in combination, refers to an unsaturated hydrocarbon chain having from 2-12 or 2-10 carbon atoms, respectively, and at least one triple bond, such as but not limited to —C≡CH, —C≡C—CH₃, —CH₂C≡CH, —CH₂—CH₂—C≡CH, —CH(CH₃)C≡CH, and the like.
The terms “(C_3-12)cycloalkyl” and “(C_3-10)cycloalkyl” refers to one or more saturated cyclic hydrocarbons having from 3-12 or 3-10 carbon atoms, respectively, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
The term “(C_5-10)cycloalkenyl” refers to a radical of one or more cyclic hydrocarbon having at least one double bond having from 5-10 carbon atoms such as, but not limited to, cyclopentenyl, cyclohexenyl, and the like.
The term “cycloalkylene” refers to a “cycloalkyl” group which has single bonds for attachment at two different carbon atoms.
The terms “(C_1-6)alkylaminocarbonyl” and “di-(C_1-6)alkylaminocarbonyl” refer to straight or branched chain hydrocarbon groups having 1 to 6 carbon atoms connected to NC(═O). Exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like.
The term “(C_1-6)alkylcarbonyl” refers to linear or branched chain and cyclic hydrocarbon groups having 1 to 6 carbon atoms connected to C(═O). Exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like.
The term (C_3-8)cycloalkylcarbonyl refers to cyclic hydrocarbon groups having 3 to 8 carbon atoms connected to C(═O). Exemplary cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The terms “(C_1-10)alkoxy”, “(C_1-8)alkoxy” and “(C_1-6)alkoxy”, alone or in combination, refers to “O” connected to alkyl, having linear or branched chains and may include cyclic portions, having from 1-10, 1-8 or 1-6 carbon atoms, respectively. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy include but are not limited to isoprpoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
The term “aryloxy” refers to an aryl group bonded to O.
The term “alkanoyl”, alone or as part of another group, refers to alkyl linked to a carbonyl group.
The term “alkylene” refers to alkyl groups which have single bonds for attachment at two different carbon atoms.
The term “alkenylene” refers to alkenyl groups which have single bonds for attachement at two different carbon atoms.
The terms “alkynylene” refers to alkynyl groups which have single bonds for attachement at two different carbon atoms.
The term “aryl” refers to monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring systems having 6 to 14 carbon atoms in the ring portion. Examples of aryl groups include but are not limited to phenyl, naphthyl, biphenyl, anthracenyl, azulenyl, and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems including 1,2,3,4-tetrahydro-naphthyl, indanyl and the like.
Examples of “aryl” include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), and the like.
The terms “arylalkenyl” and “arylalkynyl” alone or as part of another group refer to alkenyl and alkynyl groups as described above having an aryl substituent.
The terms “halogen” and “halo” refers to chloro, fluoro, bromo or iodo.
The term “alkylamino”, “arylamino”, or “arylalkylamino” alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.
The term “substituted amino” as employed herein alone or as part of another group refers to amino substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituents may be further substituted with any of the groups as set out above.
The terms “alkylthio”, “arylthio” or “aralkylthio” alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.
The term “acyl” by itself or part of another group refers to an organic radical linked to a carbonyl group; examples of acyl groups include any of the groups attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl, and the like.
The phrase “naturally occurring α-amino acid sidechain” refers to the moieties (sidechains) attached to the α-amino carbon in the following naturally occurring α-amino acids: glycine, alanine, 2-aminobutyric acid, valine, leucine, isoleucine, tert-leucine, serine, threonine, cysteine, asparagine, aspartic acid, glutamine, glutamic acid, phenylalanine, histidine, tryptophan, tyrosine, phenylglycine, lysine, methionine, and arginine. The side chains of these amino acids are well known in the art. For example, the α-amino acid sidechain of alanine is methyl; the sidechain of phenylalanine is benzyl; and the sidechain of tert-leucine is tert-butyl.
The term “polyhaloalkyl” refers to an “alkyl” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF₃CH₂, CF₃or CF₃CF₂CH₂.
The term “polyhaloalkoxy” refers to an “alkoxy” or “alkyloxy” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF₃CH₂O, CF₃O or CF₃CF₂CH₂O.
The terms “polycyclic” and “polycycle” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, aryls, heteroaryls and/or cycloheteroalkyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are “fused rings.” Fused rings that are joined through nonadjacent atoms, are also known as “bridged” rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, trifluoromethyl, cyano, or the like.
A further detailed description of the invention is given with reference to the following non-limiting examples.
A flame dried round bottom flask equipped with a magnetic stir bar was charged with N-Boc-pyrrolidine (20 g, 117 mmol, 1 eq) and dry THF (60 mL) under a nitrogen atmosphere. The clear colorless solution was cooled to −78° C. and a solution of s-BuLi (100 mL of a 1.4 M solution in cyclohexane, 140 mmol) was added slowly over a 30 minute period. The light orange colored solution was stirred at −78° C. for 3 hours followed by treatment with B(OMe)₃(39 mL, 350 mmol) after which the cooling bath was removed and the clear colorless solution slowly warmed to 0° C. Upon reaching 0° C., the reaction was quenched with a small amount of water (˜2 mL), allowed to warm to room temp then extracted into 2 N NaOH (250 mL) and backwashed with additional EtOAc (150 mL). The aqueous phase was acidified to pH 3 by the addition of 2 N HCl and then extracted with EtOAc (3×120 mL). The organic extracts were combined and dried over Na₂SO₄and concentrated to produce the free boronic acid (22.08 g, 103 mmol) as a sticky white solid in 88% yield. Without further purification the boronic acid was dissolved in tert-butyl methyl ether (150 mL) and with constant stirring (+)-pinanediol (17.5 g, 103 mmol) was added at room temperature. After 18 hr the ether was removed and the (+)-pinanediol boronic ester was purified by column chromatography (silica gel, 1:3 hexanes/EtOAc) to give a clear thick oil (26.84 g, 76.8 mmol, 76% yield, R_f=0.6 using a 2:1 hexane/ethyl acetate eluant, made visual via I₂and/or PMA stain). Removal of the Boc protecting group was achieved by dissolving the oil in dry ether, cooling to 0° C. in an ice bath and with constant stirring dry HCl (g) was bubbled into the solution for 10 minutes. After 2 hours a white precipitate developed in the flask and the ether and excess HCl were removed in vacuo to afford the racemic HCl salt as a white solid. Crystallization and isolation of the desired isomer was performed by dissolving the HCl salt in a minimal amount of dichloromethane (250 mL) with gentle heating to facilitate a homogenous solution followed by continuous stirring for 8 hours to yield a fluffy white precipitate that was collected by vacuum filtration, dried and then dissolved in minimal 2-propanol (˜200 mL) with gentle heating until homogenous. The alcoholic solution was stirred over night and the resulting white precipitate was collected by vacuum filtration affording isomerically pure 1 as a white solid. (7.0 g, 27 mmol, 23% yield). ¹H NMR (400 MHz, D₂O) δ 4.28 (d, J=8.0 Hz, 1H), 3.06 (m, 3H), 2.18 (m, 1H), 1.96 (m, 2H), 1.78 (m, 3H), 1.62 (m, 2H), 1.21 (s, 3H), 1.05 (m, 5H), 0.84 (d, J=12 Hz, 2H), 0.71 (s, 2H), 0.62 (s, 3H).
Step 1: (2R)-1-(2-Chloroacetyl)-boroPro-(1S,2S,3R,5S)-pinanediol ester (3A).
To a solution of 2 (36.7 g, 129.3 mmol) dissolved in dry CH₂Cl₂(200 mL) cooled to 0° C. was added chloroacetyl chloride (12.34 mL, 155.2 mmol) under a blanket of N₂. To this was slowly dripped 4-methylmorpholine (42.4 mL, 182 mmol) to give an almost clear light orange solution that was warmed to room temp. After 30 minutes the solution was cooled again to 0° C. and 200 mL of a 0.2N solution of HCl was added and the organic layers separated, dried and concentrated to give a dark red oil that was a single spot by TLC (2:1 hex/EtOAc, R_f=0.22, made visual via I₂and/or PMA stain) and was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ0.80 (s, 3H), 1.25 (m, 1H), 1.26 (s, 3H), 1.42 (s, 3H), 1.75-1.96 (m, 4H), 1.98-2.10 (m, 3H), 2.12-2.20 (m, 1H), 2.29-2.35 (m, 1H), 3.12-3.16 (m, 1H), 3.47-3.53 (m, 1H), 3.58-3.63 (m, 1H), 3.97-4.05 (q, 2H), 4.30-4.32 (d, 1H).
Step 2: (2R)-1-(2-Cyclopentylamino-acetyl)-boroPro-(1S,2S,3R,5S)-pinanediol ester (3B).
Compound 3A was dissolved in dry THF (˜150 mL) followed by addition of K₂CO₃(35 g) and cooled to 0° C. before addition of cyclopentylamine (21.93 g, 258 mmol). The reaction mixture was then allowed to warm to room temperature and stirred overnight. TLC indicated all starting material was consumed. The mixture was filtered through a celite and silica pad, washed with 5% MeOH in CH₂Cl₂(200 mL) and concentrated to yield a sticky, light orange solid. The red sticky solid was dissolved in CH₂Cl₂(150 mL) followed by addition of Et₂O (˜200 mL) and the solution was stirred overnight. The resulting milky white solution was then filtered and the precipitate was washed with cold EtOAc (2×60 mL) and hexane (2×50 mL) and dried to give 3B (28.92 g, 120.5 mmol) as a fluffy white solid. The dark red mother liquor filtrate was concentrated and subjected to the previous recrystallization conditions to obtain a second crop of 3B (6.17 g, 25.7 mmol) for a combined overall yield of 3B (35.09 g, 93.8 mmol) of 73% yield. R_f=0.45 (10% MeOH in CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 4.18 (d, 1H), 3.95 (d, J=16 Hz, 1H), 3.6 (d, J=16 Hz, 1H), 3.46 (m, 3H), 2.74 (m, 1H), 2.36 (m, 1H), 2.16 (m, 2H), 2.04 (m, 4H), 1.90 (s, 1H), 1.74 (m, 6H), 1.61 (s, 1H), 1.46 (m, 2H), 1.34 (s, 3H), 1.30 (s, 3H), 0.88 (s, 3H).
Step 3: (2R)-1-(2-Cyclopentylamino-acetyl)-boroPro-OH (4)
To a solution of 3B (40.59 g, 108.5 mmol) in H₂O (200 mL, adjusted to pH 2 by addition of 2 N HCl) was added hexane (200 mL) and phenyl boronic acid (13.37 g, 109.5 mmol) and the bi-phasic mixture was stirred vigorously. The hexane layer was periodically removed and replaced with fresh hexane 6 times over a 24-hour period. The aqueous layer was separated and applied to a Dowex 50-X2-100 ion exchange column (H+ form) and eluted with water until the eluate was neutral. Elution with aqueous ammonium hydroxide (2 wt %) followed by lyophilization of the appropriate fractions yielded 4 (23.91 g, 99.6 mmol) as a white crystalline solid in a 92% yield. 4-TFA salt ¹H NMR (400 MHz, D₂O) δ 3.88 (dd, J=8.0 Hz, 2H), 3.54 (m, 1H), 3.42 (m, 1H), 3.28 (m, 1H), 2.96 (m, 1H), 1.96 (m, 4H), 1.85 (m, 2H), 1.63 (m, 7H); MS (ESI) m/z 223 (M+H—H₂O)⁺.
The title compound was prepared according to the procedure of Example 2 using appropriate starting materials. ¹H NMR (D₂O) δ 4.08 (dd, J=12 Hz, 2H), 3.54 (m, 1H), 3.38 (m, 1H), 3.07 (m, 1H), 2.26 (m, 1H), 2.09 (m, 2H), 1.94 (m, 1H), 1.71 (m, 1H), 0.88 (s, 4H); MS (ESI) m/z 195.13 (MH⁺—H₂O).
The title compound was prepared according to the procedure of Example 2 using appropriate starting materials. ¹H NMR (D₂O) δ 3.94 (d, J=8 Hz, 2H), 3.54 (m, 1H), 3.40 (m, 1H), 3.09 (m, 1H), 2.41 (s, 2H), 2.09 (m, 3H), 1.93 (m, 2H), 1.87 (m, 7H), 1.71 (m, 6H), 1.56 (m, 2H); MS (ESI) m/z 305.21 (MH⁺—H₂O).
Step 1: N-Boc-5-phenylPro-(2R)-boroPro-(1S,2S,3R,5S)-pinanediol ester (5):
To an ice-cooled (0° C.) solution of N-Boc-5-phenyl-Pro-OH (0.84 mmol) in dry CH₂Cl₂was added EDAC (174 mg, 0.91 mmol) and HOBt (105 mg, 0.775 mmol). The reaction was stirred at 0° C. for 15-minutes and then 2 (200 mg, 0.7 mmol) and N-methyl morphiline (0.25 mL, 2.1 mmol) was added and the reaction was slowly warmed to room temperature and the reaction continued for 8 hours. The coupling reaction was then quenched with the addition of NaHCO₃(10 mL), extracted into EtOAc (2×15 mL), washed with brine (15 mL), dried over Na₂SO₄, concentrated and further purified via column chromatography (silica gel, eluted with a gradient of EtOAc in hexanes, 30-50%) to afford 5 (320 mg, 0.62 mmol, 88%) as an off-white solid.
Step 2: 1-(5R-Phenyl-pyrrolidine-2S-carbonyl)-pyrrolidine-(2R)-boronic acid (6):
An ice-cooled solution of 5 (320 mg, 0.62 mmol) in dry ether was saturated with dry HCl (g) and allowed to stir for 1-hour. The solution was then concentrated under vacuum to afford a sticky white solid that was taken up in H₂O (10 mL, adjusted to pH 2 by addition of 2 N HCl) and hexane (10 mL) and phenyl boronic acid (74 mg, 0.62 mmol) and the bi-phasic mixture was stirred vigorously. The hexane layer was periodically removed and replaced with fresh hexane 6 times over a 24-hour period. The aqueous layer was separated and applied to a Dowex 50-X2-100 ion exchange column (H⁺ form) and eluted with water until the eluate was neutral. Elution was continued with aqueous ammonium hydroxide (2 wt %) and the appropriate fractions were lyophilized to afford the free boronic acid B1 (76 mg, 0.26 mmol) as an amorphous white solid. ¹H NMR (D₂O) δ 7.46 (m, 5H), 3.65 (m, 1H), 3.44 (m, 1H), 3.04 (m, 1H), 2.54 (m, 1H), 2.38 (m, 2H), 2.20 (m, 1H), 2.06 (m, 2H), 1.86 (m, 1H), 1.66 (m, 1H); MS (ESI) m/z 271 (MH⁺—H₂O).
The title compound was prepared according to the procedure of Example 5 using appropriate starting materials. ¹H NMR (D₂O) δ 4.07 (m, 1H), 3.61 (m, 1H), 3.34 (m, 2H), 2.94 (m, 2H), 2.16 (m, 1H), 2.03 (m, 2H), 1.87 (m, 3H), 1.56 (m, 4H); MS (ESI) m/z 209 (MH⁺—H₂O).
The title compound was prepared according to the procedure of Example 5 using appropriate starting materials. ¹H NMR (D₂O) δ 4.54 (m, 1H), 3.73 (m, 1H), 3.58 (m, 1H), 3.34 (m, 1H), 2.48 (m, 1H), 2.37 (m, 1H), 2.06 (m, 3H), 1.83 (m, 3H), 1.58 (m, 4H), 1.32 (m, 4H); MS (ESI) m/z 249 (MH⁺—H₂O).
The title compound was prepared according to the procedure of Example 5 using appropriate starting materials. ¹H NMR (D₂O) δ 7.34 (d, J=13 Hz, 2H), 7.27 (m, 3H), 4.79 (m, 1H), 3.83 (m, 1H), 3.59 (m, 1H), 3.34 (m, 2H), 3.06 (m, 1H), 2.53 (m, 2H), 2.08 (m, 2H) 1.77 (m, 1H), 1.64 (m, 1H); MS (ESI) m/z 271 (MH⁺—H₂O).
Step 1: (2R)-1-[(2S,4S)-1-tert-Butoxycarbonyl-4-benzyloxycarbonylamino-pyrrolidine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (13)
The protocol described for the synthesis of 11 was followed employing (2S,4S)-Fmoc-4-amino-1-boc-pyrrolidine-2-carboxylic acid (628 mg, 2.2 mmol) in place of azetidine-1,2-dicarboxylic acid 1-tert-butyl ester. Compound 13 was obtained as a clear colorless oil that was used in the next step without further purification.
Step 2: (2R)-1-[(2S,4S)-1-tert-Butoxycarbonyl-4-amino-pyrrolidine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (14)
To a solution of 13 dissolved in DCM (10 ml) was added diethyl amine (5 ml) at once and the resulting colorless solution was stirred overnight at room temperature. The reaction was evaporated to dryness and additional DCM was added followed by evaporation once again to dryness. The resulting oil was purified by column chromatography (silica gel, eluted with a gradient of 2.5 to 5% MeOH in DCM, made visible by 12 and/or PMA) to give 14 as a clear colorless oil in a 48% yield over 2 steps.
Step 3: (2R)-1-[(2S,4S)-4-Amino-pyrrolidine-2-carbonyl]-boroPro-OH (15)
The protocol described above for the N-Boc deprotection and pinanediol ester hydrolysis in the synthesis of compound 12 was applied to 14. Compound 15 was obtained as a white solid. 15.TFA salt ¹H-NMR (500 MHz, D₂O) δ 4.42 (dd, 1H), 3.87 (m, 1H), 3.5 (dd, 1H), 3.28 (m, 2H), 3.07 (m, 1H), 2.73 (m, 1H), 2.64 (m, 1H), 1.86 (m, 1H), 1.72 (br m, 2H), 1.55 (br m, 2H), 1.34 (m, 2H). MS m/z (rel intensity) 228 (M+1) (55), 210 (M+1—H₂O) (95).
Step 1: (2R)-1-[(2S)-1-tert-Butoxycarbonyl-4-benzyloxycarbonyl-piperazine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (16)
The protocol described above for the synthesis of 11 was followed employing (2S)—N-1-Boc-N-4-Cbz-2-piperazine carboxylic acid (1 g, 2.6 mmol) in place of azetidine-1,2-dicarboxylic acid 1-tert-butyl ester. Compound 16 (690 mg, 1.5 mmol) was obtained in 57% yield as an oil after silica gel column chormatography. MS m/z (rel intensity) 618 (M+23)⁺(17), 596 (M+1)⁺(100), 496 (38).
Step 2: (2R)-1-[(2S)-1-tert-Butoxycarbonyl-piperazine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (17)
To a solution of compound 16 (314 mg, 0.53 mmol) in MeOH (6 mL) was added Pd/C (40 mg). The mixture was stirred under a H₂atmosphere for 2 h. Upon completion of the reaction, it was filtered through a plough of Celite. The solvents were removed under reduced pressure and the oily residue used in the next step without further purification. MS m/z (rel intensity) 462 (M+1)⁺(100), 406 (12), 362 (11).
Step 3: (2R)-1-[(2S)-1-tert-Butoxycarbonyl-4-methanesulfonyl-piperazine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (18)
To a solution of compound 17 (214 mg, 0.46 mmol) in CH₂Cl₂(5 mL) cooled to 0° C. was sequentially added N-methylmorpholine (204 μL, 1.9 mmol) and methanesulfonyl chloride (72 μL, 0.93 mmol). The reaction mixture was allowed to warm up to room temperature and stir for 3 hours. The reaction was then diluted with CH₂Cl₂(6 ml) and water (6 mL). The organic phase was isolated and dried over MgSO₄. After filtration, solvents were removed under reduced pressure. The oily residue was purified by column chromatography (silica gel) using a mixture of EtOAc/Hexanes as eluent. Compound 18 (112 mg, 0.21 mmol) was obtained in 45% yield. MS m/z (rel intensity) 562 (M+23)⁺(14), 540 (M+1) (100), 388 (75).
Step 4: (2R)-1-[(2S)-4-Methanesulfonyl-piperazine-2-carbonyl]-boroPro-OH (19)
The protocol described above for the N-Boc deprotection and pinanediol ester hydrolysis in the synthesis of compound 12 was applied to 18 (112 mg, 0.21 mg). Compound 19 (32 mg, 0.11 mmol) was obtained in 53% yield. 19.TFA salt ¹H-NMR (500 MHz, D₂O) δ 4.32 (dd, J=11.0, 3.5 Hz, 1H), 4.05 (m, 1H), 3.93 (m, 1H), 3.77 (m, 1H), 3.60 (ddd, J=10.5, 8.0, 2.5 Hz, 1H), 3.47 (ddd, J=12.5, 3.0, 3.0, 1H), 3.35 (m, 2H), 3.16 (m, 2H), 3.02 (dd, J=13.8, 11.3 Hz, 1H), 2.93 (s, 3H), 1.96 (m, 2H), 1.81 (m, 1H), 1.72 (m, 1H), 1.56 (m, 1H). MS m/z (rel intensity) 575 (12), 328 (M+23)⁺(6), 288 (M−17) (100).

Using the procedures illustrated above, the following compounds in the Table were prepared and characterized using liquid chromatography-mass spectroscopy (LC-MS).

TABLE


Compound
No.	Series	Structure	LC-MS


22	A	255 (M + 1)(13), 237 (100)

23	A	227 (M + 1)(10), 209 (100)

24	A	229 (M + 1)(18), 211 (100)

25	A	215 (M + 1)(12), 197 (100)

26	A	263 (M + 1)(5), 245 (100)

27	A	277 (M + 1)(4), 259 (100)

28	A	283 (M + 1)(22), 265 (100)

29	A	277 (M + 1)(5), 259 (100)

30	A	283 (M + 1)(21), 265 (100)

31	A	269 (M + 1)(16), 251 (100)

43	A	271 (M + 1)(100), 253 (16)

44	A	270 (M + 1)(100), 252 (17)

47	A	721 (10), 361 (M + 1)(100)

48	A	285 (M + 1)(100), 267 (12)

95	B	201 (M + 1)(100), 183 (22)

96	B	255 (M + 1)(100), 237 (100)

97	B	187 (M + 1)(5), 169 (100)

98	B	243(M + 1)(5), 225 (71)

99	B	449(5), 243(M + 1)(7), 225 (100)

100	B	223(M + 23)(3), 183(48)

101	B	223(M + 23)(4), 183(10)

102	C	228(M + 1)(55), 210 (M − 17)(95)

103	C	210(M − 17)major, 228(M + 1)minor

104	C	210(M − 17)major, 228(M + 1)minor

105	D	575(12), 328 (M + 23)(6), 288 (100)

106	D	452 (M + 1)(3), 434 (100)

107	D	368 (M + 1)(2), 350 (100)

108	D	428 (M − 17)(100)

109	D	386 (M − 17)(100)

110	D	436 (M + 1)(10), 418 (100)

111	D	436 (M + 1)(4), 418 (100)

112	D	627 (25), 332 (M + 1)(10), 314 (100)

113	D	368(M + 1)(38), 350 (100)

114	D	350 (M − 17)(100) 332 (22)

115	D	332(M + 1)(4), 314 (93)

116	D	338(M + 1)(3), 320 (98)

117	D	332(M + 1)(27), 314 (100)

118	D	338 (M + 1)(21), 320 (100)

130	G	623 (28), 312 (M + 1) (100), 294 (30)

131	G	819 (20), 410 (100)

132	G	374 (M + 1)(100), 356 (67)

133	G	759 (57), 380 (M + 1)(100), 362 (64)

While the invention has been described and exemplified in sufficient detail for those skilled in this art to make and use it, various alternatives, modifications, and improvements will be apparent to those skilled in the art without departing from the spirit and scope of the claims.
All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.
In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described.

Claims (3)

1. A pyrrolidine compound of formula I:

including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein:

n is 1 to 3;

X is CH₂; S; O; CF₂or C(CH₃)₂;

Z is H; halogen; hydroxyl; (C_1-6)alkoxy; (C_1-12)alkyl; (C_3-12)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁷;

R⁷is halogen; (C_1-10)alkyl; (C_1-10)alkoxy; (C_1-10)alkylamino; (C_1-10) dialkylamino; benzyl; benzyloxy; hydroxyl(C_1-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyamino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;

optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and

optionally, one of the bonds in the ring containing X is a double bond;

R¹and R²independently or together are hydrogen; a boronic acid protecting group; or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; and

CRⁱRⁱⁱmay be present or absent, and

when CRⁱRⁱⁱis present, then

Rⁱ, Rⁱⁱ, R³, R⁴and R⁵are selected from (aa) or (bb):

(aa) Rⁱ, Rⁱⁱ, R³and R⁴are hydrogen; and R⁵is hydrogen, (C_1-12)alkyl or (C_3-12) cycloalkyl;

(bb) Rⁱ, RⁱⁱR³, R⁴and R⁵are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl,

or alternatively,

when CRⁱRⁱⁱis absent, then R³, R⁴and R⁵are selected from (cc), (dd) or (ee):

(cc) R³and R⁴are hydrogen; and

R⁵is

a) hydrogen, provided that R⁵is not hydrogen when n is 1, X is CH₂, and Z is H;

b) (C_1-12)alkyl; (C_2-12)alkenyl; (C_2-12)alkynyl; (C_3-12)cycloalkyl; or (C_3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R⁶, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;

R⁶is (C_1-6)alkyl; (C_1-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C_1-6)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁷; amino, where the amino group is optionally mono- or independently plurisubstituted with R⁸; —SOR⁸; —SO₂R⁸; —COR⁸; —CO₂R⁸, —CONHR⁸; —CON(R⁸)₂; —OR⁸; or —S—R⁸;

R⁸is (C_1-10)alkyl; (C_2-10)alkenyl; (C_2-10)alkynyl; (C_3-10)cycloalkyl; (C_5-10)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁷;

c) aryl optionally fused to a (C_3-10)cycloalkyl; or heteroaryl optionally fused to a (C_3-10)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁷;

d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH₂)_jadamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH₂)_jadamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C_1-8)alkyl, (C_1-8)alkoxy, (C_1-8)alkanoyloxy, or R⁹R¹⁰N—CO—O—, where R⁹and R¹⁰are independently (C_1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C_1-8)alkyl, (C_1-8)alkoxy, halogen, or trifluoromethyl, or R⁹and R¹⁰together are (C_3-6)alkylene;

e) R¹¹(CH₂)_p— where R¹¹is 2-oxopyrrolidinyl; (C_1-6)alkoxy; phenyl; phenoxy; (C_1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (C_1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R¹²; where the phenoxy group is optionally mono- or independently disubstituted with (C_1-4)alkyl, (C_1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono- or independently plurisubstituted with (C_1-8)alkyl; and p is 0 to 3;

R¹²is halogen; trifluoromethyl; cyano; nitro; (C_1-6)alkyl; (C_1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C_1-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁷;

f) (R³)₂CH(CH₂)_q—, where R¹³is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R²; and q is 0 to 3;

g) a group of the formula:

where R¹⁴and R¹⁵are independently hydrogen; (C_1-8)alkyl; (C_1-6)alkylcarbonyl; (C_3-12)cycloalkyl ring; (C_3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C_1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R¹²; or R¹⁴and R¹⁵together form a (C_3-12)cycloalkyl ring; and r is 2 to 6;

h) a group of the formula:

where R¹⁶and R¹⁷are each independently hydrogen; (C_1-8)alkyl; (C_1-6)alkylcarbonyl; di-(C_1-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R¹²; or R¹⁶and R¹⁷together form a (C_3-12)cycloalkyl ring; and s is 1 to 6;

i) a group of the formula:

wherein R¹⁸and R¹⁹are independently hydrogen; (C_1-8)alkyl; (C_1-6)alkylcarbonyl; di-(C_1-6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R¹²; or wherein R¹⁸and R¹⁹together with the N form an (N, C_3-12) heterocycloalkyl ring containing the nitrogen atom; and each t is independently 0 to 6; and u is 0 to 3;

j) a group of the formula:

where the phenyl group is optionally mono- or independently plurisubstituted with R¹²;

; or

k) a group of the formula:

where R²¹is hydrogen; (C_1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R¹²; each t is independently 0 to 6; and u is 0 to 3; and,

wherein a bond containing a wavy line signifies a point of attachment;

(dd) R³, R⁴and R⁵are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl or aralkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, arylamino, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl, provided that when n is 1, X is CH₂, the ring containing X is saturated, and Z, R³and R⁵are H, R⁴is not a side chain of a naturally occurring α-amino acid, and provided that when n is 1, X is CH₂, the ring containing X is saturated, and Z and R⁵are H, R³and R⁴are not both methyl; or,

(ee) R³is hydrogen, and R⁴and R⁵together with the atoms to which they are attached form a 4 to 8 membered heterocyclic ring of 3 to 7 carbons and 1 nitrogen,

wherein the heterocyclic ring carbon atoms other than the carbon connected to N and R⁴have the formula —(CR²²R²³)_m— wherein m is 2 to 6, and R²²and R²³are independently hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, halo, amino, substituted amino, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, or alkylaminocarbonylamino; and, optionally the heterocyclic ring has an aryl, heteroaryl or a 3 to 7 membered cycloalkyl ring fused thereto, provided that when n is 1, X is CH₂, the ring containing X is saturated, and Z and R³are H, then R⁴and R⁵together are not —(CH₂)₂— or —(CH₂)₃—.

2. A linear alkyl pyrrolidine compound of formula I according to

claim 1

wherein CRⁱRⁱⁱis absent, R³, R⁴and R⁵are as given in clauses (cc), (dd) and (ee), and the linear alkyl pyrrolidine compound has formula II:

3. A linear beta pyrrolidine compound of formula I according to

claim 1

wherein CRⁱRⁱⁱis present, R³, R⁴and R⁵are as given in clauses (aa) and (bb), and the linear beta pyrrolidine compound has formula III:

US11/556,944 2003-11-12 2006-11-06 Heterocyclic boronic acid compounds Abandoned US20070185061A1 (en)

Priority Applications (1)

Application Number	Priority Date	Filing Date	Title
US11/556,944 US20070185061A1 (en)	2003-11-12	2006-11-06	Heterocyclic boronic acid compounds

Applications Claiming Priority (6)

Application Number	Priority Date	Filing Date	Title
US51956603P	2003-11-12	2003-11-12
US55701104P	2004-03-25	2004-03-25
US59297204P	2004-07-30	2004-07-30
PCT/US2004/037820 WO2005047297A1 (en)	2003-11-12	2004-11-12	Heterocyclic boronic acid compounds
US51457505A	2005-10-27	2005-10-27
US11/556,944 US20070185061A1 (en)	2003-11-12	2006-11-06	Heterocyclic boronic acid compounds

Related Parent Applications (2)

Application Number	Title	Priority Date	Filing Date
PCT/US2004/037820 Division WO2005047297A1 (en)	2003-11-12	2004-11-12	Heterocyclic boronic acid compounds
US51457505A Division	2003-11-12	2005-10-27

Publications (1)

Publication Number	Publication Date
US20070185061A1 true US20070185061A1 (en)	2007-08-09

Family

ID=34595944

Family Applications (3)

Application Number	Title	Priority Date	Filing Date
US10/514,575 Active - Reinstated 2027-01-03 US7674913B2 (en)	2003-11-12	2004-11-12	Heterocyclic boronic acid compounds
US11/556,944 Abandoned US20070185061A1 (en)	2003-11-12	2006-11-06	Heterocyclic boronic acid compounds
US12/692,276 Active 2026-01-28 US8415295B2 (en)	2003-11-12	2010-01-22	Heterocyclic boronic acid compounds

Family Applications Before (1)

Application Number	Title	Priority Date	Filing Date
US10/514,575 Active - Reinstated 2027-01-03 US7674913B2 (en)	2003-11-12	2004-11-12	Heterocyclic boronic acid compounds

Family Applications After (1)

Application Number	Title	Priority Date	Filing Date
US12/692,276 Active 2026-01-28 US8415295B2 (en)	2003-11-12	2010-01-22	Heterocyclic boronic acid compounds