HRP20040891A2 - Amino acids with affinity for the alpha-2-delta-protein - Google Patents
Amino acids with affinity for the alpha-2-delta-proteinInfo
- Publication number
- HRP20040891A2 HRP20040891A2 HRP20040891A HRP20040891A2 HR P20040891 A2 HRP20040891 A2 HR P20040891A2 HR P20040891 A HRP20040891 A HR P20040891A HR P20040891 A2 HRP20040891 A2 HR P20040891A2
- Authority
- HR
- Croatia
- Prior art keywords
- acid
- alkyl
- amino
- phenyl
- pyridyl
- Prior art date
Links
- 150000001413 amino acids Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 179
- 150000003839 salts Chemical class 0.000 claims description 70
- 238000000034 method Methods 0.000 claims description 69
- 125000001153 fluoro group Chemical group F* 0.000 claims description 55
- 208000002193 Pain Diseases 0.000 claims description 45
- -1 phenyl-(C1-C3)alkyl Chemical group 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- 125000004076 pyridyl group Chemical group 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 21
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- VCOJPHSIBVJVDU-UHFFFAOYSA-N 2-(aminomethyl)-4,4,8-trimethylnonanoic acid Chemical compound CC(C)CCCC(C)(C)CC(CN)C(O)=O VCOJPHSIBVJVDU-UHFFFAOYSA-N 0.000 claims description 9
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- IVYDEZGCXPEAHO-HTQZYQBOSA-N (2r,4r)-2-(aminomethyl)-4-methylheptanoic acid Chemical compound CCC[C@@H](C)C[C@H](CN)C(O)=O IVYDEZGCXPEAHO-HTQZYQBOSA-N 0.000 claims description 4
- KFUYJCLUBOFHHM-UHFFFAOYSA-N 2-(aminomethyl)-3-(1-methylcyclopropyl)propanoic acid Chemical compound NCC(C(O)=O)CC1(C)CC1 KFUYJCLUBOFHHM-UHFFFAOYSA-N 0.000 claims description 4
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- ZTOJKCGCPJHZPN-UHFFFAOYSA-N 2-(aminomethyl)-3-[1-(4-methylpentyl)cyclopropyl]propanoic acid Chemical compound CC(C)CCCC1(CC(CN)C(O)=O)CC1 ZTOJKCGCPJHZPN-UHFFFAOYSA-N 0.000 claims description 3
- JVYGCKSEDCBNBD-UHFFFAOYSA-N 2-(aminomethyl)-4-ethyl-8-methylnonanoic acid Chemical compound NCC(C(O)=O)CC(CC)CCCC(C)C JVYGCKSEDCBNBD-UHFFFAOYSA-N 0.000 claims description 3
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- JITKOZNMMSGRKJ-MJGOQNOKSA-N tert-butyl (3S,5R)-5-methyl-3-(phenylmethoxycarbonylamino)nonanoate Chemical compound C(C)(C)(C)OC(C[C@H](C[C@@H](CCCC)C)NC(=O)OCC1=CC=CC=C1)=O JITKOZNMMSGRKJ-MJGOQNOKSA-N 0.000 description 1
- HUIHVTVFRDJFTM-FKPGQJDZSA-N tert-butyl (3r,5r)-5-methyl-3-[(4s,5r)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidine-3-carbonyl]octanoate Chemical compound O1C(=O)N(C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](C)CCC)[C@@H](C)[C@H]1C1=CC=CC=C1 HUIHVTVFRDJFTM-FKPGQJDZSA-N 0.000 description 1
- ZCEOVQSIOGHSOW-LLVKDONJSA-N tert-butyl (3s)-3-amino-5,5-dimethyloctanoate Chemical compound CCCC(C)(C)C[C@H](N)CC(=O)OC(C)(C)C ZCEOVQSIOGHSOW-LLVKDONJSA-N 0.000 description 1
- DKPAQXMFEIGQCB-NEPJUHHUSA-N tert-butyl (3s,5r)-3-amino-5-methylnonanoate Chemical compound CCCC[C@@H](C)C[C@H](N)CC(=O)OC(C)(C)C DKPAQXMFEIGQCB-NEPJUHHUSA-N 0.000 description 1
- GSRYOMXTHAIEMA-ZTRFORPCSA-N tert-butyl (3s,5r)-5-methyl-3-[(4r,5s)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidine-3-carbonyl]heptanoate Chemical compound O1C(=O)N(C(=O)[C@H](CC(=O)OC(C)(C)C)C[C@H](C)CC)[C@H](C)[C@@H]1C1=CC=CC=C1 GSRYOMXTHAIEMA-ZTRFORPCSA-N 0.000 description 1
- ZCEOVQSIOGHSOW-UHFFFAOYSA-N tert-butyl 3-amino-5,5-dimethyloctanoate Chemical compound CCCC(C)(C)CC(N)CC(=O)OC(C)(C)C ZCEOVQSIOGHSOW-UHFFFAOYSA-N 0.000 description 1
- DQRWHAAHPMNUSA-UHFFFAOYSA-N tert-butyl 5,5-dimethyl-3-(phenylmethoxycarbonylamino)octanoate Chemical compound CCCC(C)(C)CC(CC(=O)OC(C)(C)C)NC(=O)OCC1=CC=CC=C1 DQRWHAAHPMNUSA-UHFFFAOYSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
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- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
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- C07C229/28—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
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Description
Pozadina izuma
Ovaj izum odnosi se na izvjesne β-aminokiseline, koje se vežu na alfa-2-delta (α2δ)-podjedinicu kalcijskog kanala. Ti spojevi i njihove farmaceutski prihvatljive soli korisni su u liječenju niza različitih psihijatrijskih, bolnih i drugih poremećaja.
Bit izuma
Ovaj izum odnosi se na spojeve formule I
[image]
gdje
R1 je vodik ili (C1-C6)alkil, izborno supstituiran s 1 do 5 atoma fluora;
R2 je vodik ili (C1-C6)alkil, izborno supstituiran s 1 do 5 atoma fluora; ili
R1 i R2, zajedno s ugljikom na koji su vezani, tvore 3- do 6- člani cikloalkilni prsten;
R3 je (C1-C6)alkil, (C3-C6)cikloalkil, (C3-C6)cikloalkil-(C1-C3)alkil, fenil, fenil-(C1-C3)alkil, piridil, piridil-(C1-C3)alkil, fenil-N(H)- ili piridil-N(H)-, gdje svaki od gore navedenih alkilnih ostataka može izborno biti supstituiran s 1 do 5 atoma fluora, po mogućnosti 0 do 3 atoma fluora, gdje navedeni fenilni i navedeni piridilni, te fenilni i piridilni ostaci u navedenom fenil-(C1-C3)alkilu, odnosno navedenom piridil(C1-C3) alkilu, mogu izborno biti supstituirani s 1 do 3 supstituenta, po mogućnosti 0 do 2 supstituenta, koje se neovisno bira između klora, fluora, amino, nitro, cijano, (C1-C3)alkilamino, (C1-C3)alkila, izborno supstituiranog s 1 do 3 atoma fluora i (C1-C3)alkoksi, izborno supstituiranog s 1 do 3 atoma fluora;
R4 je vodik ili (C1-C6)alkil, izborno supstituiran s 1 do 5 atoma fluora;
R5 je vodik ili (C1-C6)alkil, izborno supstituiran s 1 do 5 atoma fluora; a
R6 je vodik ili (C1-C6)alkil;
i farmaceutski prihvatljive soli takvih spojeva.
Specifične izvedbe ovog izuma uključuju sljedeće spojeve formule I i njihove farmaceutski prihvatljive soli:
3-amino-5,8-dimetilnonansku kiselinu;
3-amino-5,5,7-trimetiloktansku kiselinu;
3-amino-5,5,8-trimetilnonansku kiselinu;
3-amino-5,5,6-trimetilheptansku kiselinu;
(3S,5S)-3-amino-5,8-dimetilnonansku kiselinu;
(3S,5R)-3-amino-5,8-dimetilnonansku kiselinu;
(3S)-3-amino-5,5,6-trimetilheptansku kiselinu;
(3S)-3-amino-5,5,7-trimetiloktansku kiselinu;
(3S)-3-amino-5,5,8-trimetilnonansku kiselinu; i
(3S)-3-amino-5,5,9-trimetildekansku kiselinu.
Drugi primjeri specifičnih izvedaba ovog izuma su sljedeći spojevi formule I i njihove farmaceutski prihvatljive soli:
3-amino-6-ciklobutil-5-metilheksanska kiselina;
3-amino-7-ciklopropil-5-metilheptanska kiselina;
3-amino-7-ciklobutil-5-metilheptanska kiselina;
3-amino-7-ciklopentil-5-metilheptanska kiselina;
3-amino-7-cikloheksil-5-metilheptanska kiselina;
3-amino-8-ciklopropil-5-metiloktanska kiselina;
3-amino-8-ciklobutil-5-metiloktanska kiselina;
3-amino-8-ciklopentil-5-metiloktanska kiselina;
3-amino-8-cikloheksil-5-metiloktanska kiselina;
3-amino-6-ciklopropil-5,5-dimetilheksanska kiselina;
3-amino-6-ciklobutil-5,5-dimetilheksanska kiselina;
3-amino-6-ciklopentil-5,5-dimetilheksanska kiselina;
3-amino-6-cikloheksil-5,5-dimetilheksanska kiselina;
3-amino-7-ciklopropil-5,5-dimetilheptanska kiselina;
3-amino-7-ciklobutil-5,5-dimetilheptanska kiselina;
3-amino-7-ciklopentil-5,5-dimetilheptanska kiselina;
3-amino-7-cikloheksil-5,5-dimetilheptanska kiselina;
(3S,5R)-3-amino-6-ciklobutil-5-metilheksanska kiselina;
(3S,5R)-3-amino-7-ciklopropil-5-metilheptanska kiselina;
(3S,5R)-3-amino-7-ciklobutil-5-metilheptanska kiselina;
(3S,5R)-3-amino-7-ciklopentil-5-metilheptanska kiselina;
(3S,5R)-3-amino-7-cikloheksil-5-metilheptanska kiselina;
(3S,5R)-3-amino-8-ciklopropil-5-metiloktanska kiselina;
(3S,5R)-3-amino-8-ciklobutil-5-metiloktanska kiselina;
(3S,5R)-3-amino-8-ciklopentil-5-metiloktanska kiselina;
(3S,5R)-3-amino-8-cikloheksil-5-metiloktanska kiselina;
(3S,5S)-3-amino-6-ciklobutil-5-metilheksanska kiselina;
(3S,5S)-3-amino-7-ciklopropil-5-metilheptanska kiselina;
(3S,5S)-3-amino-7-ciklobutil-5-metilheptanska kiselina;
(3S,5S)-5-amino-7-ciklopentil-5-metilheptanska kiselina;
(3S,5S)-3-amino-7-cikloheksil-5-metilheptanska kiselina;
(3S,5S)-3-amino-8-ciklopropil-5-metiloktanska kiselina;
(3S,5S)-3-amino-8-ciklobutil-5-metiloktanska kiselina;
(3S,5S)-3-amino-8-ciklopentil-5-metiloktanska kiselina;
(3S,5S)-3-amino-8-cikloheksil-5-metiloktanska kiselina;
(3S)-3-amino-6-ciklopropil-5,5-dimetilheksanska kiselina;
(3S)-3-amino-6-ciklobutil-5,5-dimetilheksanska kiselina;
(3S)-3-amino-6-ciklopentil-5,5-dimetilheksanska kiselina;
(3S)-3-amino-6-cikloheksil-5,5-dimetilheksanska kiselina;
(3S)-3-amino-7-ciklopropil-5,5-dimetilheptanska kiselina;
(3S)-3-amino-7-ciklobutil-5,5-dimetilheptanska kiselina;
(3S)-3-amino-7-ciklopentil-5,5-dimetilheptanska kiselina; i
(3S)-3-amino-7-cikloheksil-5,5-dimetilheptanska kiselina.
Druge specifične izvedbe ovog izuma uključuju sljedeće spojeve formule I i njihove farmaceutski prihvatljive soli:
3-amino-5-metilheptansku kiselinu;
3-amino-5-metiloktansku kiselinu;
3-amino-5-metilnonansku kiselinu;
3-amino-5,5-dimetilnonansku kiselinu;
3-amino-5,5-dimetildekansku kiselinu;
(3S)-3-amino-5,5-dimetilnonansku kiselinu; i
(3S)-3-amino-5,5-dimetildekansku kiselinu.
Ovaj izum također se odnosi na spojeve formule IA:
[image]
gdje
R1 je vodik ili (C1-C3)alkil, izborno supstituiran s 1 do 5 atoma fluora;
R2 je vodik ili (C1-C3)alkil, izborno supstituiran s 1 do 5 atoma fluora; ili
R1 i R2, zajedno s ugljikom na koji su vezani, tvore 3- do 6- člani cikloalkilni prsten;
R3 je (C1-C6)alkil, (C3-C6)cikloalkil, (C3-C6)cikloalkil-(C1-C3)alkil, fenil, fenil-(C1-C3)alkil, piridil, piridil-(C1-C3)alkil, fenil-N(H)- ili piridil-N(H)-, gdje svaki od gore navedenih alkilnih ostataka može izborno biti supstituiran s 1 do 5 atoma fluora, po mogućnosti 0 do 3 atoma fluora, gdje navedeni fenilni i navedeni piridilni, te fenilni i piridilni ostaci navedenog fenil-(C1-C3)alkila, odnosno navedenog piridil-(C1-C3)alkila, mogu izborno biti supstituirani s 1 do 3 supstituenta, po mogućnosti s 0 do 2 supstituenta, koje se neovisno bira između klora, fluora, amino, nitro, cijano, (C1-C3)alkilamino, (C1-C3)alkila, izborno supstituiranog s 1 do 3 atoma fluora i (C1-C3)alkoksi, izborno supstituiranog s 1 do 3 atoma fluora;
uz uvjet da kada R1 je vodik, tada R2 nije vodik;
i farmaceutski prihvatljive soli takvih spojeva.
Ovaj izum također se odnosi na spojeve formule IA-1
[image]
gdje R3 je definiran kao za formulu I, gore, i farmaceutski prihvatljive soli takvih spojeva.
Druge specifične izvedbe ovog izuma uključuju sljedeće spojeve formule IA i njihove farmaceutski prihvatljive soli:
3-amino-5-metil-8-fenilaminooktansku kiselinu;
3-amino-5-metil-7-fenilaminoheptansku kiselinu;
3-amino-5-metil-6-fenilaminoheksansku kiselinu;
(3S,5R)-3-amino-5-metil-8-fenilaminooktansku kiselinu;
(3S,5R)-3-amino-5-metil-7-fenilaminoheptansku kiselinu;
(3S,5R)-3-amino-5-metil-6-fenilaminoheksansku kiselinu;
(3S,5S)-3-amino-5-metil-8-fenilaminooktansku kiselinu;
(3S,5S)-3-amino-5-metil-7-fenilaminoheptansku kiselinu;
(3S,5S)-3-amino-5-metil-6-fenilaminoheksansku kiselinu;
3-amino-5-metil-8-feniloktansku kiselinu;
3-amino-8-(2-fluorfenil)-5-metiloktansku kiselinu;
3-amino-8-(3-fluorfenil)-5-metiloktansku kiselinu;
3-amino-8-(4-fluorfenil)-5-metiloktansku kiselinu;
3-amino-8-(2-trifluorfenil)-5-metiloktansku kiselinu;
3-amino-8-(3-trifluorfenil)-5-metiloktansku kiselinu;
3-amino-8-(4-trifluorfenil)-5-metiloktansku kiselinu;
3-amino-5-metil-8-o-toliloktansku kiselinu;
3-amino-5-metil-8-m-toliloktansku kiselinu;
3-amino-5-metil-8-p-toliloktansku kiselinu;
3-amino-5-metil-8-p-toliloktansku kiselinu;
3-amino-8-(2,3-difluorfenil)-5-metiloktansku kiselinu;
3-amino-8-(2,4-difluorfenil)-5-metiloktansku kiselinu;
3-amino-8-(2,5-difluorfenil)-5-metiloktansku kiselinu;
3-amino-8-(2,6-difluorfenil)-5-metiloktansku kiselinu;
(3S,5R)-3-amino-5-metil-8-feniloktansku kiselinu;
(3S,5S)-5-amino-5-metil-8-feniloktansku kiselinu;
(3S,5R)-3-amino-8-(2-fluorfenil)-5-metiloktansku kiselinu;
(3S,5S)-3-amino-8-(2-fluorfenil)-5-metiloktansku kiselinu;
(3S,5R)-3-amino-8-(3-fluorfenil)-5-metiloktansku kiselinu;
(3S,5S)-3-amino-8-(3-fluorfenil)-5-metiloktansku kiselinu;
(3S,5R)-3-amino-8-(4-fluorfenil)-5-metiloktansku kiselinu;
(3S,5S)-3-amino-8-(4-fluorfenil)-5-metiloktansku kiselinu;
(3S,5R)-3-amino-8-(2-trifluorfenil)-5-metiloktansku kiselinu;
(3S,5S)-3-amino-8-(2-trifluorfenil)-5-metiloktansku kiselinu;
(3S,5R)-3-amino-8-(3-trifluorfenil)-5-metiloktansku kiselinu;
(3S,5S)-3-amino-8-(3-trifluorfenil)-5-metiloktansku kiselinu;
(3S,5R)-3-amino-8-(4-trifluorfenil)-5-metiloktansku kiselinu;
(3S,5S)-3-amino-8-(4-trifluorfenil)-5-metiloktansku kiselinu;
(3S,5R)-3-amino-5-metil-8-o-toliloktansku kiselinu;
(3S,5S)-3-amino-5-metil-8-o-toliloktansku kiselinu;
(3S,5R)-3-amino-5-metil-8-m-toliloktansku kiselinu;
(3S,5S)-3-amino-5-metil-8-m-toliloktansku kiselinu;
(3S,5R)-3-amino-5-metil-8-p-toliloktansku kiselinu;
(3S,5S)-3-amino-5-metil-8-p-toliloktansku kiselinu;
(3S,5R)-3-amino-8-(2,3-difluorfenil)-5-metiloktansku kiselinu;
(3S,5S)-3-amino-8-(2,3-difluorfenil)-5-metiloktansku kiselinu;
(3S,5R)-3-amino-8-(2,4-difluorfenil)-5-metiloktansku kiselinu;
(3S,5S)-3-amino-8-(2,4-difluorfenil)-5-metiloktansku kiselinu;
(3S,5R)-3-amino-8-(2,5-difluorfenil)-5-metiloktansku kiselinu;
(3S,5S)-3-amino-8-(2,5-difluorfenil)-5-metiloktansku kiselinu;
(3S,5R)-3-amino-8-(2,6-difluorfenil)-5-metiloktansku kiselinu; i
(3S,5S)-3-amino-8-(2,6-difluorfenil)-5-metiloktansku kiselinu.
Poželjni spojevi prema ovom izumu uključuju one formule IA-2,
[image]
gdje R1, R2 i R3 su definirani kao za formulu I, gore.
Primjeri poželjnijih spojeva prema ovom izumu spojevi su formule IA-2, gdje R1 je vodik, R2 je metil, a R3 je definiran kao za formulu I, gore.
Primjeri specifičnih izvedaba ovog izuma su sljedeći spojevi formule IA-2 i njihove farmaceutski prihvatljive soli:
(3S,5R)-3-amino-5-metilheptanska kiselina;
(3S,5R)-3-amino-5-metiloktanska kiselina; i
(3S,5R)-3-amino-5-metilnonanska kiselina.
Ovaj izum također se odnosi na spojeve formule IB
[image]
i njihove farmaceutski prihvatljive soli, gdje R3 je definiran kao gore, gdje se navedene spojeve bira između sljedećih spojeva i njihovih farmaceutski prihvatljive soli:
3-amino-4,5-dimetilheksanske kiseline;
3-amino-4,6-dimetilheptanske kiseline;
3-amino-4,7-dimetiloktanske kiseline;
3-amino-4,8-dimetilnonanske kiseline;
3-amino-4,9-dimetildekanske kiseline;
3-amino-4-ciklopropilpentanske kiseline;
3-amino-4-ciklobutilpentanske kiseline;
3-amino-4-ciklopentilpentanske kiseline;
3-amino-4-cikloheksilpentanske kiseline;
3-amino-5-ciklopropil-4-metilpentanske kiseline;
3-amino-5-ciklobutil-4-metilpentanske kiseline;
3-amino-5-ciklopentil-4-metilpentanske kiseline;
3-amino-5-cikloheksil-4-metilpentanske kiseline;
3-amino-6-ciklopropil-4-metilheksanske kiseline;
3-amino-6-ciklobutil-4-metilheksanske kiseline;
3-amino-6-ciklopentil-4-metilheksanske kiseline;
3-amino-6-cikloheksil-4-metilheksanske kiseline;
3-amino-7-ciklopropil-4-metilheptanske kiseline;
3-amino-7-ciklobutil-4-metilheptanske kiseline;
3-amino-7-ciklopentil-4-metilheptanske kiseline;
3-amino-7-cikloheksil-4-metilheptanske kiseline;
3-amino-8-ciklopropil-4-metiloktanske kiseline;
3-amino-8-ciklobutil-4-metiloktanske kiseline;
3-amino-8-ciklopentil-4-metiloktanske kiseline;
3-amino-8-cikloheksil-4-metiloktanske kiseline;
3-amino-9-ciklopropil-4-metilnonanske kiseline;
3-amino-9-ciklobutil-4-metilnonanske kiseline;
3-amino-9-ciklopentil-4-metilnonanske kiseline;
3-amino-9-cikloheksil-4-metilnonanske kiseline;
3-amino-4-metiloktanske kiseline;
3-amino-4-metilnonanske kiseline;
3-amino-4-metildekanske kiseline;
(3R,4R)-3-amino-4,5-dimetilheksanske kiseline;
(3R,4R)-3-amino-4,6-dimetilheptanske kiseline;
(3R,4R)-3-amino-4,7-dimetiloktanske kiseline;
(3R,4R)-3-amino-4,8-dimetilnonanske kiseline;
(3R,4R)-3-amino-4,9-dimetildekanske kiseline;
(3R,4R)-3-amino-4-ciklopropilpentanske kiseline;
(3R,4R)-3-amino-4-ciklobutilpentanske kiseline;
(3R,4R)-3-amino-4-ciklopentilpentanske kiseline;
(3R,4R)-3-amino-4-cikloheksilpentanske kiseline;
(3R,4R)-3-amino-5-ciklopropil-4-metilpentanske kiseline;
(3R,4R)-3-amino-5-ciklobutil-4-metilpentanske kiseline;
(3R,4R)-3-amino-5-ciklopentil-4-metilpentanske kiseline;
(3R,4R)-3-amino-5-cikloheksil-4-metilpentanske kiseline;
(3R,4R)-3-amino-6-ciklopropil-4-metilheksanske kiseline;
(3R,4R)-3-amino-6-ciklobutil-4-metilheksanske kiseline;
(3R,4R)-3-amino-6-ciklopentil-4-metilheksanske kiseline;
(3R,4R)-3-amino-6-cikloheksil-4-metilheksanske kiseline;
(3R,4R)-3-amino-7-ciklopropil-4-metilheptanske kiseline;
(3R,4R)-3-amino-7-ciklobutil-4-metilheptanske kiseline;
(3R,4R)-3-amino-7-ciklopentil-4-metilheptanske kiseline;
(3R,4R)-3-amino-7-cikloheksil-4-metilheptanske kiseline;
(3R,4R)-3-amino-8-ciklopropil-4-metiloktanske kiseline;
(3R,4R)-3-amino-8-ciklobutil-4-metiloktanske kiseline;
(3R,4R)-3-amino-8-ciklopentil-4-metiloktanske kiseline;
(3R,4R)-3-amino-8-cikloheksil-4-metiloktanske kiseline;
(3R,4R)-3-amino-9-ciklopropil-4-metilnonanske kiseline;
(3R,4R)-3-amino-9-ciklobutil-4-metilnonanske kiseline;
(3R,4R)-3-amino-9-ciklopentil-4-metilnonanske kiseline;
(3R,4R)-3-amino-9-cikloheksil-4-metilnonanske kiseline;
(3R,4R)-3-amino-4-metiloktanske kiseline;
(3R,4R)-3-amino-4-metilnonanske kiseline;
(3R,4R)-3-amino-4-metildekanske kiseline;
(3R,4S)-3-amino-4,5-dimetilheksanske kiseline;
(3R,4S)-3-amino-4,6-dimetilheptanske kiseline;
(3R,4S)-3-amino-4,7-dimetiloktanske kiseline;
(3R,4S)-3-amino-4,8-dimetilnonanske kiseline;
(3R,4S)-3-amino-4,9-dimetildekanske kiseline;
(3R,4S)-3-amino-4-ciklopropilpentanske kiseline;
(3R,4S)-3-amino-4-ciklobutilpentanske kiseline;
(3R,4S)-3-amino-4-ciklopentilpentanske kiseline;
(3R,4S)-3-amino-4-cikloheksilpentanske kiseline;
(3R,4S)-3-amino-5-ciklopropil-4-metilpentanske kiseline;
(3R,4S)-3-amino-5-ciklobutil-4-metilpentanske kiseline;
(3R,4S)-3-amino-5-ciklopentil-4-metilpentanske kiseline;
(3R,4S)-3-amino-5-cikloheksil-4-metilpentanske kiseline;
(3R,4S)-3-amino-6-ciklopropil-4-metilheksanske kiseline;
(3R,4S)-3-amino-6-ciklobutil-4-metilheksanske kiseline;
(3R,4S)-3-amino-6-ciklopentil-4-metilheksanske kiseline;
(3R,4S)-3-amino-6-cikloheksil-4-metilheksanske kiseline;
(3R,4S)-3-amino-7-ciklopropil-4-metilheptanske kiseline;
(3R,4S)-3-amino-7-ciklobutil-4-metilheptanske kiseline;
(3R,4S)-3-amino-7-ciklopentil-4-metilheptanske kiseline;
(3R,4S)-3-amino-7-cikloheksil-4-metilheptanske kiseline;
(3R,4S)-3-amino-8-ciklopropil-4-metiloktanske kiseline;
(3R,4S)-3-amino-8-ciklobutil-4-metiloktanske kiseline;
(3R,4S)-3-amino-8-ciklopentil-4-metiloktanske kiseline;
(3R,4S)-3-amino-8-cikloheksil-4-metiloktanske kiseline;
(3R,4S)-3-amino-9-ciklopropil-4-metilnonanske kiseline;
(3R,4S)-3-amino-9-ciklobutil-4-metilnonanske kiseline;
(3R,4S)-3-amino-9-ciklopentil-4-metilnonanske kiseline;
(3R,4S)-3-amino-9-cikloheksil-4-metilnonanske kiseline;
(3R,4S)-3-amino-4-metiloktanske kiseline;
(3R,4S)-3-amino-4-metilnonanske kiseline; i
(3R,4S)-3-amino-4-metildekanske kiseline.
Ovaj izum također se odnosi na spojeve formule IC
[image]
i njihove farmaceutski prihvatljive soli, gdje R3 je definiran kao gore, gdje se navedene spojeve bira između sljedećih spojeva i njihovih farmaceutski prihvatljivih soli:
3-amino-6-metildekanske kiseline;
3-amino-6-ciklopropilheptanske kiseline;
3-amino-6-ciklobutilheptanske kiseline;
3-amino-6-ciklopentilheptanske kiseline;
3-amino-6-cikloheksilheptanske kiseline;
3-amino-7-ciklopropil-6-metilheptanske kiseline;
3-amino-7-ciklobutil-6-metilheptanske kiseline;
3-amino-7-ciklopentil-6-metilheptanske kiseline;
3-amino-7-cikloheksil-6-metilheptanske kiseline;
3-amino-8-ciklopropil-6-metiloktanske kiseline;
3-amino-8-ciklobutil-6-metiloktanske kiseline;
3-amino-8-ciklopentil-6-metiloktanske kiseline;
3-amino-8-cikloheksil-6-metiloktanske kiseline;
3-amino-9-ciklopropil-6-metilnonanske kiseline;
3-amino-9-ciklobutil-6-metilnonanske kiseline;
3-amino-9-ciklopentil-6-metilnonanske kiseline;
3-amino-9-cikloheksil-6-metilnonanske kiseline;
3-amino-10-ciklopropil-6-metildekanske kiseline;
3-amino-10-ciklobutil-6-metildekanske kiseline;
3-amino-10-ciklopentil-6-metildekanske kiseline;
3-amino-10-cikloheksil-6-metildekanske kiseline;
3-amino-6-izopropilheptanske kiseline;
3-amino-6,8-dimetilnonanske kiseline;
3-amino-6,9-dimetildekanske kiseline;
(3S,6R)-3-amino-6-metildekanske kiseline;
(3S,6R)-3-amino-6-ciklopropilheptanske kiseline;
(3S,6R)-3-amino-6-ciklobutilheptanske kiseline;
(3S,6R)-3-amino-6-ciklopentilheptanske kiseline;
(3S,6R)-3-amino-6-cikloheksilheptanske kiseline;
(3S,6R)-3-amino-7-ciklopropil-6-metilheptanske kiseline;
(3S,6R)-3-amino-7-ciklobutil-6-metilheptanske kiseline;
(3S,6R)-3-amino-7-ciklopentil-6-metilheptanske kiseline;
(3S,6R)-3-amino-7-cikloheksil-6-metilheptanske kiseline;
(3S,6R)-3-amino-8-ciklopropil-6-metiloktanske kiseline;
(3S,6R)-3-amino-8-ciklobutil-6-metiloktanske kiseline;
(3S,6R)-3-amino-8-ciklopentil-6-metiloktanske kiseline;
(3S,6R)-3-amino-8-cikloheksil-6-metiloktanske kiseline;
(3S,6R)-3-amino-9-ciklopropil-6-metilnonanske kiseline;
(3S,6R)-3-amino-9-ciklobutil-6-metilnonanske kiseline;
(3S,6R)-3-amino-9-ciklopentil-6-metilnonanske kiseline;
(3S,6R)-3-amino-9-cikloheksil-6-metilnonanske kiseline;
(3S,6R)-3-amino-10-ciklopropil-6-metildekanske kiseline;
(3S,6R)-3-amino-10-ciklobutil-6-metildekanske kiseline;
(3S,6R)-3-amino-10-ciklopentil-6-metildekanske kiseline;
(3S,6R)-3-amino-10-cikloheksil-6-metildekanske kiseline;
(3S,6R)-3-amino-6-izopropilheptanske kiseline;
(3S,6R)-3-amino-6,8-dimetilnonanske kiseline;
(3S,6R)-3-amino-6,9-dimetildekanske kiseline;
(3S,6S)-3-amino-6-metiloktanske kiseline;
(3S,6S)-3-amino-6-metilnonanske kiseline;
(3S,6S)-3-amino-6-metildekanske kiseline;
(3S,6S)-3-amino-6-ciklopropilheptanske kiseline;
(3S,6S)-3-amino-6-ciklobutilheptanske kiseline;
(3S,6S)-3-amino-6-ciklopentilheptanske kiseline;
(3S,6S)-3-amino-6-cikloheksilheptanske kiseline;
(3S,6S)-3-amino-7-ciklopropil-6-metilheptanske kiseline;
(3S,6S)-3-amino-7-ciklobutil-6-metilheptanske kiseline;
(3S,6S)-3-amino-7-ciklopentil-6-metilheptanske kiseline;
(3S,6S)-3-amino-7-cikloheksil-6-metilheptanske kiseline;
(3S,6S)-3-amino-8-ciklopropil-6-metiloktanske kiseline;
(3S,6S)-3-amino-8-ciklobutil-6-metiloktanske kiseline;
(3S,6S)-3-amino-8-ciklopentil-6-metiloktanske kiseline;
(3S,6S)-3-amino-8-cikloheksil-6-metiloktanske kiseline;
(3S,6S)-3-amino-9-ciklopropil-6-metilnonanske kiseline;
(3S,6S)-3-amino-9-ciklobutil-6-metilnonanske kiseline;
(3S,6S)-3-amino-9-ciklopentil-6-metilnonanske kiseline;
(3S,6S)-3-amino-9-cikloheksil-6-metilnonanske kiseline;
(3S,6S)-3-amino-10-ciklopropil-6-metildekanske kiseline;
(3S,6S)-3-amino-10-ciklobutil-6-metildekanske kiseline;
(3S,6S)-3-amino-10-ciklopentil-6-metildekanske kiseline;
(3S,6S)-3-amino-10-cikloheksil-6-metildekanske kiseline;
(3S,6S)-3-amino-6-izopropilheptanske kiseline;
(3S,6S)-3-amino-6,8-dimetilnonanske kiseline; i
(3S,6S)-3-amino-6,9-dimetildekanske kiseline.
Ovaj izum također se odnosi na spojeve formule II:
[image]
gdje R1, R2 i R3 su definirani kao za formulu I, gore, i farmaceutski prihvatljive soli takvih spojeva.
Primjer specifične izvedbe ovog izuma je sljedeći spoj formule IV i njegove farmaceutski prihvatljive soli:
2-aminometil-4-propilheptanska kiselina.
Ovaj izum također se odnosi na spojeve formule IIA
[image]
gdje R3 je definiran kao za formulu I, gore, i farmaceutski prihvatljive soli takvih spojeva.
Druge specifične izvedbe ovog izuma uključuju sljedeće spojeve formule IIA i njihove farmaceutski prihvatljive soli:
2-aminometil-4-metil-7-fenilheptansku kiselinu;
2-aminometil-4-metil-6-fenilheksansku kiselinu;
2-aminometil-7-(4-fluorfenil)-4-metilheptansku kiselinu;
2-aminometil-7-(3-fluorfenil)-4-metilheptansku kiselinu;
2-aminometil-7-(2-fluorfenil)-4-metilheptansku kiselinu;
2-aminometil-7-(2,4-difluorfenil)-4-metilheptansku kiselinu;
2-aminometil-7-(3,4-difluorfenil)-4-metilheptansku kiselinu;
2-aminometil-4-metil-7-(2-trifluormetilfenil)heptansku kiselinu;
2-aminometil-4-metil-7-(3-trifluormetilfenil)heptansku kiselinu;
2-aminometil-4-metil-7-(4-trifluormetilfenil)heptansku kiselinu;
2-aminometil-4-metil-6-fenilaminoheksansku kiselinu;
2-aminometil-4-metil-7-fenilaminoheptansku kiselinu;
2-aminometil-4-metil-8-fenilaminooktansku kiselinu;
(2R,4R)-2-aminometil-4-metil-7-fenilheptansku kiselinu;
(2R,4R)-2-aminometil-4-metil-6-fenilheksansku kiselinu;
(2R,4R)-2-aminometil-7-(4-fluorfenil)-4-metilheptansku kiselinu;
(2R,4R)-2-aminometil-7-(3-fluorfenil)-4-metilheptansku kiselinu;
(2R,4R)-2-aminometil-7-(2-fluorfenil)-4-metilheptansku kiselinu;
(2R,4R)-2-aminometil-7-(2,4-difluorfenil)-4-metilheptansku kiselinu;
(2R,4R)-2-aminometil-7-(3,4-difluorfenil)-4-metilheptansku kiselinu;
(2R,4R)-2-aminometil-4-metil-7-(2-trifluormetilfenil)heptansku kiselinu;
(2R,4R)-2-aminometil-4-metil-7-(3-trifluormetilfenil)heptansku kiselinu;
(2R,4R)-2-aminometil-4-metil-7-(4-trifluormetilfenil)heptansku kiselinu;
(2R,4R)-2-aminometil-4-metil-6-fenilaminoheksansku kiselinu;
(2R,4R)-2-aminometil-4-metil-7-fenilaminoheptansku kiselinu;
(2R,4R)-2-aminometil-4-metil-8-fenilaminooktansku kiselinu;
(2R,4S)-2-aminometil-4-metil-7-fenilheptansku kiselinu;
(2R,4S)-2-aminometil-4-metil-6-fenilheksansku kiselinu;
(2R,4S)-2-aminometil-7-(4-fluorfenil)-4-metilheptansku kiselinu;
(2R,4S)-2-aminometil-7-(3-fluorfenil)-4-metilheptansku kiselinu;
(2R,4S)-2-aminometil-7-(2-fluorfenil)-4-metilheptansku kiselinu;
(2R,4S)-2-aminometil-7-(2,4-difluorfenil)-4-metilheptansku kiselinu;
(2R,4S)-2-aminometil-7-(3,4-difluorfenil)-4-metilheptansku kiselinu;
(2R,4S)-2-aminometil-4-metil-7-(2-trifluormetilfenil)heptansku kiselinu;
(2R,4S)-2-aminometil-4-metil-7-(3-trifluormetilfenil)heptansku kiselinu;
(2R,4S)-2-aminometil-4-metil-7-(4-trifluormetilfenil)heptansku kiselinu;
(2R,4S)-2-aminometil-4-metil-6-fenilaminoheksansku kiselinu;
(2R,4S)-2-aminometil-4-metil-7-fenilaminoheptansku kiselinu;
(2R,4S)-2-aminometil-4-metil-8-fenilaminooktansku kiselinu;
(2R,4S)-2-aminometil-6-cikloheksil-4-etilheksansku kiselinu;
2-aminometil-3-(1-metilciklopropil)propionsku kiselinu;
2-aminometil-3-(1-etilciklopropil)propionsku kiselinu;
2-aminometil-3-(1-propilciklopropil)propionsku kiselinu;
2-aminometil-3-(1-izopropilciklopropil)propionsku kiselinu;
2-aminometil-3-(1-butilciklopropil)propionsku kiselinu;
2-aminometil-3-(1-izobutilciklopropil)propionsku kiselinu;
2-aminometil-3-[1-(4-metilpentil)ciklopropil]propionsku kiselinu;
2-aminometil-3-(1-metilciklobutil)propionsku kiselinu;
2-aminometil-3-(1-etilciklobutil)propionsku kiselinu;
2-aminometil-3-(1-propilciklobutil)propionsku kiselinu;
2-aminometil-3-(1-metilciklopentil)propionsku kiselinu;
2-aminometil-3-(1-etilciklopentil)propionsku kiselinu;
2-aminometil-3-(1-propilciklopentil)propionsku kiselinu;
2-aminometil-3-(1-metilcikloheksil)propionsku kiselinu;
2-aminometil-3-(1-etilcikloheksil)propionsku kiselinu;
2-aminometil-3-(1-propilcikloheksil)propionsku kiselinu;
2-aminometil-4-etilheksansku kiselinu;
2-aminometil-4-etil-5-metilheksansku kiselinu;
2-aminometil-4-etilheptansku kiselinu;
2-aminometil-4-etil-6-metilheptansku kiselinu;
2-aminometil-4-etiloktansku kiselinu;
2-aminometil-4-etil-7-metiloktansku kiselinu;
2-aminometil-4-etilnonansku kiselinu;
2-aminometil-4-etil-8-metilnonansku kiselinu;
2-aminometil-4,4-dimetilheptansku kiselinu;
2-aminometil-4,4,8-trimetilnonansku kiselinu;
2-aminometil-5-etilheptansku kiselinu;
2-aminometil-5-etil-6-metilheptansku kiselinu;
2-aminometil-7-ciklopropil-5-etilheptansku kiselinu;
2-aminometil-7-ciklobutil-5-etilheptansku kiselinu;
2-aminometil-7-ciklopentil-5-etilheptansku kiselinu;
2-aminometil-7-cikloheksil-5-etilheptansku kiselinu;
2-aminometil-5-etiloktansku kiselinu;
2-aminometil-5-etil-7-metiloktansku kiselinu;
2-aminometil-5-etilnonansku kiselinu;
2-aminometil-5-etil-8-metilnonansku kiselinu;
2-aminometil-4-ciklopropilmaslačnu kiselinu;
2-aminometil-4-(1-metilciklopropil)maslačnu kiselinu;
2-aminometil-4-(1-etilciklopropil)maslačnu kiselinu;
2-aminometil-4-ciklobutilmaslačnu kiselinu;
2-aminometil-4-(1-metilciklobutil)maslačnu kiselinu;
2-aminometil-4-(1-etilciklobutil)maslačnu kiselinu;
2-aminometil-4-ciklopentilmaslačnu kiselinu;
2-aminometil-4-(1-metilciklopentil)maslačnu kiselinu;
2-aminometil-4-(1-etilciklopentil)maslačnu kiselinu;
2-aminometil-4-cikloheksilmaslačnu kiselinu;
2-aminometil-4-(1-metilcikloheksil)maslačnu kiselinu;
2-aminometil-4-(1-etilcikloheksil)maslačnu kiselinu;
(2R,4S)-2-aminometil-6-ciklopentil-4-etilheksansku kiselinu;
(2R,4S)-2-aminometil-6-ciklobutil-4-etilheksansku kiselinu; i
(2R,4S)-2-aminometil-6-ciklopropil-4-etilheksansku kiselinu.
Druge specifične izvedbe ovog izuma uključuju sljedeće spojeve formule IIA i njihove farmaceutski prihvatljive soli:
2-aminometil-4-metilheksansku kiselinu;
2-aminometil-4-metilheptansku kiselinu;
2-aminometil-4-metiloktansku kiselinu;
2-aminometil-4-metilnonansku kiselinu;
2-aminometil-4-metildekansku kiselinu;
(2R,4R)-2-aminometil-4-metilheksansku kiselinu;
(2R,4R)-2-aminometil-4-metilheptansku kiselinu;
(2R,4R)-2-aminometil-4-metiloktansku kiselinu;
(2R,4R)-2-aminometil-4-metilnonansku kiselinu;
(2R,4R)-2-aminometil-4-metildekansku kiselinu;
(2R,4S)-2-aminometil-4-metilheksansku kiselinu;
(2R,4S)-2-aminometil-4-metilheptansku kiselinu;
(2R,4S)-2-aminometil-4-metiloktansku kiselinu;
(2R,4S)-2-aminometil-4-metilnonansku kiselinu;
(2R,4S)-2-aminometil-4-metildekansku kiselinu;
2-aminometil-5-ciklopropil-4-metilpentansku kiselinu;
2-aminometil-5-ciklobutil-4-metilpentansku kiselinu;
2-aminometil-5-ciklopentil-4-metilpentansku kiselinu;
2-aminometil-5-cikloheksil-4-metilpentansku kiselinu;
2-aminometil-6-ciklopropil-4-metilheksansku kiselinu;
2-aminometil-6-ciklobutil-4-metilheksansku kiselinu;
2-aminometil-6-ciklopentil-4-metilheksansku kiselinu;
2-aminometil-6-cikloheksil-4-metilheksansku kiselinu;
2-aminometil-7-ciklopropil-4-metilheptansku kiselinu;
2-aminometil-7-ciklobutil-4-metilheptansku kiselinu;
2-aminometil-7-ciklopentil-4-metilheptansku kiselinu;
2-aminometil-7-cikloheksil-4-metilheptansku kiselinu;
2-aminometil-8-ciklopropil-4-metiloktansku kiselinu;
2-aminometil-8-ciklobutil-4-metiloktansku kiselinu;
2-aminometil-8-ciklopentil-4-metiloktansku kiselinu;
2-aminometil-8-cikloheksil-4-metiloktansku kiselinu;
(2R,4S)-2-aminometil-5-ciklopropil-4-metilpentansku kiselinu;
(2R,4S)-2-aminometil-5-ciklobutil-4-metilpentansku kiselinu;
(2R,4S)-2-aminometil-5-ciklopentil-4-metilpentansku kiselinu;
(2R,4S)-2-aminometil-5-cikloheksil-4-metilpentansku kiselinu;
(2R,4S)-2-aminometil-6-ciklopropil-4-metilheksansku kiselinu;
(2R,4S)-2-aminometil-6-ciklobutil-4-metilheksansku kiselinu;
(2R,4S)-2-aminometil-6-ciklopentil-4-metilheksansku kiselinu;
(2R,4S)-2-aminometil-6-cikloheksil-4-metilheksansku kiselinu;
(2R,4S)-2-aminometil-7-ciklopropil-4-metilheptansku kiselinu;
(2R,4S)-2-aminometil-7-ciklobutil-4-metilheptansku kiselinu;
(2R,4S)-2-aminometil-7-ciklopentil-4-metilheptansku kiselinu;
(2R,4S)-2-aminometil-7-cikloheksil-4-metilheptansku kiselinu;
(2R,4S)-2-aminometil-8-ciklopropil-4-metiloktansku kiselinu;
(2R,4S)-2-aminometil-8-ciklobutil-4-metiloktansku kiselinu;
(2R,4S)-2-aminometil-8-ciklopentil-4-metiloktansku kiselinu;
(2R,4S)-2-aminometil-8-cikloheksil-4-metiloktansku kiselinu;
(2R,4R)-2-aminometil-5-ciklopropil-4-metilpentansku kiselinu;
(2R,4R)-2-aminometil-5-ciklobutil-4-metilpentansku kiselinu;
(2R,4R)-2-aminometil-5-ciklopentil-4-metilpentansku kiselinu;
(2R,4R)-2-aminometil-5-cikloheksil-4-metilpentansku kiselinu;
(2R,4R)-2-aminometil-6-ciklopropil-4-metilheksansku kiselinu;
(2R,4R)-2-aminometil-6-ciklobutil-4-metilheksansku kiselinu;
(2R,4R)-2-aminometil-6-ciklopentil-4-metilheksansku kiselinu;
(2R,4R)-2-aminometil-6-cikloheksil-4-metilheksansku kiselinu;
(2R,4R)-2-aminometil-7-ciklopropil-4-metilheptansku kiselinu;
(2R,4R)-2-aminometil-7-ciklobutil-4-metilheptansku kiselinu;
(2R,4R)-2-aminometil-7-ciklopentil-4-metilheptansku kiselinu;
(2R,4R)-2-aminometil-7-cikloheksil-4-metilheptansku kiselinu;
(2R,4R)-2-aminometil-8-ciklopropil-4-metiloktansku kiselinu;
(2R,4R)-2-aminometil-8-ciklobutil-4-metiloktansku kiselinu;
(2R,4R)-2-aminometil-8-ciklopentil-4-metiloktansku kiselinu; i
(2R,4R)-2-aminometil-8-cikloheksil-4-metiloktansku kiselinu.
Ovaj izum također se odnosi na spojeve formule III
[image]
i njihove farmaceutski prihvatljive soli, gdje R3 je definiran kao za formulu I, gore.
Ovaj izum također se odnosi na spojeve formule IV
[image]
i njihove farmaceutski prihvatljive soli, gdje R1 i R3 su definirani kao za spojeve formule I, gore.
Druge specifične izvedbe ovog izuma uključuju sljedeće spojeve formule IV i njihove farmaceutski prihvatljive soli:
2-aminometil-6-ciklopropil-5-metilheksansku kiselinu;
2-aminometil-6-ciklobutil-5-metilheksansku kiselinu;
2-aminometil-6-ciklopentil-5-metilheksansku kiselinu;
2-aminometil-6-cikloheksil-5-metilheksansku kiselinu;
2-aminometil-7-ciklopropil-5-metilheptansku kiselinu;
2-aminometil-7-ciklobutil-5-metilheptansku kiselinu;
2-aminometil-7-ciklopentil-5-metilheptansku kiselinu;
2-aminometil-7-cikloheksil-5-metilheptansku kiselinu;
2-aminometil-8-ciklopropil-5-metiloktansku kiselinu;
2-aminometil-8-ciklobutil-5-metiloktansku kiselinu;
2-aminometil-8-ciklopentil-5-metiloktansku kiselinu;
2-aminometil-8-cikloheksil-5-metiloktansku kiselinu;
2-aminometil-5-metilheptansku kiselinu;
2-aminometil-5-metiloktansku kiselinu;
2-aminometil-5-metilheptansku kiselinu;
2-aminometil-5-metilnonansku kiselinu;
(2R,6S)-2-aminometil-6-ciklopropil-5-metilheksansku kiselinu;
(2R,6S)-2-aminometil-6-ciklobutil-5-metilheksansku kiselinu;
(2R,6S)-2-aminometil-6-ciklopentil-5-metilheksansku kiselinu;
(2R,6S)-2-aminometil-6-cikloheksil-5-metilheksansku kiselinu;
(2R,6S)-2-aminometil-7-ciklopropil-5-metilheptansku kiselinu;
(2R,6S)-2-aminometil-7-ciklobutil-5-metilheptansku kiselinu;
(2R,6S)-2-aminometil-7-ciklopentil-5-metilheptansku kiselinu;
(2R,6S)-2-aminometil-7-cikloheksil-5-metilheptansku kiselinu;
(2R,6S)-2-aminometil-8-ciklopropil-5-metiloktansku kiselinu;
(2R,6S)-2-aminometil-8-ciklobutil-5-metiloktansku kiselinu;
(2R,6S)-2-aminometil-8-ciklopentil-5-metiloktansku kiselinu;
(2R,6S)-2-aminometil-8-cikloheksil-5-metiloktansku kiselinu;
(2R,6S)-2-aminometil-5-metilheptansku kiselinu;
(2R,6S)-2-aminometil-5-metiloktansku kiselinu;
(2R,6S)-2-aminometil-5-metilheptansku kiselinu;
(2R,6S)-2-aminometil-5-metilnonansku kiselinu;
(2R,6R)-2-aminometil-6-ciklopropil-5-metilheksansku kiselinu;
(2R,6R)-2-aminometil-6-ciklobutil-5-metilheksansku kiselinu;
(2R,6R)-2-aminometil-6-ciklopentil-5-metilheksansku kiselinu;
(2R,6R)-2-aminometil-6-cikloheksil-5-metilheksansku kiselinu;
(2R,6R)-2-aminometil-7-ciklopropil-5-metilheptansku kiselinu;
(2R,6R)-2-aminometil-7-ciklobutil-5-metilheptansku kiselinu;
(2R,6R)-2-aminometil-7-ciklopentil-5-metilheptansku kiselinu;
(2R,6R)-2-aminometil-7-cikloheksil-5-metilheptansku kiselinu;
(2R,6R)-2-aminometil-8-ciklopropil-5-metiloktansku kiselinu;
(2R,6R)-2-aminometil-8-ciklobutil-5-metiloktansku kiselinu;
(2R,6R)-2-aminometil-8-ciklopentil-5-metiloktansku kiselinu;
(2R,6R)-2-aminometil-8-cikloheksil-5-metiloktansku kiselinu;
(2R,6R)-2-aminometil-5-metilheptansku kiselinu;
(2R,6R)-2-aminometil-5-metiloktansku kiselinu;
(2R,6R)-2-aminometil-5-metilheptansku kiselinu; i
(2R,6R)-2-aminometil-5-metilnonansku kiselinu.
Ovaj izum također se odnosi na farmaceutski pripravak, koji sadrži terapijski djelotvornu količinu spoja formule I, IA, IA-1, IA-2, IB, IC, II, IIA, III ili IV ili njegove farmaceutski prihvatljive soli i farmaceutski prihvatljivu podlogu.
Ovaj izum također se odnosi na postupak liječenja poremećaja ili stanja koje se bira između epilepsije, napadaja, nesvjestice fibromialgije, hipokinezije, kranijalnih poremećaja, napadaja vrućine, esencijalnog tremora, navike i ovisnosti o kemijskim sredstvima, (npr. navika ili ovisnost o alkoholu, amfetaminima (ili tvarima sličnim amfetaminima), kofeinu, kanabisu, kokainu, heroinu, halucinogenima, duhanu, inhalansima i pogonskim plinovima za aerosole, nikotinu, opioidima, fenilglicidinskim derivatima, sedativima, hipnoticima, benzodiazepinima i drugim anksioliticima), te simptoma povezanih s takvim navikama ili ovisnostima, ovisničkog ponašanja, poput kockanja; migrene, spazama, artritisa, sindroma iritabilnog crijeva (irritable bowel syndrome, IBS), kronične boli, akutne bol, neuropatske boli, vaskularne glavobolje, sinusne glavobolje, upalnih poremećaja (npr. reumatoidni artritis, osteoartritis, psorijaza), diureze (prekomjernog mokrenja), predmenstruacijskog sindroma, predmenstruacijskog disforičnog poremećaja, tinitusa (šum u ušima), te oštećenja želuca kod sisavca, uključujući čovjeka, koji se sastoji u primjeni na sisavcu kojem je potrebno takvo liječenje terapijski djelotvorne količine spoja formule I, IA, IA-1, IA-2, IB, IC, II, IIA, III ili IV ili njegove farmaceutski prihvatljive soli.
Ovaj izum također pokriva liječenje neurodegenerativnih poremećaja, pod nazivom akutne ozljede mozga. To uključuje, no ne ograničuje se na: inzult, ozljedu glave i asfiksiju.
Inzult se odnosi na cerebralnu vaskularnu bolest i može također ga se može navesti i kao cerebralni vaskularni incident (cerebral vascular incident, CVA) i uključuje akutni tromboembolički inzult. Inzult uključuje i fokalnu i globalnu ishemiju. Također su uključeni i prolazni napadaji cerebralne ishemije i drugi cerebralni vaskularni problemi koje prati cerebralna ishemija, poput onih do kojih dolazi kod pacijenata na kojima se vrši endarterektomiju karotide ili drugi kirurški zahvati na cerebralnim ili drugim krvnim žilama, ili dijagnostički zahvati na krvnim žilama, uključujući cerebralnu angiografiju i slično.
Spojevi formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III i IV također su korisni u liječenju ozljede glave, ozljede kralježnične moždine, ili ozljede uzrokovane općom anoksijom, hipoksijom, hipoglikemijom, hipotenzijom kao i sličnim ozljedama koje se sreće tijekom zahvata zbog embolusa, hiperfuzije i hipoksije. Oni su također korisni u sprječavanju oštećenje živčanog tkiva do kojeg dolazi tijekom kirurškog zahvata postavljanja premosnice na srcu, u incidentima intrakranijalnog krvarenja, kod perinatalne asfiksije, kod srčanog zastoja, te status epileptikusa.
Ovaj izum također se odnosi na postupak liječenja poremećaja ili stanja koje se bira iz grupe koju čine delirij, demencija, i amnestički i drugi kognitivni ili neurodegenerativni poremećaji, poput Parkinsonove bolest (Parkinson's disease, PD), Huntingtonove bolesti (Huntington's disease, HD), Alzheimerove bolesti, senilne demencije, demencije Alzheimerovog tipa, poremećaja pamćenja, vaskularne demencija i drugih demencija, primjerice zbog infekcije HIV-om, ozljede glave, Parkinsonove bolesti, Huntingtonove bolesti, Pickove bolesti, Creutzfeldt-Jakobove bolesti, ili zbog višestruke etiologije; poremećaji kretanja, poput akinezije, diskinezije, uključujući porodične paroksizmalne diskinezije, spazme, Touretteov sindrom, Scottov sindrom, PALSYS i akinetički rigidni sindrom; ekstrapiramidalni poremećaji kretanja, poput poremećaja kretanja uzrokovanih medikamentoznim liječenjem, primjerice, Parkinsonizam uzrokovan neurolepticima, maligni neuroleptični sindrom, akutna distonija uzrokovana neurolepticima, akutna akatizija uzrokovana neurolepticima, tardivna diskinezija uzrokovana neurolepticima i posturalni tremor uzrokovan medikamentoznim liječenjem; Downov sindrom; demijelinizirajuće bolesti poput multiple skleroze (MS) i amiolateralne skleroze (ALS), periferne neuropatije, primjerice dijabetične i neuropatije uzrokovane kemoterapijom, te postherpetične neuralgije, trigeminalne neuralgije, segmentane ili interkostalne neuralgije i druge neuralgije; te cerebrovaskularni poremećaji uzrokovani akutnim ili kroničnim cerebrovaskularnim oštećenjem, poput cerebralnog infarkta, subarahnoidalnog krvarenja ili cerebralnog edema kod sisavca, uključujući čovjeka, koji se sastoji u primjeni na navedenom sisavcu količine spoja formule I, IA, IA-1, IA-2, IB, IC, II, IIA, III ili IV, ili njegove farmaceutski prihvatljive soli, djelotvorne u liječenju takvog poremećaja ili stanja.
Bol se odnosi na akutnu kao i kroničnu bol. Akutna bol obično je kratkotrajna i povezana je s hiperaktivnošću simpatičkog živčanog sustava. Primjeri su postoperativna bol i alodinija. Kroničnu bol obično se definira kao bol koja traje 3-6 mjeseci i uključuje somatogenu i psihogenu bol. Druga bol je nociceptivna.
Primjeri tipova boli koje se može liječiti spojevima formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III i IV prema ovom izumu i njihovim farmaceutski prihvatljivim solima uključuju bol uzrokovanu oštećenje mekog tkiva i periferije, poput akutne ozljede, bol povezanu s osteoartritisom i reumatoidnim artritisom, mišićnoskeletnu bol, poput boli koju se osjeća nakon ozljede; spinalnu bol, dentalnu bol, sindrome miofascijalne boli, bol zbog epiziotomije, te bol uzrokovanu opeklinama; duboku i visceralnu bol, poput srčane boli, mišićne boli, boli u oku, orofacijalne boli, primjerice odontalgiju, abdominalnu bol, ginekološku bol, primjerice dismenoreju, porođajnu bol i bol povezanu s endometriozom; bol povezanu s oštećenjem živca i korijena živca, poput boli povezane s poremećajima perifernih živaca, primjerice uklještenjem živca i avulzijom brahijalnog spleta, amputacijom, perifernim neuropatijama, tic douloureux (bolni tik), atipičnu facijalnu bol, oštećenje korijena živca, trigeminalnu neuralgiju, neuropatsku bol u donjem dijelu leđa, neuropatsku bol povezanu s HIV-infekcijom, neuropatsku bol povezanu s rakom, dijabetičnu neuropatsku bol, te arahnoiditis; neuropatsku i neneuropatsku bol povezanu s karcinomom, koju se često navodi kao kanceroznu bol (bol uzrokovanu rakom); bol u središnjem živčanom sustavu, poput boli uzrokovane oštećenjem kralježnične moždine ili moždanog debla; bol u donjem dijelu leđa; ishijas; bol u fantomskom udu, glavobolju, uključujući migrenu i druge vaskularne glavobolje, akutnu ili kroničnu tenzijsku glavobolju, klaster glavobolju, temporomandibularnu bol i bol u maksilarnom sinusu; bol zbog ankilozantnog spondilitisa i gihta; bol uzrokovanu pojačanim kontrakcijama mokraćnog mjehura; postoperativnu bol; ožiljnu bol; te kroničnu neneuropatsku bol, poput boli povezane s fibromialgijom, infekcijom HIV-om, reumatoidnim i osteoartritisom, artralgije i mialgije, iščašenja, nategnuća i ozljede poput slomljenih kostiju; te bol nakon kirurškog zahvata.
Još daljnju bol uzrokuje ozljeda ili infekcija perifernih senzornih živaca. To uključuje, no ne ograničuje se na bol zbog ozljede perifernog živca, infekcije herpes virusom, dijabetes melitusa, fibromialgije, kauzalgije, avulzije živčanog spleta, neuroma, amputacije uda, te vaskulitisa. Neuropatsku bol također uzrokuje oštećenje živca zbog kroničnog alkoholizma, infekcije humanim imunodeficijencijskim virusu, hipotireoidizma, uremije, ili nedostataka vitamina. Neuropatska bol uključuje, no ne ograničuje se na bol uzrokovanu ozljedom živca, poput, primjerice, boli od koje pate dijabetičari.
Psihogena bol je ona koja nije organskog podrijetla, poput boli u donjem dijelu leđa, atipične facijalne boli, te kronične glavobolje.
Drugi tipovi boli su: upalna bol, osteoartritična bol, trigeminalna neuralgija, kancerozna bol, dijabetična neuropatija, sindrom nemirnih nogu, akutna herpetična i postherpetična neuralgija, kauzalgija, avulzija brahijalnog spleta, okcipitalna neuralgija, giht, fantomski ud, opekline i drugi oblici neuralgije, te sindrom neuropatske i idiopatske boli.
Spojevi prema ovom izumu također su korisni u liječenju depresije. Do depresije može doći zbog organske bolesti, stresa povezanog s osobnim gubitkom, ili je idiopatskog podrijetla. Postoji izrazita sklonost pojavi nekih oblika depresije u porodici, što ukazuje na mehanički uzrok u najmanju ruku nekih oblika depresije. Depresiju se primarno dijagnosticira kvantificiranjem promjena raspoloženja kod pacijenta. Takve procjene raspoloženja općenito provodi liječnik ili ih kvantificira neuropsiholog, pomoću vrednovanih ljestvica procjena, poput Hamiltonove ljestvice procjene depresije ili Kratke ljestvice psihijatrijske procjene. Razvijene su i brojne druge ljestvice za kvantificiranje i mjerenje stupnja promjene raspoloženja kod pacijenata s depresijom, poput nesanice, otežanog koncentriranja, nedostatka energije, osjećanja bezvrijednosti i krivice. Standardi dijagnoze depresije kao i sve psihijatrijske dijagnoze sabrane su u Dijagnostičkom i statističkom priručniku duševnih poremećaja (4. izdanje), kojeg se navodi kao DSM-IV-R priručnik (Diagnostical and Statistical Manual of Mental Disorders, Fourth Edition), kojeg je objavila Američka psihijatrijska udruga, 1994.
Ovaj izum također se odnosi na postupak liječenja poremećaja ili stanja koje se bira iz grupe koju čine poremećaji raspoloženja, poput depresije, ili preciznije, depresivnih poremećaja, primjerice jedna depresivna epizoda ili povratni veliki depresivni poremećaji, distimični poremećaji, depresivna neuroza i neurotska depresija, melankolična depresija, uključujući anoreksiju, gubitak na težini, nesanica, ranojutarnje buđenje i psihomotorička retardacija, atipična depresija (ili reaktivna depresija), uključujući pojačani tek, hipersomniju, psihomotoričku uzbuđenost ili razdražljivost, sezonski afektivni poremećaj i pedijatrijsku depresiju; ili bipolarni poremećaji ili manična depresija, primjerice bipolarni I poremećaj, bipolarni II poremećaj i ciklotimični poremećaj; poremećaj ponašanja i poremećaj anarhoidnog ponašanja; poremećaji anksioznosti, poput paničnog poremećaja sa ili bez agorafobije, agorafobije bez paničnog poremećaja u anamnezi, specifičnih fobija, primjerice specifičnih animalnih fobija, socijalne anksioznosti, socijalnih fobija, opsesivno-kompulzivnog poremećaja, stresnih poremećaja, uključujući posttraumatski stresni poremećaj i akutni stresni poremećaj, te generaliziranih anksioznih poremećaja; granični poremećaj ličnosti; shizofrenija i drugi psihotični poremećaji, primjerice, shizofreniformni poremećaji, shizoafektivni poremećaji, sumanuti poremećaji, kratkotrajni psihotični poremećaji, dijeljeni psihotični poremećaji, psihotični poremećaji s obmanama ili halucinacijama, psihotične epizode anksioznosti, anksioznost povezana s psihozom, psihotični poremećaji raspoloženja poput teškog velikog depresivnog poremećaja; poremećaji raspoloženja povezani s psihotičnim poremećajima poput akutne manije i depresije povezane s bipolarnim poremećajem, poremećaja raspoloženja povezanih sa shizofrenijom; poremećaji ponašanja povezani s mentalnom retardacijom, autistični poremećaj i poremećaj ponašanja kod sisavca, uključujući čovjeka, koji se sastoji u primjeni na navedenom sisavcu količine spoja formule I, IA, IA-1, IA-2, IB, IC, II, IIA, III ili IV, ili njegove farmaceutski prihvatljive soli, djelotvorne u liječenju takvog poremećaja ili stanja.
Spojevi prema ovom izumu također su korisni u liječenju poremećaj spavanja. Poremećaji spavanja su poremećaji koji utječu na sposobnost da se zaspi i/ili ostane spavati, što uključuje prekomjerno soavanje, ili što rezultira nenormalnim ponašanjem povezani sa spavanjem. Ti poremećaji uključuju, primjerice, nesanicu, besanost povezanu s lijekovima, hipersomniju, narkolepsiju, sindrome apneje u snu, te parasomnije.
Ovaj izum također se odnosi na postupak liječenja poremećaja ili stanja koje se bira iz grupe koju čine poremećaj spavanja (npr. nesanica, besanost povezana s lijekovima, poremećaji REM-sna, hipersomnija, narkolepsija, poremećaji ritma spavanja i budnosti, sindromi apneje u snu, parasomnije, te poremećaji spavanja povezani s radom u smjenama i nepravilnim radnim vremenom) kod sisavca, uključujući čovjeka, koji se sastoji u primjeni na navedenom sisavcu količine spoja formule I, IA, IA-1, IA-2, IB, IC, II, IIA, III ili IV, ili njegove farmaceutski prihvatljive soli, djelotvorne u liječenju takvog poremećaja ili stanja.
Spojevi formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III i IV sadrže najmanje jedan kiralni centar, te stoga mogu postojati u različitim enantiomernim i dijastereomernim oblicima. Ovaj izum odnosi se na sve optičke izomere i sve stereoizomere spojeva formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III i IV, i u obliku racemskih smjesa i u obliku pojedinačnih enantiomera i dijastereoizomera takvih spojeva i njihovih smjesa, te na sve farmaceutske pripravke i postupke liječenja definirane gore koji ih sadrže, odnosno upotrebljavaju. Pojedinačne izomere može se dobiti poznatim postupcima, poput optičkog razdvajanja, optički selektivne reakcije, ili kromatografskim razdvajanjem prilikom dobivanja konačnog produkta ili njegovog međuprodukta. Pojedinačni enantiomeri spojeva prema ovom izumu mogu biti pogodniji u usporedbi s racemskim smjesama tih spojeva u liječenju niza različitih poremećaja ili stanja.
Ovaj izum također uključuje izotopno obilježene spojeve, koji su istovjetni s onima nabrojanim u formulama I, IA, IA-1, IA-2, IB, IC, II, IIA, III i IV, s tim što su jedan ili više atoma zamijenjeni atomom s atomskom masom, odnosno masenim brojem koji se razlikuju od onih koje se obično sreće u prirodi. Primjeri izotopa koje se može ugraditi u spojeve prema ovom izumu uključuju izotope vodika, ugljika, dušika, kisik, fosfora, sumpora, fluora i klora, poput 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, odnosno 36Cl. U opseg zaštite ovog izuma ulaze spojevi prema ovom izumu, njihovi predlijekovi i farmaceutski prihvatljive soli navedenih spojeva ili navedenih predlijekova koji sadrže gore navedene izotope i/ili druge izotope drugih atoma. Izvjesni izotopno obilježeni spojevi prema ovom izumu, primjerice oni u koje su ugrađeni radioaktivni izotopi poput 3H i 14C, korisni su u testovima raspodjele lijeka i/ili supstratnog tkiva. Zbog lakoće svog dobivanja i detekcije osobito poželjni izotopi su tricij, tj. 3H, i ugljik-14, tj. 14C. Nadalje, zamjena težim izotopima poput deuterija, tj. 2H, može, zbog veće metaboličke stabilnosti, pružiti izvjesne terapijske prednosti, primjerice produljeni poluvijek in vivo ili smanjene potrebne doze, te, stoga, može biti poželjna u izvjesnim okolnostima. Izotopno obilježene spojeve formule I prema ovom izumu i njihove predlijekove obično se može dobiti postupcima opisanim u Shemama i/ili u Primjerima i Dobivanjima, niže, zamjenom izotopno neobilježenog reagensa lako dostupnim izotopno obilježenim.
Termin "alkil", kao što ga se upotrebljava u ovoj specifikaciji, ukoliko se drugačije ne naznači, uključuje zasićene jednovalentne ugljikovodične radikale s nerazgranatim, razgranatim ili prstenastim ostacima ili njihovim kombinacijama. Primjeri "alkilnih" skupina uključuju, no ne ograničuju se na metil, etil, propil, izopropil, butil, iso-, sec- i tert-butil, pentil, heksil, heptil, 3-etilbutil, ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheptil, norbornil i slično.
Termin "alkoksi", kao što ga se upotrebljava u ovoj specifikaciji, ukoliko se drugačije ne naznači, znači "alkil-O-", gdje "alkil" je definiran kao gore. Primjeri "alkoksi" skupina uključuju, no ne ograničuju se na metoksi, etoksi, propoksi, butoksi i pentoksi.
Termin "liječiti", kao što ga se upotrebljava u ovoj specifikaciji, odnosi se na povlačenje, ublažavanje, sprječavanje napredovanja, ili sprječavanje poremećaja ili stanja na koje se takav termin odnosi, ili sprječavanje jednog ili više simptoma takvog stanja ili poremećaja. Termin "liječenje", kao što ga se upotrebljava u ovoj specifikaciji, odnosi se na čin liječenja, kao što je "liječiti" definirano neposredno gore.
Kako su aminokiseline amfoterne, farmakološki kompatibilne soli mogu biti soli odgovarajućih anorganskih ili organskih kiselina, primjerice, klorovodične, sumporne, fosforne, octene, oksalne, mliječne, limunske, jabučne, salicilne, malonske, maleinske, jantarne, te askorbinske. Počevši s odgovarajućim hidroksidima ili karbonatima, dobiva se soli s alkalnim ili zemnoalkalnim metalima, primjerice natrijem, kalijem, magnezijem ili kalcij. Također se može dobiti i soli s kvaternim amonijevim ionima, primjerice s tetrametilamonijevim ionom.
Djelotvornost oralno primijenjenog lijeka ovisi o djelotvornom transportu lijeka kroz epitel sluznice i njegovoj stabilnosti u enterohepatičkom krvotoku. Lijekovi koji su djelotvorni nakon parenteralne primjene no manje djelotvorni oralno, ili čiji se poluvijek u plazmi smatra prekratkim, može se kemijski modificirati u oblik predlijeka.
Predlijek je lijek koji kemijski modificiran, a može biti biološki inaktivan na mjestu svog djelovanja, no koji se jednim ili više enzimskim ili drugim procesima in vivo može razgraditi ili modificirati do osnovnog bioaktivnog oblika.
Ovaj kemijski modificirani lijek, ili predlijek, treba imati drugačiji farmakokinetički profil od osnovnog lijeka, omogućujući tako lakšu apsorpciju kroz epitel sluznice, bolju formulaciju soli i/ili topivost, povećanu sistemnu stabilnost (primjerice radi produljenog poluvijeka u plazmi). Te kemijske modifikacije mogu biti
Esterski ili amidni derivati, koje, primjerice, mogu cijepati esteraze ili lipaze. Kod esterskih derivata ester se na poznate načine dobiva iz karboksilnokiselinskog ostatka molekule lijeka. Kod amidnih derivata amid se može na poznate načine dobiti iz karboksilnokiselinskog ili aminskog ostatak molekule lijeka.
Peptidi koje mogu prepoznati specifične ili nespecifične proteinaze. Peptid se može na poznate načine vezati na molekulu lijeka tvorbom amidne veza s aminskim ili karboksilnokiselinskim ostatkom molekule lijeka.
Berivati koji se nakupljaju na mjestu djelovanja putem membranske selekcije predlijeka ili modificiranog predlijeka kao oblika lijeka,
Bilo koja kombinacija 1-3.
Trenutno istraživanje u eksperimentima na životinjama pokazalo je da se oralnu apsorpciju izvjesnih lijekova može povećati tvorbom "mekih" kvaternih soli. Kvaternu sol naziva se "mekom" kvaternom soli stoga što, za razliku od normalnih kvaternih soli, npr. R-N+(CH3)3, može otpustiti aktivni lijek prilikom hidrolize.
"Meke" kvaterne soli imaju korisna fizička svojstva u usporedbi s bazičnim lijekom ili njegovim solima. Topivost u vodi može biti povećana u usporedbi s ostalim solima, poput hidroklorida, no tu je važnije moguća je i povećana apsorpcija lijeka iz crijeva. Apsorpcija je povećana vjerojatno zbog činjenice da "meka" kvaterna sol ima surfaktantska svojstva, te može tvoriti micele i neionizirane ionske parove sa žučnim kiselinama, itd., koji mogu djelotvornije proći kroz crijevni epitel. Predlijek se nakon apsorpcije brzo hidrolizira uz otpuštanje aktivnog osnovnog lijeka.
U opseg zaštite ovog izuma uključeni su predlijekovi spojeva formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III i IV. Predlijekovi i meki lijekovi poznati su u ovom području tehnike (E. Palomino: Drugs of Future, 15(4), 361-368, (1990.)). Posljednja dva citata uključena su u ovoj specifikaciji kao reference.
Izvjesni spojevi prema ovom izumu mogu postojati u nesolvatiranim kao i solvatiranim oblicima, uključujući hidratirane oblike. Općenito, solvatirani oblici, uključujući hidratirane oblike, ekvivalentni su nesolvatiranim oblicima i namjera je da ih se obuhvati u opseg zaštite ovog izuma.
Detaljni opis izuma
Spojeve prema ovom izumu može se dobiti kao što je opisano niže. U sljedećim reakcijskim shemama i raspravi strukturne formule I, IA, IA-1, IA-2, IB, IC, II, IIA, III i IV, te radikali R1, R2, R3, R4 R5 i R6, su definirani kao gore, ukoliko se drugačije ne navede.
Postoje različiti postupci dobivanja kiralnih i racemskih β-aminokiselina. Takve postupke može se naći u "Enantioselective Synthesis of β-Amino Acids", urednik Eusebio Juaristi, SAD, Wiley-VCH, New York, N.Y., (1997.).
Niže opisani postupci ilustracija su postupaka koje se može upotrijebiti u dobivanju takvih spojeva, no oni ne ograničuju opseg zaštite.
Postupak A
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Postupkom prema Lázáru i suradnici: Synth. Commun., 28(2), 219-224, (1998.), spojeve formule IA može se dobiti grijanjem do refluksa spojeva formule 1 u alkoholnom otapalu poput etanola, u prisustvu malonske kiseline i amonijevog acetata. Aldehide formule 1 može se dobiti iz materijala dostupnih na tržištu postupcima dobro poznatim stručnjacima u ovom području tehnike.
Spojevi koje se može načiniti gore navedenim postupkom uključuju, no ne ograničuju se na sljedeće:
3-amino-6-ciklopropil-5-metilheksansku kiselinu;
3-amino-6-ciklobutil-5-metilheksansku kiselinu;
3-amino-6-ciklopentil-5-metilheksansku kiselinu;
3-amino-6-cikloheksil-5-metilheksansku kiselinu;
3-amino-7-ciklopropil-5-metilheptansku kiselinu;
3-amino-7-ciklobutil-5-metilheptansku kiselinu;
3-amino-7-ciklopentil-5-metilheptansku kiselinu;
3-amino-7-cikloheksil-5-metilheptansku kiselinu;
3-amino-8-ciklopropil-5-metiloktansku kiselinu;
3-amino-8-ciklobutil-5-metiloktansku kiselinu;
3-amino-8-ciklopentil-5-metiloktansku kiselinu;
3-amino-8-cikloheksil-5-metiloktansku kiselinu;
3-amino-6-ciklopropil-5,5-dimetilheksansku kiselinu;
3-amino-6-ciklobutil-5,5-dimetilheksansku kiselinu;
3-amino-6-ciklopentil-5,5-dimetilheksansku kiselinu;
3-amino-6-cikloheksil-5,5-dimetilheksansku kiselinu;
3-amino-7-ciklopropil-5,5-dimetilheptansku kiselinu;
3-amino-7-ciklobutil-5,5-dimetilheptansku kiselinu;
3-amino-7-ciklopentil-5,5-dimetilheptansku kiselinu; i
3-amino-7-cikloheksil-5,5-dimetilheptansku kiselinu.
Postupak B
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Upotreba dodavanja kiralnih amina u α,β-nezasićene sustave kao sintetski pristup β-aminokiselinama, kao što je prikazano u Postupku B, gore, opisana je ranije (vidjeti, npr., S.G. Davies i suradnici: J. Chem. Soc. Chem. Commun., 1153, (1993.); S.G. Davies: Synlett., 117, (1994.); Ishikawa i suradnici: Synlett., 1291, (1998.); Hawkins: J. Org. Chem., 51, 2820, (1985.)). Osvrnuvši se na Postupak B, gore, spojeve formule IA može se dobiti iz odgovarajućih spojeva formule 7, gdje PG (protecting group) predstavlja pogodnu estersku zaštitnu skupinu, koju se može ukloniti hidrolizom ili hidrogenolizom, uz uvjete dobro poznate stručnjacima u ovom području tehnike. (Vidjeti T.W. Greene i P.G.M. Wuts.: "Protective groups in organic synthesis", Wiley, (1991.) za detaljni opis dobivanja i uklanjanja pogodnih zaštitnih skupina). Kao primjer, ovu reakciju može se provesti u hidrolitičkim uvjetima obradom odgovarajućom kiselinom, poput klorovodične ili sumporne kiseline, na temperaturi od približno sobne do približno temperature refluksa reakcijske smjese, po mogućnosti na temperaturi refluksa, ili obradom s odgovarajućom anorganskom bazom, poput natrijevog, kalijevog ili litijevog hidroksida, po mogućnosti natrijevog hidroksida, na temperaturi od približno sobne do približno temperature refluksa, po mogućnosti približno na sobnoj temperaturi. Ovu reakciju po mogućnosti se provodi uz upotrebu klorovodične kiseline, na temperaturi refluksa. Međutim, kada PG je t-butil, reakciju se po mogućnosti provodi u trifluoroctenoj kiselini (trifluoroacetic acid, TFA). Kada PG je bazična skupina, hidrolizu se može provesti u bazičnim uvjetima, postupcima dobro poznatim stručnjacima u ovom području tehnike, primjerice uz upotrebu natrijevog ili kalijevog hidroksida.
Spojeve formule 7 može se dobiti iz odgovarajućih spojeva formule 6 u uvjetima hidrogenolize dobro poznatim stručnjacima u ovom području tehnike. Kao primjer, ovu reakciju može se provesti obradom spojeva formule 6 metalnom paladijem kao katalizatorom, poput, primjerice, paladijevog hidroksida na ugljiku, ili paladija na ugljiku, ili uz Raneyev nikal, u otapalu poput, primjerice, metanola, etanola ili tetrahidrofurana, u atmosferi vodika (pod tlakom od između približno 101,3 i 506,6 kPa (1 i 5 atmosfera)) kako bi se dobilo željeni spoj formule 7. Po mogućnosti, reakciju se provodi uz paladij na ugljiku u etanolu, pod tlakom vodika od približno 101,3 kPa (1 atmosfera).
Spojeve formule 6 može se dobiti obradom odgovarajućih spojeva formule 4 odgovarajućim aminom, poput (R)-(+)-N-benzil-α-metilbenzilamina, (S)-(–)-N-benzil-α-metilbenzilamina, nakon obrade odgovarajućom bazom, poput litijevog diizopropilamida, n-butillitija ili litijevog ili kalijevog bis(trimetilsilil)amida, u otapalu poput etil-etera, ili, po mogućnosti, tetrahidrofurana (THF), na temperaturi od približno -80°C do približno 25°C, te uz dodavanje odgovarajućeg spoja formule 4. Stereokemija dušika u aminu određuje stereokemiju dušika konačnog produkta. Po mogućnosti, ovu reakciju se provodi uz upotrebu bilo (R)-(+)-N-benzil-α-metilbenzilamina ili (S)-(–)-N-benzil-α-metilbenzilamina nakon deprotoniranja n-butillitijem u tetrahidrofuranu, na temperaturi od približno -78°C, postupkom opisanim u Steven D. Bull, Stephen G. Davies i Andrew D. Smith: J. Chem. Soc, Perkin Trans. 1, 22, 2931-2938, (2001.). Po mogućnosti, ovu reakciju se provodi uz upotrebu bilo (R)-(+)-N-benzil-α-metilbenzilamina ili (S)-(–)-N-benzil-α-metilbenzilamina, nakon deprotoniranja n-butillitijem u tetrahidrofuranu, na temperaturi od približno -78°C, postupkom opisanim u Steven D. Bull, Stephen G. Davies i Andrew D. Smith: J. Chem. Soc. Perkin Trans. 1, 22, 2931-2938, (2001.).
Spojeve formule 4 može se dobiti iz odgovarajućih spojeva formule 3 njihovom obradom odgovarajućim fosfonatnim esterom u prisustvu pogodne baze, poput natrijevog hidrida, litijevog diizopropilamida ili trietilamina i bilo litijevog klorida ili litijevog bromida, u otapalu poput etera ili THF-a. Po mogućnosti, spoj formule 3 reagira s fosfonatnim esterom (ALK = metil, etil, izopropil, benzil ili slično) u prisustvu litijevog bromida i trietilamina u tetrahidrofuranu, na približno sobnoj temperaturi. Spojeve formule 3 može se dobiti iz materijala dostupnih na tržištu, postupcima dobro poznatim stručnjacima u ovom području tehnike. Treba imati na umu da spojevi formule 3 mogu posjedovati jedan ili više stereogenih centara. Gore navedenim postupkom može se dobiti i spojeve sa specifičnim stereokemijskim konfiguracijama.
Spojevi koje se može načiniti ovim postupkom uključuju, no ne ograničuju se na sljedeće:
(3S,5R)-3-amino-6-ciklopropil-5-metilheksansku kiselinu;
(3S,5R)-3-amino-6-ciklobutil-5-metilheksansku kiselinu;
(3S,5R)-3-amino-6-ciklopentil-5-metilheksansku kiselinu;
(3S,5R)-3-amino-6-cikloheksil-5-metilheksansku kiselinu;
(3S,5R)-3-amino-8-ciklopropil-5-metiloktansku kiselinu;
(3S,5R)-3-amino-8-ciklobutil-5-metiloktansku kiselinu;
(3S,5R)-3-amino-8-ciklopentil-5-metiloktansku kiselinu;
(3S,5R)-3-amino-8-cikloheksil-5-metiloktansku kiselinu;
(3S,5S)-3-amino-6-ciklopropil-5-metilheksansku kiselinu;
(3S,5S)-3-amino-6-ciklobutil-5-metilheksansku kiselinu;
(3S,5S)-3-amino-6-ciklopentil-5-metilheksansku kiselinu;
(3S,5S)-3-amino-6-cikloheksil-5-metilheksansku kiselinu;
(3S,5S)-3-amino-8-ciklopropil-5-metiloktansku kiselinu;
(3S,5S)-3-amino-8-ciklobutil-5-metiloktansku kiselinu;
(3S,5S)-3-amino-8-ciklopentil-5-metiloktansku kiselinu;
(3S,5S)-3-amino-8-cikloheksil-5-metiloktansku kiselinu;
(3S)-3-amino-6-ciklopropil-5,5-dimetilheksansku kiselinu;
(3S)-3-amino-6-ciklobutil-5,5-dimetilheksansku kiselinu;
(3S)-3-amino-6-ciklopentil-5,5-dimetilheksansku kiselinu;
(3S)-3-amino-6-cikloheksil-5,5-dimetilheksansku kiselinu;
(3S)-3-amino-7-ciklopropil-5,5-dimetilheptansku kiselinu;
(3S)-3-amino-7-ciklobutil-5,5-dimetilheptansku kiselinu;
(3S)-3-amino-7-ciklopentil-5,5-dimetilheptansku kiselinu; i
(3S)-3-amino-7-cikloheksil-5,5-dimetilheptansku kiselinu.
Postupak C
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Dijastereoalkilacija imida poput onih formule 10 kako bi se dobilo kiralne sukcinatne analoge poput onih formule 11 opisana je ranije, kao pristup dobivanju β-aminokiselina (vidjeti, npr., Evans i suradnici: J. Org. Chem., 64, 6411, (1999.); Sibi i Deshpande: J. Chem. Soc. Perkin Trans 1., 1461, (2000.); Arvanitis i suradnici: J. Chem. Soc. Perkin Trans. 1, 521, (1998.)).
Spojeve strukture 11 može se dobiti iz spojeva strukture 10, u prisustvu pogodno dobivenog estera (PG je kao što definirano gore, LG = Br, I ili Cl (LG = leaving group, izlazna grupa)) poput, primjerice, t-butil-bromacetata, benzil-bromacetata s organometalnom bazom poput, primjerice, litijevog diizopropilamida ili litijevog bis(trimetilsilil)amida ili natrijevog bis(trimetilsilil)amida i slično, u otapalu poput, primjerice tetrahidrofurana, etera i slično. Reakciju se može provesti uz upotrebu natrijevog bis(trimetilsilil)amida u tetrahidrofuranu, na -78°C, uz obradu nastalog anionskog međuprodukta t-butil-bromacetatom na -78°C do
-30°C.
Spojeve formule 12 može se dobiti hidrolizom odgovarajućih spojeva formule 11, u prisustvu litijevog hidroksida i vodikovog peroksida u otapalu poput vode ili THF-a, na temperaturi od približno 0°C do približno sobne temperature. Po mogućnosti, ovu reakciju se provodi uz upotrebu vodikovog peroksida i litijevog hidroksida u vodenoj otopini tetrahidrofurana, na približno 0°C, postupkom opisanim u literaturi (vidjeti P-W. Yuen, G.D. Kanter, C.P. Taylor i M.G. Vartanian: Bioorganic and Medicinal Chem. Lett., 4(6), 823-826, (1994.)).
Obradom spoja formule 12 difenilfosforil-azidom, u prisustvu pogodnog alkohola, poput t-butanola, benzil-alkohola ili p-metoksibenzil-alkohola, u pogodnom otapalu poput toluena, benzena ili THF-a, na temperaturi od približno 50°C do približno temperature refluksa reakcijske smjese dobije se odgovarajući spoj formule 13, gdje R5 je metil, etil, t-butil, benzil ili p-metoksibenzil. R5 ovisi o izboru upotrijebljenog alkohola. Po mogućnosti, ovu reakciju se provodi uz upotrebu toluena kao otapala, u prisustvu p-metoksibenzil-alkohola u uvjetima refluksa.
Spojeve formule 13 može se prevesti u željene spojeve formule IA hidrolizom ili hidrogenolizom, uz uvjete dobro poznate stručnjacima u ovom području tehnike. (Vidjeti T.W. Greene i P.G.M. Wuts: "Protective groups in organic synthesis", Wiley, (1991.) za detaljni opis dobivanja i uklanjanja pogodnih zaštitnih skupina). Kao primjer, ovu reakciju može se provesti u hidrolitičkim uvjetima, obradom odgovarajućom kiselinom, poput klorovodične ili sumporne kiseline, na temperaturi od približno sobne do približno temperature refluksa reakcijske smjese, po mogućnosti na temperaturi refluksa, ili obradom odgovarajućom anorganskom bazom, poput natrijevog, kalijevog ili litijevog hidroksida, po mogućnosti natrijevog hidroksida, na temperaturi od približno sobne do približno temperature refluksa, po mogućnosti približno na sobnoj temperaturi. Ovu reakciju po mogućnosti se provodi uz upotrebu klorovodične kiseline, na temperaturi refluksa. Međutim, kada PG je t-butil reakciju se po mogućnosti provodi u trifluoroctenoj kiselini (TFA). Kada PG je bazična skupina, hidrolizu se može provesti u bazičnim uvjetima, uz postupke dobro poznate stručnjacima u ovom području tehnike, primjerice uz upotrebu natrijevog ili kalijevog hidroksida.
Spojeve formule 10 može se dobiti obradom odgovarajućih spojeva formule 8 aminskom bazom, poput trietilamina, u prisustvu trimetilacetil-klorida, u eterskom otapalu, poput THF-a, a zatim obradom međuprodukata dobivenih ovom reakcijom [na licu mjesta] s kiralnim oksazolidinonom formule 9. Primjeri drugih oksazolidonona koje se može upotrijebiti u ovom postupku su: (4S)-(–)-4-izopropil-2-oksazolidinon; (S)-(–)-4-benzil-2-oksazolidinon; (4S,5R)-(–)-4-metil-5-fenil-2-oksazolidinon; (R)-(+)-4-benzil-2-oksazolidinon, (S)-(+)-4-fenil-2-oksazolidinon; (R)-(–)-4-fenil-2-oksazolidinon; (R)-4-izopropil-2-oksazolidinon; te (4R,5S)-(+)-4-metil-5-fenil-2-oksazolidinon)) i litijev klorid. Po mogućnosti, ovu reakciju provodi se obradom kiseline formule 8 trimetilacetil-kloridom i trietilaminom u tetrahidrofuranu, na približno -20°C, a zatim obradom međuprodukta dobivenog takvom reakcijom oksazolidinonom formule 9 i litijevim kloridom na približno sobnoj temperaturi, postupcima iz literature (Vidjeti G-J. Ho i D.J. Mathre: J. Org. Chem., 60, 2271-2273, (1995.)).
Alternativno se spojeve formule 10 može dobiti obradom odgovarajućih spojeva formule 9 kiselinskim kloridom dobivenim obradom odgovarajućeg spoja formule 8 oksalil-kloridom, u otapalu poput diklormetana, u prisustvu dimetilformamida (DMF). Kiseline formule 8 može se dobiti iz materijala dostupnih na tržištu, postupcima dobro poznatim stručnjacima u ovom području tehnike. Te kiseline mogu posjedovati jedan ili više kiralnih centara. Upotreba citronelil-bromida i citronelola u sintezi takvih kiseline opisana je u Primjerima 1, 2 i 3 ove patentne prijave.
Spojevi koje se može dobiti gore navedenim Postupkom C uključuju, no ne ograničuju se na sljedeće:
(3S,5R)-3-amino-5-metilheptansku kiselinu;
(3S,5R)-3-amino-5-metiloktansku kiselinu;
(3S,5R)-3-amino-5-metilnonansku kiselinu;
(3S,5R)-3-amino-5-metildekansku kiselinu;
(3S,5S)-3-amino-5-metilheptansku kiselinu;
(3S,5S)-3-amino-5-metiloktansku kiselinu;
(3S,5S)-3-amino-5-metilnonansku kiselinu;
(3S,5S)-3-amino-5-metildekansku kiselinu;
(3S)-3-amino-5,5-dimetilheptansku kiselinu;
(3S)-3-amino-5,5-dimetiloktansku kiselinu;
(3S)-3-amino-5,5-dimetilnonansku kiselinu;
(3S)-3-amino-5,5-dimetildekansku kiselinu;
(3S,5R)-3-amino-7-ciklopropil-5-metilheptansku kiselinu;
(3S,5R)-3-amino-7-ciklobutil-5-metilheptansku kiselinu;
(3S,5R)-3-amino-7-ciklopentil-5-metilheptansku kiselinu;
(3S,5R)-3-amino-7-cikloheksil-5-metilheptansku kiselinu;
(3S,5S)-3-amino-7-ciklopropil-5-metilheptansku kiselinu;
(3S,5S)-3-amino-7-ciklobutil-5-metilheptansku kiselinu;
(3S,5S)-3-amino-7-ciklopentil-5-metilheptansku kiselinu; i
(3S,5S)-3-amino-7-cikloheksil-5-metilheptansku kiselinu.
Alternativno, osvrnuvši se na reakcijsku shemu (Postupak D), niže, spojeve formule 11 može se obraditi odgovarajućom kiselinom (primjerice trifluoroctenom kiselinom (TFA) kada se upotrebljava t-butilni ester) kako bi se dobilo odgovarajuće spojeve formule 14, koje se zatim može podvrgnuti Curtiusovoj pregradnji (gdje R5 je definiran kao gore) kako bi se dobilo odgovarajuće spojeve formule 15 (vidjeti Arvanitis i suradnici: J. Chem. Soc. Perkin Trans. 1, 521, (1998.) za opis ovog pristupa). Daljnjom hidrolizom imidne skupine (kako bi se dobilo odgovarajući spoj formule 16) i karbamatne skupine dobije se željene β-aminokiseline formule II.
Spoj 16 može se dobiti iz spoja 15 kao što je opisano gore za prevođenje spojeva formule 11 u spojeve formule 12. Spojeve formule 17 može se dobiti iz odgovarajućih spojeva formule 16 obradom jakom kiselinom, poput klorovodične kiseline ili slično, jakom bazom, poput natrijevog ili kalijevog hidroksida ili, ako R5 je benzil ili p-metoksibenzil, u hidrogenolitičkim uvjetima, uz upotrebu paladija na ugljiku u etanolu ili THF-u, u atmosferi vodika. Ovaj pristup, koji čuva stereokemiju oko kiralnog centra u spojevima formule 11, koja je također prisutna u produktu formule II, opisan je u Primjeru 4 ove patentne prijave.
Postupak D
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Spojevi koje se može načiniti ovim postupkom uključuju, no ne ograničuju se na sljedeće:
(2R,4R)-2-aminometil-4-metilheksansku kiselinu;
(2R,4R)-2-aminometil-4-metilheptansku kiselinu;
(2R,4R)-2-aminometil-4-metiloktansku kiselinu;
(2R,4R)-2-aminometil-4-metilnonansku kiselinu;
(2R,4R)-2-aminometil-4-metildekansku kiselinu;
(2R,4S)-2-aminometil-4-metilheksansku kiselinu;
(2R,4S)-2-aminometil-4-metilheptansku kiselinu;
(2R,4S)-2-aminometil-4-metiloktansku kiselinu;
(2R,4S)-2-aminometil-4-metilnonansku kiselinu;
(2R,4S)-2-aminometil-4-metildekansku kiselinu;
(2R,4S)-2-aminometil-6-ciklopropil-4-metilheksansku kiselinu;
(2R,4S)-2-aminometil-6-ciklobutil-4-metilheksansku kiselinu;
(2R,4S)-2-aminometil-6-ciklopentil-4-metilheksansku kiselinu; i
(2R,4S)-2-aminometil-6-cikloheksil-4-metilheksansku kiselinu.
Drugi alternativni pristupi sintezi α-supstituiranih β-aminokiselina koje se može upotrijebiti u dobivanju spojeva prema ovom izumu uključuju one opisane u Juaristi i suradnici: Tetrahedron Asymm., 7, (8), 2233, (1996.) i Seebach i suradnici: Eur. J. Org. Chem., 335, (1999.), ili u Arvanitis i suradnici: J. Chem. Soc. Perkin Trans. 1, 521, (1998.), kao što je prikazano u Postupku E, niže.
Postupak E
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Postupak F, niže, ilustrira alternativni postupak dobivanja spojeva formule II.
Postupak F
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Postupkom otkrivenim u Hoffmann-La Roche (FR 1377736 19641106), spojeve formule 3 može se dobiti iz nezasićenih cijanoestera formule 2 redukcijom i hidrolizom. S druge strane, cijanoestere 2 može se dobiti Knoevenagelovom kondenzacijom aldehida 1 s esterima cijanooctene kiseline (npr. J.B. Paine, R.B. Woodward, D. Dolphin: J. Org. Chem., 41, 2826, (1976.)). Aldehide formule 1 može se dobiti materijala dostupnih na tržištu, postupcima poznatim stručnjacima u ovom području tehnike.
Spojeve formula III i IV može se dobiti postupcima analognim onima u Postupku F koji će biti očiti stručnjacima u ovom području tehnike. Prilikom sinteze spoja formule III polazni materijal treba biti spoj sličan onom formule 1 u Postupku F, no gdje je vodik vezan na karbonilnu skupinu u formuli 1 zamijenjen metilnom skupinom.
Upotreba kiralnih imina kako bi se dobilo β-aminokiseline, kao što je prikazano u Postupku G, niže, opisana je ranije (vidjeti, npr., T.P. Tang, J.A. Ellman: J. Org. Chem., 64, 12-13, (1999.)).
Postupak G
[image]
Konačni korak u shemi gore je hidroliza i sulfonamidne i esterske skupine. Ovu reakciju općenito se provodi uz upotrebu jake kiseline, poput klorovodične, bromovodične ili sumporne kiseline, u otapalu poput vode ili dioksana ili smjesi vode i dioksana, na temperaturi od približno 20 °C do približno 50°C, po mogućnosti približno na sobnoj temperaturi.
Dobivanje spojeva prema ovom izumu koji nisu specifično opisani u prethodnom eksperimentalnom odsječku može se postići uz upotrebu kombinacija gore opisanih reakcija koje će biti očite stručnjacima u ovom području tehnike.
U svakoj od reakcija prodiskutiranih ili prikazanih gore tlako nije kritičan, ukoliko nije drugačije navedeno. Općenito je prihvatljiv tlak od približno 50,7 kPa (0,5 atmosfera) do približno 506,6 kPa (5 atmosfera), a kao stvar pogodnosti poželjan je okolišni tlak, tj. približno 101,3 kPa (1 atmosfera).
Spojeve formule 1 i Skupinu A spojeva i međuprodukata prikazanih u reakcijskim shemama, gore, može se izdvojiti i pročistiti konvencionalnim postupcima, poput prekristalizacije ili kromatografskog razdvajanja.
Sposobnost spojeva prema ovom izumu da se vežu na α2δ-podjedinicu kalcijskog kanala može se odrediti sljedećim testom vezanja.
Upotrijebljen je test vezanja radioliganada uz upotrebu [3H]-gabapentina i α2δ-podjedinice dobivene iz tkiva svinjskog mozga (Vidjeti, Nicolas S. Gee i suradnici: "The novel anticonvulsant drug, gabapentin (Neurontin), binds to the α2δ subunit of calcium channel", J. Biol. Chem., 271(10), 5768-76, (1996.)). Spojevi prema ovo izumu vežu se s nanomolarnim do mikromolarnim afinitetom za α2δ-protein. Kao primjer, R-3-amino-5,9-dimetildekanska kiselina veže se na α2δ-protein s afinitetom od 527 nM, (3S,5S)-3-amino-5-metiloktanska kiselina veže se s afinitetom od 1 µM, (2R,4R)-2-aminometil-4-metilheptanska kiselina veže se s afinitetom 29 nM, a 2-aminometil-4,4-dimetilheptanska kiselina veže se s afinitetom od 83 nM.
Aktivnost spojeva prema ovom izumu in vivo može se odrediti u životinjskim modelima hiperalgezije (vidjeti K. Sluka i suradnici: "Unilateral Intramuscular Injections Of Acidic Saline Produce A Bilateral, Long-Lasting Hyperalgesia", Muscle Nerve, 24, 37-46, (2001.); W. Dixon: (1980.), "Efficient analysis of experimental observations", Ann. Rev. Pharmacol. Toxicol., 20, 441-462; L.O. Randall i J.J. Selitto: "A Method For Measurement Of Analgesic Activity On Inflamed Tissue", Arch. Int. Pharmacodyn., 4, 409-419, (1957.); K. Hargreaves, R. Dubner, F. Brown, C. Flores i J. Joris: "A New And Sensitive Metod For Measuring Thermal Nociception In Cutaneous Hyperalgesia", Pain, 32, 77-88, (1988.)), anksioznosti (J.R. Vogel, B. Beer i D.E. Clody: "A Simple And Reliable Conflict Procedure For Testing Anti-Anxiety Agents", Psychopharmacologia, 21, 1-7, (1971.)),
Spojeve prema ovom izumu, kao i njihove farmaceutski prihvatljive soli, može se primijeniti na sisavcima bilo oralno, parenteralno (primjerice supkutano, intravenski, intramuskularno, intrasternalno, te infuzijskim tehnikama), rektalno, bukalno ili intranazalno.
Nove spojeve prema ovom izumu može se primijeniti same, ili u kombinaciji s farmaceutski prihvatljivim podlogama ili razrjeđivačima, na bilo koji od gore nabrojanih načina, a takvu primjenu može se provesti u jednoj ili više doza. Preciznije, nova terapijska sredstva prema ovom izumu može se primijeniti u nizu različitih oblika doziranja, tj. može ih se kombinirati s različitim farmaceutski prihvatljivim inertnim podlogama u oblik tableta, kapsula, pastila, dražeja, tvrdih bombona, supozitorija, želea, gelova, pasta, masti, vodenih suspenzija, otopina za injekcije, ljekovitih napitaka, sirupa i slično. Takve podloge uključuju čvrste razrjeđivače ili punila, sterilne vodene medije i različita netoksična organska otapala itd. Osim toga, oralne farmaceutske pripravke može se pogodno zasladiti i/ili aromatizirati. Općenito, odnos težine novih spojeva prema ovom izumu prema farmaceutski prihvatljivoj podlozi bit će u rasponu od približno 1:6 do približno 2:1, po mogućnosti od približno 1:4 do približno 1:1.
Prilikom oralne primjene tablete koje sadrže različite pomoćne tvari, poput mikrokristalne celuloze, natrijevog citrata, kalcijevog karbonata, dikalcijevog fosfata i glicina može se upotrijebiti zajedno s različitim sredstvima za raspadanje, poput škroba (po mogućnosti kukuruznog, krumpirovog ili tapiokinog škroba), alginske kiseline i izvjesnih složenih silikata, zajedno s granulacijskim vezivima, poput polivinilpirolidona, saharoze, želatine i arapske gume. Uz to, prilikom tabletiranja često su vrlo korisna i maziva, poput magnezijevog stearata, natrijevog lauril-sulfata i talka. Čvrste pripravke sličnog tipa također se može upotrijebiti i kao punila u želatinskim kapsulama; poželjni materijali s tim u vezi također uključuju laktozu, odnosno mliječni šećer, kao i visokomolekulske polietilen-glikole. Kada se za oralnu primjenu želi upotrijebiti vodene suspenzije i/ili ljekovite napitke, aktivni sastojak može se kombinirati s različitim sladilima ili aromama, bojama ili bojilima, te, po želji, s emulgatorima i/ili suspendirajućim sredstvima, zajedno s razrjeđivačima poput vode, etanola, propilen-glikola, glicerola i njihovim različitim sličnim kombinacijama.
Prilikom parenteralne primjene može se upotrijebiti otopine spoja prema ovom izumu u sezamovom ili kikirikijevom ulju, ili u vodenoj otopini propilen-glikola. Vodene otopine treba po potrebi pogodno puferirati (po mogućnosti na pH iznad 8), a tekući razrjeđivač najprije izotonizirati. Te vodene otopine pogodne su za intravenske injekcije. Uljne otopine pogodne su za intraartikularne, intramuskularne i supkutane injekcije. Pripravu svih tih otopina u sterilnim uvjetima lako se postiže standardnim farmaceutskim tehnikama, dobro poznatim stručnjacima u ovom području tehnike.
Prilikom intranazalne primjene ili primjene inhalacijom se nove spojeve prema ovom izumu na pogodan način unosi u obliku otopine ili suspenzije iz spremnika za sprej s pumpicom koju stišće ili pumpa pacijent ili kao prezentaciju u obliku aerosolnog spreja iz spremnika pod tlakom ili nebulizatora, uz upotrebu pogodnog pogonskog plina, npr. diklordifluormetana, triklorfluormetana, diklortetrafluoretana, ugljičnog dioksida ili drugog pogodnog plina. U slučaju aerosola pod tlakom, jedinicu doziranja može se odrediti pomoću ventila, kojim se otpušta odmjerena količina. Spremnik pod tlakom ili nebulizator može sadržavati otopinu ili suspenziju aktivnog spoja. Kapsule i uloške (načinjene, primjerice, iz želatine) namijene upotrebi u inhalatoru ili insuflatoru može se tako formulirati da sadrže praškastu smjesu spoja prema ovom izumu i pogodne praškaste podloge, poput laktoze ili škroba. Formulacije aktivnih spojeva prema ovom izumu namijenjene liječenju gore navedenih stanja kod prosječnog odraslog čovjeka po mogućnosti su tako podešene da svaka odmjerena doza ili "dašaka" aerosola sadrži 20-1000 µg aktivnog spoja. Ukupna dnevna doza s aerosolom bit će u rasponu od 100 µg do 10 mg. Primjenu se može vršiti nekoliko puta dnevno, primjerice 2, 3, 4 ili 8 puta, uzevši kao primjer 1, 2 ili 3 doze svaki put.
Spojeve prema ovom izumu može se oblikovati i primijeniti u nizu različitih oralnih i parenteralnih oblika doziranja. Tako se spojeve prema ovom izumu može primijeniti injekcijom, tj. intravenski, intramuskularno, intrakutano, supkutano, intraduodenalno ili intraperitonealno. Spojeve prema ovom izumu također se može primijeniti inhalacijom, primjerice intranazalno. Uz to, spojeve prema ovom izumu može se primijeniti transdermalno. Stručnjacima u ovom području tehnike bit će očito da sljedeći oblici doziranja mogu kao aktivnu komponentu sadržavati bilo spoj formule I, IA, IA-1, IA-2, IB, IC, II, IIA, III ili IV, ili odgovarajuću farmaceutski prihvatljivu sol takvog spoja.
Prilikom priprave farmaceutskih pripravaka iz spojeva prema ovom izumu farmaceutski prihvatljive podloge mogu biti bilo čvrste ili tekuće. Čvrsti oblici pripravaka uključuju praške, tablete, pilule, kapsule, kašete, supozitorije i disperzibilne granule. Čvrsta podloga može biti jedna ili više tvari, koje također mogu djelovati kao razrjeđivači, arome, veziva, konzervansi, tabletna sredstava za raspadanje ili inkapsulacijski materijal. U prahu podloga je fino razdijeljena krutina, koja je u smjesi s fino razdijeljenom aktivnom komponentom. U tabletama, aktivna komponenta je pomiješana s podlogom nužnih vezivnih svojstava, u pogodnim odnosima, te komprimirana u željeni oblik i veličinu.
Prašci i tablete po mogućnosti sadrže 5 ili 10 do približno 70 % aktivnog spoja. Pogodne podloge su magnezijev karbonat, magnezijev stearat, talk, šećer, laktoza, pektin, dekstrin, škrob, želatina, tragakant, metilceluloza, natrijeva karboksimetilceluloza, vosak niskog tališta, kakao-maslac i slično. Namjera je da termin "pripravak" uključuje formulaciju aktivnog spoja s inkapsulacijskim materijalom kao podlogom koji osigurava kapsulu u kojoj aktivnu komponentu, sa ili bez drugih podloga, okružuje podloga, koja je tako s njom u kontaktu. Slično tome, uključene su kašete i pastile. Kao čvrste oblike doziranja pogodne za oralnu primjenu može se upotrijebiti tablete, praške, kapsule, pilule, kašete i pastile.
Priliko priprave supozitorija najprije se rastali vosak niskog tališta, poput smjese glicerida masnih kiselina ili kakao-maslaca, a aktivnu komponentu homogeno dispergira unutar toga, primjerice miješanjem. Rastaljenu homogenu smjesu se zatim izlije u pogodno oblikovane kalupe, pusti neka se ohladi, te skrutne.
Tekući oblici pripravaka uključuju otopine, suspenzije i emulzije, primjerice otopine u vodi ili smjesi vode i propilen-glikola. Prilikom parenteralnih injekcija tekuće se pripravke može formulirati u otopini u vodenoj otopini polietilen-glikola. Vodene otopine pogodne za oralnu upotrebu može se pripraviti otapanjem aktivne komponente u voda, uz dodatak pogodnih boja, aroma, stabilizacijskih i sredstava za zgušćivanje, po želji. Vodene suspenzije pogodne za oralnu upotrebu može se načiniti dispergiranjem fino razdijeljene aktivne komponente u vodi s viskoznim materijalom, poput prirodnih ili sintetskih guma, smola, metilceluloze, natrijeve karboksimetilceluloze i drugih dobro poznatih sredstava za suspendiranje.
Također su uključeni i čvrsti oblici pripravaka koje treba pretvoriti, neposredno prije upotrebe, u tekuće oblike pripravaka za oralnu primjenu. Takvu tekući oblici uključuju otopine, suspenzije i emulzije. Ti pripravci mogu sadržavati, uz aktivnu komponentu, boje, arome, stabilizatore, pufere, umjetna i prirodna sladila, sredstva za dispergiranje, sredstva za zgušćivanje, solubilizacijska sredstva i slično.
Farmaceutski pripravak po mogućnosti je u obliku jedinice doziranja. U takvom obliku pripravak je razdijeljen u jedinice doziranja, koje sadrže odgovarajuće količine aktivne komponente. Oblik jedinice doziranja može biti ambalažirani pripravak, gdje pakiranje sadrži diskretne količine pripravka, poput pakiranih tableta, kapsula i prašaka u bočicama ili ampulama. Također, oblik jedinice doziranja mogu biti i same kapsule, tableta, kašeta ili pastila, ili to može biti odgovarajući broj bilo kojeg od navedenog u pakiranom obliku.
Količina aktivne komponente u jedinici doziranja pripravka može varirati ili s podesiti od 0,01 mg do 1 g prema pojedinoj primjeni i potentnosti aktivne komponente. Prilikom medicinske upotrebe lijek se može primijeniti 3 × dnevno, kao primjer, kapsule od 100 ili 300 mg. Pripravak može, po želji, također sadržavati i druga kompatibilna terapijska sredstva.
Prilikom terapijske upotrebe spojevi upotrijebljeni u farmaceutskom postupku prema ovom izumu primjenjuje se u početnoj dozi približno 0,1 mg približno 1 g dnevno. Doze, međutim, mogu varirati ovisno o potrebama pacijenta, težini stanja kojeg se liječi i spoju kojeg se upotrebljava. Određivanje doze odgovarajuće za određenu situaciju dio je vještine ovog područja tehnike. Općenito, liječenje se započinje manjim dozama, koje su manje od optimalne doze spoja. Dozu se zatim povećava malim prirastima dok se ne postigne optimalni učinak za dotične uvjete. Pogodnosti radi ukupnu dnevnu dozu se može, po želji, podijeliti i primijeniti u dijelovima tijekom dana.
Primjeri koji slijede ilustriraju dobivanje spojeva prema ovom izumu, no nije namjera da budu i ograničenje opsega zaštite. Tališta su nekorigirana. NMR podaci su iznijeti u dijelovima na milijun, a referentni signal je deuterijski ključni signal iz otapala za uzorak.
PRIMJERI
Primjer 1
Hidroklorid (3S,5R)-3-amino-5-metiloktanske kiseline
(R)-2,6-dimetilnon-2-en
(S)-citronelil-bromidu (50 g, 0,228 mol) u THF-u (800 ml) na 0°C doda se LiCl (4,3 g), a zatim CuCl2 (6,8 g). Nakon 30 minuta doda se metilmagnezijev klorid (152 ml 3 M otopine u THF-u, Aldrich), a otopinu zagrije do sobne temperature. Nakon 10 sati otopinu se ohladi do 0°C, te se polako doda zasićena vodena otopina amonijevog klorida. Nastala dva sloja se razdvoji, a vodenu fazu ekstrahira eterom. Zajedno prikupljene organske faze se osuši (MgSCl2), te koncentrira kako bi se dobilo (R)-2,6-dimetilnon-2-en; 32,6 g; 93 %. Upotrebljava ga se bez daljnjeg pročišćavanja.
1H-NMR (400 MHz; CDCl3) δ 5,1 (m, 1H), 1,95 (m, 2H), 1,62 (s, 3H), 1,6 (s, 3H), 1,3 (m, 4H), 1,2 (m, 2H), 0,8 (s, 6H).
13C-NMR (100 MHz; CDCl3) δ 131,13, 125,28, 39,50, 37,35, 32,35, 25,92, 25,77, 20,31, 19,74, 17,81, 14,60.
(R)-4-metilheptanska kiselina
(R)-2,6-dimetilnon-2-enu (20 g, 0,13 mol) u acetonu (433 ml) se u trajanju od 50 minuta dodaje otopina CrO3 (39 g, 0,39 mol) u H2SO4 (33 ml)/H2O (146 ml). Nakon 6 sati doda se još CrO3 (26 g, 0,26 mol) u H2SO4 (22 ml)/H2O (100 ml). Nakon 12 sati otopinu se razrijedi slanom vodom, a otopinu ekstrahira eterom. Zajedno prikupljene organske faze se osuši (MgSCl2), te koncentrira. Flash-kromatografijom (gradijent od 6:1 do 2:1 smjese heksan/EtOAc (etil-acetat)) dobije se (R)-4-metilheptanska kiselina u obliku ulja; 12,1 g; 65 %.
MS, m/z (relativni intenzitet): 143 [M – H, 100 %].
1H-NMR (400 MHz; CDCl3) δ 2,35 (m, 2H), 1,6 (m, 1H), 1,4 (m, 1H), 1,3 (m, 4H), 1,1 (m, 1H), 0,85 (s, 6H).
(4R,5S)-4-metil-3-((R)-4-metilheptanoil)-5-fenil-oksazolidin-2-on
(R)-4-metilheptanskoj kiselini (19 g, 0,132 mol) i trietilaminu (49,9 g, 0,494 mol) u THF-u (500 ml) na 0°C doda se trimetilacetil-klorid (20 g, 0,17 mol). Nakon 1 sata doda se LiCl (7,1 g, 0,17 mol), a zatim (4R,5S)-(+)-4-metil-5-fenil-2-oksazolidinon) 3 (30 g, 0,17 mol). Smjesu se zagrije do sobne temperature, a nakon 16 sati filtrat se ukloni filtracijom, a otopinu koncentrira pod sniženim tlakom. Flash-kromatografijom (7:1 smjesa heksan/EtOAc) dobije se (4R,5S)-4-metil-3-((R)-4-metilheptanoil)-5-feniloksazolidin-2-on u obliku ulja; 31,5 g; 79 %.
[α]D = +5,5 (c = 1 u CHCl2).
MS, m/z (relativni intenzitet): 304 [M + H, 100 %].
1H-NMR (400 MHz; CDCl3) δ 7,4-7,2 (m, 5H), 5,6 (d, J = 7,32 Hz, 1H), 4,75 (m, 1H), 2,96 (m, 1H), 2,86 (m, 1H), 1,62 (m, 1H), 1,43 (m, 1H), 1,25 (m, 4H), 1,12 (m, 1H), 0,85 (m, 9H).
13C-NMR (100 MHz; CDCl3) δ 173,70, 153,23, 133,81, 133,59, 128,92, 128,88, 128,92, 128,88, 125,83, 79,12, 54,93, 39,24, 33,66, 32,32, 31,47, 27,18, 26,52, 20,25, 19,57, 14,75, 14,52.
tert-butilni ester (3S,5R)-5-metil-3-((4R,5S)-4-metil-2-okso-5-feniloksazolidin-3-karbonil)oktanske kiseline
(4R,5S)-4-metil-3-((R)-4-metilheptanoil)-5-feniloksazolidin-2-onu (12,1 g, 0,04 mol) u THF-u (200 ml) na -50°C doda se natrijev bis(trimetilsilil)amid (48 ml 1 M otopine u THF-u). Nakon 30 minuta doda se t-butil-bromacetat (15,6 g, 0,08 mol). Otopinu se miješa 4 sata na -50°C, te grije do sobne temperature. Nakon 16 sati doda se zasićena vodena otopina amonijevog klorida, a dva sloja razdvoji. Vodenu fazu ekstrahira se eterom, a zajedno prikupljene organske faze osuši (MgSO4), te koncentrira. Flash-kromatografijom (9:1 smjesa heksan/EtOAc) dobije se tert-butilni ester (3S,5R)-5-metil-3-((4R,5S)-4-metil-2-okso-5-feniloksazolidin-3-karbonil)oktanske kiseline u obliku bijele krutine; 12 g; 72 %.
[α]D = +30,2 (c = 1 u CHCl3).
13C-NMR (100 MHz; CDCl3) δ 176,47, 171,24, 152,72, 133,63, 128,87, 125,86, 80,85, 78,88, 55,34, 39,98, 38,77, 38,15, 37,58, 30,60, 28,23, 20,38, 20,13, 14,50, 14,28.
4-tert-butilni ester (S)-2-((R)-2-metilpentil)jantarne kiseline
tert-butilnom esteru (3S,5R)-5-metil-3-((4R,5S)-4-metil-2-okso-5-feniloksazolidin-3-karbonil)-oktanske kiseline (10,8 g, 0,025 mol) u H2O (73 ml) i THF-u (244 ml) na 0°C doda se prethodno pomiješana otopina LiOH (51,2 ml 0,8 M otopine) i H2O2 (14,6 ml 30 % otopine). Nakon 4 sata doda se još 12,8 ml LiOH (0,8 M otopina) i 3,65 ml H2O2 (30 % otopina). Nakon 30 minuta doda se natrijev bisulfit (7 g), natrijev sulfit (13 g) i voda (60 ml), a zatim heksan (100 ml) i eter (100ml). Dva sloja se razdvoji, a vodeni ekstrahira eterom. Zajedno prikupljene organske faze koncentrira se do ulja, koje se otopi u heptanu (300 ml). Nastalu krutinu se otfiltrira, a filtrat osuši (MgSO4) i koncentrira kako bi se dobilo 4-tert-butilni ester (S)-2-((R)-2-metilpentil)jantarne kiseline (6 g, 93 %), koji se upotrijebi odmah, bez dodatnog pročišćavanja.
MS, m/z (relativni intenzitet): 257[M + H, 100 %].
tert-butilni ester (3S,5R)-3-benziloksikarbonilamino-5-metiloktanske kiseline
Otopinu 4-tert-butilnog estera (S)-2-((R)-2-metilpentil)jantarne kiseline (6,0 g, 23,22 mmol) i trietilamina (3,64 ml, 26,19 mmol) u toluenu (200 ml) obradi se difenilfosforil-azidom (5,0 ml, 23,22 ml), te miješa na sobnoj temperaturi 30 minuta. Nakon toga se reakcijsku smjesu grije na refluksu 3 sata, te nakratko ohladi, doda se benzil-alkohol (7,2 ml, 69,7 mmol), a otopinu grije još 3 sata. Nakon toga se reakcijsku smjesu pusti da se ohladi, razrijedi etil-eterom (200 ml), a zajedno prikupljene organske slojeve uzastopce ispere zasićenom otopinom NaHCO3 i slanom vodom, te osuši (Na2SO4). Koncentriranu organsku komponentu pročisti se kromatografijom (MPLC (medium pressure liquid chromatography = srednjetlačna tekućinska kromatografija)), uz eluiranje 8:1 smjesom heksani:etil-acetat kako bi se dobilo tert-butilni ester (3S,5R)-3-benziloksikarbonilamino-5-metiloktanske kiseline (6,4 g, 75,8 %).
MS: M + 1: 364,2, 308,2.
1H-NMR (400 MHz, CDCl3) δ 0,83 (t, 3H, J = 6,59 Hz), 0,87 (d, 3H, J = 6,59 Hz), 1,08-1,34 (m, 6H), 1,39 (s, 9H), 1,41-1,52 (m, 2H), 2,39 (m, 2H), 4,02 (m, 1H), 5,05 (s, 2H), 5,09 (m, 1H) i 7,24-7,32 (m, 5H) ppm.
tert-butilni ester (3S,5R)-3-amino-5-metiloktanske kiseline
Otopinu tert-butilnog estera (3S,5R)-3-benziloksikarbonilamino-5-metiloktanske kiseline (2,14g, 5,88 mmol) u THF-u (50 ml) 2 sata se obrađuje s Pd/C (0,2 g) i H2, pod tlakom od 344,7 kPa (50 psi). Reakciju smjesu se zatim filtrira, te u vakuumu koncentrira do ulja kako bi se dobilo tert-butilni ester (3S,5R)-3-amino-5-metiloktanske kiseline, uz kvantitativni prinos.
MS: M+1: 230,2, 174,1.
1H-NMR (400 MHz, CDCl3) δ 0,85-0,86 (preklapanje t i d, 6H), 1,13-1,40 (m, 6H), 1,44 (s, 9H), 1,60 (m, 1H), 2,31 (dd, 1H, J = 7,81 i 15,86 Hz), 2,38 (dd, 1H, J = 5,13 i 15,86 Hz), 3,31 (m, 1H), i 3,45 (br s, 2H) ppm.
Hidroklorid (3S,5R)-3-amino-5-metiloktanske kiseline
Mulj tert-butilnog estera (3S,5R)-amino-5-metiloktanske kiseline (2,59g, 11,3 mmol) u 6 N HCl (100 ml) grije se 18 sati na refluksu, ohladi, te filtrira preko Celite-a. Filtrat se koncentrira u vakuumu do 25 ml, a nastale kristale prikupi i osuši kako bi se dobilo hidroklorid (3S,5R)-3-amino-5-metiloktanske kiseline; 1,2 g, 50,56 %.
Talište = 142,5-142,7°C.
Drugi prinos (0,91 g) dobije se iz filtrata.
[image] MS: M+1: 174,1.
1H-NMR (CD3OD) δ 0,89 (t, 3H, J = 7,32 Hz), 0,92 (d, 3H, J = 6,35 Hz), 1,12-1,18 (m, 1H), 1,25-1,35 (m, 2H), 1,35-1,42 (m, 2H), 1,54-1,64 (m, 2H), 2,50 (dd, 1H, J = 7,81 i 17,33 Hz), 2,65 (dd, 1H, J = 4,64 i 17,32 Hz) i 3,52 (m, 1H) ppm.
Primjer 2
(3S,5R)-amino-5-metilheptanska kiselina
(S)-3,7-dimetilokt-6-enilni ester metansulfonske kiseline
S-(–)-citronelolu (42,8 g, 0,274 mol) i trietilaminu (91 ml, 0,657 mol) u CH2Cl2 (800 ml) na 0°C doda se metansulfonil-klorid (26 ml, 0,329 mol) u CH2Cl2 (200 ml). Nakon 2 sata na 0°C otopinu se ispere s 1 N HCl, te slanom vodom. Organsku fazu se osuši (MgSO4) i koncentrira kako bi se dobilo naslovni spoj u obliku ulja (60,5 g, 94 %), kojeg se upotrijebi bez daljnjeg pročišćavanja.
MS, m/z (relativni intenzitet): 139 [100 %], 143 [100 %].
1H-NMR (400 MHz; CDCl3) δ 5,05 (1H, m), 4,2 (2H, m), 2,95 (3H, s), 1,98 (2H, m), 1,75 (1H, m), 1,6 (3H,s), 1,5 (4H, m), 1,35 (2H, m), 1,2 (1H, m), 0,91 (3H, d, J = 6,5 Hz).
(R)-2,6-dimetilokt-2-en
(S)-3,7-dimetilokt-6-enilnom esteru metansulfonske kiseline (60 g, 0,256 mol) u THF-u (1 l) na 0°C doda se litijev aluminijev hidrid (3,8 g, 0,128 mol). Nakon 7 sati doda se još 3,8 g litijevog aluminijevog hidrida, a otopinu zagrije do sobne temperature. Nakon 18 sati doda se još 3,8 g litijevog aluminijevog hidrida. Nakon još 21 sata reakcijsku smjesu se oprezno ugasi 1 N limunskom kiselinom, a otopinu daljnje razrijedi slanom vodom. Nastale dvije faze se razdvoji, a organsku fazu osuši (MgSO4) i koncentrira kako bi se dobilo naslovni spoj u obliku ulja, kojeg se upotrijebi bez daljnjeg pročišćavanja.
MS, m/z (relativni intenzitet): 139 [M + H, 100 %].
(R)-4-metilheksanska kiselina
Upotrebljava se postupak sličan sintezi (R)-4-metilheptanske kiseline, gdje se dobije kiselina u obliku ulja (9,3 g, 56 %).
IR (film) 2963, 2931, 2877, 2675, 1107, 1461, 1414 cm–1.
MS, m/z (relativni intenzitet): 129 [M – H, 100 %].
1H-NMR (400 MHz; CDCl3) δ 2,35 (m, 2H), 1,66 (m, 1H), 1,37 (m, 4H), 1,29 (m, 1H), 0,86 (m, 6H).
13C-NMR (100 MHz; CDCl3) δ 181,02, 34,09, 32,12, 31,39, 29,29, 18,94, 11,44.
(4R,5S)-4-metil-3-((R)-4-metilheksanoil)-5-feniloksazolidin-2-on
Upotrebljava se postupak sličan sintezi (4R,5S)-4-metil-3-((R)-4-metilheptanoil)-5-feniloksazolidin-2-ona, gdje se dobije naslovni spoj u obliku ulja (35,7 g, 95 %).
MS, m/z (relativni intenzitet): 290 [M + H, 100 %].
1H-NMR (400 MHz; CDCl3) δ 7,4-7,25 (m, 5H), 5,6 (d, J = 7,32 Hz, 1H), 4,75 (m, 1H), 2,97 (m, 1H), 2,85 (m, 1H), 1,68 (m, 1H), 1,43 (m, 2H), 1,12 (m, 2H), 0,87 (m, 9H).
13C-NMR (100 MHz; CDCl3) δ 173,71, 153,24, 133,56, 128,94, 128,90, 125,83, 79,14, 54,95, 34,22, 33,72, 31,07, 29,45, 27,20, 26,52, 19,19, 19,15, 14,77, 14,53, 11,54.
tert-butilni ester (3S,5R)-5-metil-3-[1-((4R,5S)-4-metil-2-okso-5-feniloksazolidin-3-il)metanoil]heptanske kiseline
Upotrijebljen je postupak sličan onom za dobivanje tert-butilnog estera (3S,5R)-5-metil-3-((4R,5S)-4-metil-2-okso-5-feniloksazolidin-3-karbonil)oktanske kiseline, gdje se dobije naslovni spoj u obliku ulja (7,48 g; 31 %).
IR (film) 2967, 2934, 1770, 1716, 1696, 1344, 1148, 1121, 1068, 1037, 947 cm–1.
MS, m/z (relativni intenzitet): 178 [100 %], 169 [100 %].
[α]D = + 21,6 (c = 1 u CHCl3).
4-tert-butilni ester (S)-2-((R)-2-metilbutil)jantarne kiseline
tert-butilnom esteru (3S,5R)-5-metil-3-[1-((4R,5S)-4-metil-2-okso-5-feniloksazolidin-3-il)metanoil]heptanske kiseline (7,26 g, 0,018 mol) u H2O (53 ml) i THF-u (176 ml) na 0°C doda se prethodno pomiješana otopina LiOH (37 ml 0,8 M otopine) i H2O2 (10,57 ml 30 % otopine) i otopina zagrije do sobne temperature. Nakon 2 sata doda se natrijev bisulfit (7 g), natrijev sulfit (13 g) i vodu (60 ml), dva sloja razdvoji, a vodeni sloj ekstrahira eterom. Zajedno prikupljene organske faze koncentrira se do ulja, koje se otopi u heptanu (200 ml). Nastalu krutinu se otfiltrira, a filtrat osuši (MgSO4) i koncentrira kako bi se dobilo naslovni spoj u obliku ulja (4,4 g), kojeg se upotrijebi bez daljnjeg pročišćavanja.
MS, m/z (relativni intenzitet): 243 [100 %].
1H-NMR (400 MHz; CDCl3) δ 2,88 (m, 1H), 2,59 (m, 1H), 2,36 (m, 1H), 1,65 (m, 1H), 1,41 (s, 9H), 1,20 (m, 4H), 0,84 (m, 6H).
tert-butilni ester (3S,5R)-3-benziloksikarbonilamino-5-metilheptanske kiseline
Ovaj spoj dobije se kako što je opisano gore, počevši s 4-tert-butilnim esterom (S)-2-((R)-2-metilbutil)jantarne kiseline kako bi se dobilo tert-butilni ester (3S,5R)-3-benziloksikarbonilamino-5-metilheptanske kiseline u obliku ulja (prinos 73,3 %).
1H-NMR (400 MHz; CDCl3) δ 0,84 (t, 3H, J = 7,33 Hz), 0,89 (d, 3H, J = 6,60 Hz), 1,12-1,38 (m, 4H), 1,41 (s, 9H), 1,43-1,59 (m, 2H), 2,42 (m, 2H), 4,05 (m, 1H), 5,07 (t, 2H J = 12,95 Hz), i 7,28-7,34 (m, 5H).
tert-butilni ester (3S,5R)-amino-5-metilheptanske kiseline
Ovaj spoj dobije se kao što je opisano gore, počevši s tert-butilnim esterom (3S,5R)-3-benziloksikarbonilamino-5-metilheptanske kiseline umjesto tert-butilnog estera (3S,5R)-3-benziloksikarbonilamino-5-metiloktanske kiseline kako bi se dobilo naslovni spoj.
1H-NMR (400 MHz; CDCl3) δ 0,84 (preklapanje t i d, 6H), 1,08-1,16(m, 2H), 1,27-1,30 (m, 2H), 1,42 (s, 9H), 1,62 (br s, 2H), 2,15 (dd, 1H, J = 8,54 i 15,62 Hz), 2,29 (dd, 1H, J = 4,15 i 15,37 Hz) i 3,20 (br s, 2H).
Hidroklorid (3S,5R)-amino-5-metilheptanske kiseline
Mulj tert-butilnog estera (3S,5R)-amino-5-metilheptanske kiseline (1,44 g, 6,69 mmol) u 3 N HCl grije se na refluksu 3 sata, filtrira vruć preko Celite-a, te koncentrira do suhog. Trituracijom nastale krutine u etil-eteru dobije se hidroklorid (3S,5R)-3-amino-5-metilheptanske kiseline, (0,95 g, 85 %).
Talište = 126,3-128,3 °C.
1H-NMR (400 MHz; CD3OD) δ 0,92 (t, 3H, J = 7,32 Hz), 0,92 (d, 3H, J = 6,35 Hz), 1,15-1,24 (m, 1H), 1,33-1,43 (m, 2H), 1,44-1,52 (m, 1H), 1,60-1,67 (m, 1H), 2,57 (ddd, 1H, J = 7,32 17,67 i 5,12 Hz), 2,69 (ddd, 1H, J = 0,97, 4,88 i 17,32 Hz) i 3,28 (m, 1H).
[image] MS: M + 1: 160,2.
Primjer 3
(3S,5R)-3-amino-5-metilnonanska kiselina
(R)-4-metiloktanska kiselina
Litijev klorid (0,39 g, 9,12 mmol) i bakreni(I) klorid (0,61 g, 4,56 mmol) pomiješa se u 45 ml THF-a na temperaturi okoliša, te miješa 15 minuta, i zatim ohladi do 0°C za koje vrijeme se dodaje etilmagnezijev bromid (1 M otopina u THF-u, 45 ml, 45 mmol). Ukapava se (S)-citronelil-bromid (5,0 g, 22,8 mmol), a otopinu pusti neka se polako zagrije do temperature okoliša uz miješanje preko noći. Reakciju se ugasi opreznim dodavanjem zasićene otopine NH4Cl(aq), te 30 minuta miješa s Et2O i zasićenom otopinom NH4Cl(aq). Faze se razdvoji, a organsku osuši (MgSO4) i koncentrira. Sirovi (R)-2,6-dimetildec-2-en upotrijebi se bez pročišćavanja. U otopinu (R)-2,6-dimetildec-2-ena (3,8 g, 22,8 mmol) u 50 ml acetona na 0°C doda se Jonesov reagens (2,7 M u H2SO4(aq), 40 ml, 108 mmol), a otopinu pusti neka se polako zagrije do temperature okoliša, uz miješanje preko noći. Smjesu se razdijeli između Et2O i H2O, faze se razvoji, a organsku ispere slanom vodom, osuši (MgSO4), te koncentrira. Ostatak se pročisti flash-kromatografijom (8:1 smjesa heksani:EtOAc) kako bi se dobilo 2,14 g (59 %) naslovnog spoja u obliku bezbojnog ulja.
LRMS: m/z 156,9 (M +).
1H-NMR (400 MHz; CDCl3): δ 2,33 (m, 2H), 1,66 (m, 1H), 1,43 (m, 2H), 1,23 (m, 5H), 1,10 (m, 1H), 0,86 (m, 6H).
Jonesov reagens dobije se u obliku 2,7 M otopine, miješanjem 26,7g CrO3 i 23 ml H2SO4, uz razrjeđivanje do 100 ml s H2O.
(4R,5S)-4-metil-3-((R)-4-metiloktanoil)-5-feniloksazolidin-2-on
(R)-4-metiloktanskoj kiselini (2,14 g, 13,5 mmol) u 25 ml CH2Cl2 na 0°C doda se 3 kapi DMF-a, a zatim oksalil-klorid (1,42 ml, 16,2 mmol), što rezultira snažnim razvijanjem plina. Otopinu se izravno zagrije do temperature okoliša, miješa 30 minuta, te koncentrira. U međuvremenu, u otopinu oksazolidinona (2,64 g, 14,9 mmol) u 40 ml THF-a na -78°C ukapava se n-butillitij (1,6 M otopina u heksanima, 9,3 ml, 14,9 mmol). Smjesu se miješa 10 minuta, za koje vrijeme se ukapava kiselinski klorid u 10 ml THF-a. Reakcijsku smjesu miješa se 30 minuta na -78°C, a zatim izravno zagrije do temperature okoliša, te ugasi zasićenom otopinom NH4Cl. Smjesu se razdijeli između Et2O i zasićene otopine NH4Cl(aq), faze se razvoji, a organsku osuši (MgSO4), te koncentrira kako bi se dobilo 3,2 g naslovnog spoja u obliku bezbojnog ulja.
LRMS: m/z 318,2 (M+).
1H-NMR (400 MHz; CDCl3) δ 7,34 (m, 5H), 5,64 (d, J = 7,3 Hz, 1H), 4,73 (quint, J = 6,8 Hz, 1H), 2,96 (m, 1H), 2,86 (m, 1H), 1,66 (m, 1H), 1,47 (m, 2H), 1,26 (m, 5H), 1,13 (m, 1H), 0,88 (m, 9H).
Sirovi produkt upotrebljava se bez pročišćavanja.
tert-butilni ester (3S,5R)-5-metil-3-((4R,5S)-4-metil-2-okso-5-feniloksazolidin-3-karbonil)nonanske kiseline
U otopinu diizopropilamina (1,8 ml, 12,6 mmol) u 30 ml THF-a na -78°C doda se n-butillitij (1,6 M otopina u heksanima, 7,6 ml, 12,1 mmol), a smjesu miješa 10 minuta, za koje vrijeme se ukapava (4R,5S)-4-metil-3-((R)-4-metiloktanoil)-5-feniloksazolidin-2-on (3,2 g, 10,1 mmol) u 10 ml THF-a. Otopinu se miješa 30 minuta, te se na -50°C brzo ukapava t-butil-bromacetat (1,8 ml, 12,1 mmol), a smjesu pusti neka se, u trajanju od 3 sata, polako grije do 10°C. Smjesu se razdijeli između Et2O i zasićene otopine NH4Cl(aq), faze se razdvoji, a organsku osuši (MgSO4), te koncentrira. Ostatak se pročisti flash-kromatografijom (16:1 do 8:1 smjesa heksani:EtOAc) kako bi se dobilo 2,65 g (61 %) naslovnog spoja u obliku bezbojne kristalne krutine.
Talište = 84-86 °C.
[α]D23 +17,1 (c = 1,00, CHCl3).
1H-NMR (400 MHz; CDCl3) δ 7,34 (m, 5H), 5,62 (d, J = 7,3 Hz, 1H), 4,73 (quint, J = 6,8 Hz, 1H), 4,29 (m, 1H), 2,67 (dd, J = 9,8, 16,4 Hz, 1H), 2,40 (dd, J = 5,1, 16,4 Hz, 1H), 1,69 (m, 1H), 1,38 (s, 9H), 1,28 (m, 7H), 1,08 (m, 1H), 0,88 (m, 9H).
13C-NMR (400 MHz; CDCl3) δ 176,45, 171,22, 152,71, 133,64, 128,86, 125,86, 80,83, 78,87, 55,33, 40,02, 38,21, 37,59, 36,31, 30,86, 29,29, 28,22, 23,14, 20,41, 14,36, 14,26.
[image]
4-tert-butilni ester (S)-2-((R)-2-metilheksil)jantarne kiseline
U otopinu tert-butilnog estera (3S,5R)-5-metil-3-((4R,5S)-4-metil-2-okso-5-feniloksazolidin-3-karbonil)nonanske kiseline (2,65 g, 6,14 mmol) u 20 ml THF-a na 0 °C doda se prethodno ohlađena (0°C) otopina LiOH monohidrata (1,0 g, 23,8 mmol) i vodik peroksida (30 tež. % vodene otopine, 5,0 ml) u 10 ml H2O. Smjesu se snažno miješa 90 minuta, te zagrije do temperature okoliša i miješa 90 minuta. Reakcijsku smjesu ugasi se na 0°C dodavanjem 100 ml 10 % NaHSO3(aq), zatim zagrije s Et2O. Faze se razdvoji, i organsku ispere slanom vodom, osuši (MgSO4), te koncentrira. Naslovni spoj upotrebljava se bez pročišćavanja.
tert-butilni ester (3S,5R)-3-benziloksikarbonilamino-5-metilnonanske kiseline
Ovaj spoj dobije se slično kao što je opisano gore, počevši s 4-tert-butilnim esterom (S)-2-((R)-2-metilheksil)jantarne kiseline umjesto 4-tert-butilnog estera (S)-2-((R)-2-metilpentil)jantarne kiseline kako bi se dobilo naslovni spoj u obliku ulja (prinos 71,6 %).
1H-NMR (400 MHz; CDCl3) δ 0,81 (t, 3H, J = 4,40 Hz), 0,85 (d, 3H, J = 6,55 Hz), 1,06-1,20 (m, 7H), 1,36 (s, 9H), 1,38-1,50 (m, 2H), 2,36 (m, 2H), 3,99 (m, 1H), 5,02 (m + s, 3H) i 7,28-7,28 (m, 5H).
tert-butilni ester (3S,5R)-3-amino-5-metilnonanske kiseline
Ovaj spoj dobije se kao što je opisano gore, počevši s tert-butilnim esterom (3S,5R)-benziloksikarbonilamino-5-metilnonanske kiseline umjesto tert-butilnog estera (3S,5R)-3-benziloksikarbonilamino-5-metiloktanske kiseline. Prinos = 97 %.
1H-NMR (400 MHz; CDCl3) δ 0,82 (preklapanje d i t, 6H), 1,02-1,08 (m, 1H), 1,09-1,36 (m, 6H), 1,39 (s, 9H), 1,47 (br s, 1H), 1,80 (s, 2H), 2,13 (dd, 1H, J = 8,54 i 15,61 Hz) i 2,27 (dd, 1H, J = 4,15 i 15,38 Hz).
Hidroklorid (3S,5R)-3-amino-5-metilnonanske kiseline
Smjesu tert-butilnog estera (3S,5R)-3-amino-5-metilnonanske kiseline (1,50 g, 6,16 mmol) u 3 N HCl (100 ml) grije se na refluksu 3 sata, filtrira vruću preko Celite-a, te koncentrira do 30 ml u vakuumu. Nastale kristale se prikupi, ispere s još 3 N HCl, te osuši kako bi se dobilo naslovni spoj.
Talište = 142,5-143,3°C.
Dodatne prinose dobije se iz filtrata kako bi se dobilo 1,03 g (70,4 %).
1H-NMR (400 MHz; CD3OD) δ 0,91(t, 3H, J = 6,84 Hz), 0,92 (d, 3H, J = 6,35 Hz), 1,16-1,26 (m, 1H), 1,27-1,35 (m, 4H), 1,38-1,45 (m, 1H), 1,61 (brs, 1H), 1,63-1,68 (m, 1H), 2,58 (dd, 1H, J = 7,32 i 17,34 Hz), 2,69 (dd, 1H, J = 5,13 i 17,59 Hz) i 3,59 (m, 1H).
[image] MS: M + 1: 188,1.
Primjer 4
(2R,4R)-2-aminometil-4-metilheptanska kiselina
5R-metil-3R-(4S-metil-2-okso-5R-feniloksazolidin-3-karbonil)oktanska kiselina
Otopinu tert-butilnog estera (3R,5R)-5-metil-3-((4S,5R)-4-metil-2-okso-5-feniloksazolidin-3-karbonil) oktanske kiseline (3,9 g, 9,34 mmol) u diklormetan (150 ml) obradi se trifluoroctenom kiselinom (7,21 ml, 93,4 ml), te miješa 18 sati na temperaturi okoliša. Nakon što se otapala i reagens ukloni u vakuumu, nastali ostatak se triturira u 100 ml heksana kako bi se dobilo 3,38 g naslovnog spoja (100 %).
Talište = 142-143 °C.
MS M + 1 = 362,1.
1H-NMR (400 M Hz; CDCl3) δ 0,85 (2t, 6H, J = 7,1 Hz), 0,93 (d, 3H, J = 6,1 Hz), 1,14 (m, 1H), 1,2-1,49 (m, 6H), 2,56 (dd, 1H, J = 4,15 i 17,57 Hz), 2,81 (dd, 1H, J = 17,33 i 10,74 Hz), 4,28 (m, 1H), 4,74 (quint, 1H, J = 6,84 Hz), 5,64 (d, 1H, J = 7,32 Hz), 7,29-7,43 (m, 5H).
Benzilni ester [4R-metil-2R-(4S-metil-2-okso-5R-feniloksazolidin-3-karbonil)heptil]karbaminske kiseline
Otopinu 5R-metil-3R-(4S-metil-2-okso-5R-feniloksazolidin-3-karbonil)oktanske kiseline (1,98 g, 5,48 mmol) i trietilamina (0,92 ml, 6,57 mmol) obradi se difenilfosforil-azidom (1,2 ml, 5,48 mmol), miješa 30 minuta na temperaturi okoliša, te 3 sata grije na refluksu. Nakon kratkog hlađenja reakcijsku smjesu se obradi benzil-alkoholom (2,8 ml, 27,4 mmol), te grije još 3 sata na refluksu. Reakcijsku smjesu se ohladi, razrijedi etil-eterom (150 ml), ispere uzastopce zasićenom otopinom NaHCO3 i slanom vodom, osuši (MgSO4), te koncentrira u vakuumu do ulja. Kromatografijom (MPLC, eluiranje 4:1 smjesom heksani:etil-acetat) dobije se naslovni spoj (2,0 g, 78,3 %) u obliku ulja.
MS M + 1 = 467,1.
1H-NMR (400 M Hz; CDCl3) δ 0,86 (2t, 6H, J = 7,1 Hz), 0,93 (d, 3H, J = 5,9 Hz), 1,14 (m, 1H), 1,09-1,36 (m, 6H), 1,50 (d, 1H, J = 5,2 Hz), 3,49 (t, 1H, J = 6,1 Hz), 4,10 (m, 1H), 4,71 (quint, 1H, J = 6,61 Hz), 5,06 (d, 2H, J = 3,42 Hz), 5,20 (t, 1H, J = 5,61 Hz), 5,64 (d, 1H, J = 7,08 Hz), 7,29-7,43 (m, 10H).
2R-(benziloksikarbonilaminometil)-4R-metilheptanska kiselina
Otopinu benzilnog estera 4R-metil-2R-(4S-metil-2-okso-5R-feniloksazolidin-3-karbonil)heptil]karbaminske kiseline (4,12 g, 8,83 mmol) u 3:1 smjesi THF:voda (100 ml) ohladi se do 0°C, te obradi smjesom 0,8 N LiOH (17,5 ml, 14 mmol) i 30 % H2O2 (4,94 ml, 44 mmol). Nakon reakcijsku smjesu se miješa na hladnom 3 sata, ugasi je se muljem NaHSO3 (2,37 g) i Na2SO3 (4,53 g) u vodi (30 ml), te miješa 1 sat. Reakcijsku smjesu razrijedi se etil-eterom (200 ml), razdijeli, a organski sloj ispere slanom vodom, te osuši (MgSO4). Koncentrirani organski ekstrakt se kromatografira (MPLC), uz eluiranje etil-acetatom, kako bi se dobilo 1,25 g 2R-(benziloksikarbonilaminometil)-4R-metilheptanske kiseline (46 %).
MS M + 1 = 308,1.
1H-NMR (400 M Hz; CDCl3) δ 0,83 (t, 3H, J = 6,84 Hz), 0,87 (t, 3H, J = 6,35 Hz), 1,14 (m, 1H), 1,06-1,54 (m, 7H), 2,7 (br s, 1H), 3,30 (m, 2H), 5,05 (q, 2H, J = 12,2 Hz), 5,14 (t,1H, J = 5,61 Hz),7,30 (brs,5H).
Hidroklorid (2R,4R)-2-amino-4-metilheptanske kiseline
Smjesu 2R-(benziloksikarbonilaminometil)-4R-metilheptanske kiseline (1,25 g, 4,07 mmol) i Pd/C (20 %, 0,11 g) u metanolu (50 ml) hidrogenira se 18 sati pod tlakom od 344,7 kPa (50 psi). Nakon što se katalizator ukloni filtracijom, otapalo se ukloni u vakuumu, a nastalu krutinu triturira u eteru kako bi se dobilo hidroklorid (2S,4R)-2-amino-4-metilheptanske kiseline (0,28 g, 40 %).
Talište = 226,3-228,0°C.
MS M + 1 = 174,0.
1H-NMR (400 M Hz; CD3OD) δ 0,89 (t + d, 6H, J = 6,35 Hz), 1,11 (m, 1H), 1,25-1,40 (m, 4H), 1,47-1,62 (m, 2H), 2,48 (br s, 1H), 2,93 (m, 2H).
[image]
Primjer 5
Hidroklorid 2-aminometil-4,4-dimetilheptanske kiseline
Etilni ester 2-cijano-4,4-dimetilhepta-2,6-dienske kiseline
Otopinu 2,2-dimetilpent-4-enala (5,0 g, 44 mmol), etilnog estera cijanooctene kiseline (5,12 ml, 48 mmol), piperidina (1,3 ml, 14 mmol) i octene kiseline (4,52 ml, 80 mmol) u 170 ml toluena grije se na refluksu 18 sati u tikvicu opremljenoj Dean-Starkovim separatorom. Nekoliko ml vode prikupi se u zamci. Reakcijsku smjesu se ohladi, te uzastopce ispere s 1 N HCl, NaHCO3 i slanom vodom. Organske slojeve osuši se preko Na2SO4, te koncentrira do ulja. Ovo ulje kromatografira se uz eluiranje s 20 % EtOAc u heksanu kako bi se dobilo kombinaciju dva prinosa od ukupno 8,3 g (91 %).
1H-NMR (400 MHz; CDCl3) 1,28 (s, 6H), 1,32 (t, 3H, J = 7 Hz), 2,26 (d, 2H, J = 7,6 Hz), 4,27 (q, 2H, J = 7,2 Hz), 5,08 (d, 1H, J = 12 Hz), 5,10 (d, 1H, J = 4Hz), 5,72 (m,1H).
Hidroklorid 2-aminometil-4,4-dimetilheptanske kiseline
Etilni ester 2-cijano-4,4-dimetilhepta-2,6-dienske kiseline (5,88 g, 28 mmol) otopi se u smjesi 91 ml etanola i 6 ml HCl, te obradi s 0,4 g PtO2. Reakciju se provede pod tlakom od 689,5 kPa (100 psi) vodika, na sobnoj temperaturi, u trajanju od 15 sati. Katalizator se filtrira, a filtrat koncentrira kako bi se dobilo 3,8 g željenog produkta, etilnog estera 2-aminometil-4,4-dimetilheptanske kiseline, u obliku ulja.
MS (APCI): 216,2 (M + 1)+.
Ovo ulje refluksira se 18 sati u 75 ml 6 N HCl. Dok se reakcijska smjesa hladi, nastaje talog. Krutinu se filtrira, ispere s još otopine HCl, te triturira s eterom kako bi se dobilo čisti naslovni spoj.
MS (APCI): 188,1 (M + 1)+, 186,1 (M-1)+.
1H-NMR (400 MHz; CD3OD): 0,91 (9H, m), 1,30 (5H, m), 1,81 (dd, 1H, J = 7,2 Hz, 14,4 Hz), 2,72 (1H, m), 3,04 (2H, m).
[image] Talište = 229,5-231,0 °C.
Primjer 6
(S)-3-amino-5,5-dimetiloktanska kiselina
3-(4,4-dimetilheptanoil)-(R)-4-metil-(S)-5-feniloksazolidin-2-on
Otopinu 4,4-dimetilheptanske kiseline (1,58 g, 10 mmol) i trietilamina (4,6 ml) u 50 ml THF-a ohladi se do 0°C, te obradi 2,2-dimetilpropionil-kloridom (1,36 ml). Nakon 1 sata doda se 4R-metil-5S-feniloksazolidin-2-on (1,95 g, 11 mmol) i litijev klorid (0,47 g, 11 mmol), a smjesu miješa 18 sati. Talog se filtrira i pomno ispere s još THF. Filtrat se koncentrira u vakuumu kako bi se dobilo uljevitu krutinu. Ovu krutinu otopi se u 200 ml Et2O, ispere uzastopce zasićenom otopinom NaHCO3, 0,5 N HCl i zasićenom otopinom NaCl, osuši (MgSO4), te koncentrira u vakuumu kako bi se dobilo naslovni spoj u obliku ulja (3,0 g, 95 %).
1H-NMR (400 MHz; CDCl3): 0,73-0,84 (m, 12H), 1,10-1,22 (m, 4H), 1,46-1,54 (m, 2H), 2,75-2,87 (m, 2H), 4,70 (m, 1H, J = 7 Hz), 5,59 (d, 1H, J = 7 Hz), 7,22-7,37 (m, 5H).
tert-butilni ester 5,5-dimetil-(S)-3-((R)-4-metil-2-okso-(S)-5-feniloksazolidin-3-karbonil)oktanske kiseline
Prema Primjeru 1, 5,07 g (16 mmol) 3-(4,4-dimetilheptanoil)-4-metil-5-feniloksazolidin-2-ona, 18 ml (1 N, 18 mmol) otopine NaHMDS (natrijev heksametildisilazan) i 4,72 ml (32 mmol) tert-butilnog estera bromoctene kiseline daje 3,40 g (49,3 %) naslovnog spoja u obliku kristalne krutine.
1H-NMR (400 MHz; CDCl3): 0,85-0,89 (m, 12H), 1,18-1,32 (m,6H), 1,41 (s, 9H), 1,88 (dd, 1H, J = 6 Hz, 8,4 Hz), 2,41 (dd, 1H, J = 6 Hz, 16 Hz), 2,62 (dd, 1H, J = 8,4 Hz, 16 Hz), 4,30-4,40 (m, 1H), 4,72 (m, 1H), 5,62 (d, 1H, J = 7 Hz), 7,30-7,40 (m, 5H)
Talište = 83-85°C.
4-tert-butilni ester (S)-2-(2,2-dimetilpentil)jantarne kiseline
Prema Primjeru 1, 3,4 g (7,9 mmol) tert-butilnog estera 5,5-dimetil-3-(4-metil-2-okso-5-feniloksazolidin-3-karbonil)oktanske kiseline, 16 ml (12,8 mmol) 0,8 N LiOH i 4,5 ml 30 % H2O2 daje 2,42 g (>100 %) naslovnog spoja u obliku ulja.
1H-NMR (400 MHz; CDCl3): 0,77-0,82 (m, 9H), 1,14-1,29 (m, 5H), 1,42 (s, 9H), 1,77 (dd, 1H, J = 8 Hz, 16 Hz), 2,36 (dd, 1H, J = 6 Hz, 16 Hz), 2,59 (dd, 1H, J = 8 Hz, 16 Hz), 2,75-2,85 (m, 1H).
tert-butilni ester (S)-3-benziloksikarbonilamino-5,5-dimetiloktanske kiseline
Prema Primjeru 1, 2,14 g (7,9 mmol) 4-tert-butilnog estera 2-(2,2-dimetilpentil)jantarne kiseline, 1,7 ml DPPA (diphenylphosphoryl azide = difenilfosforil-azid), 1,1 ml Et3N i 2,44 ml BnOH (benzil-alkohol) daje 1,63 g (54,8 % u dva koraka) naslovnog spoja u obliku ulja.
1H-NMR (400 MHz; CDCl3): 0,78-0,89 (m, 9H), 1,10-1,30 (m, 5H), 1,36 (s, 9H), 2,39 (t, 2H, J = 5 Hz), 4,95-4,05 (m, 1H), 5,00 (s, 2H), 5,09 (d, 1H, J = 9,6 Hz), 7,22-7,30 (m, 5H).
tert-butilni ester (S)-3-amino-5,5-dimetiloktanske kiseline
Prema Primjeru 1, 1,63 g tert-butilnog estera 3-benziloksikarbonilamino-5,5-dimetiloktanske kiseline i 0,2 g 20 % Pd/C daje naslovni spoj.
1H-NMR (400 MHz; CDCl3): 0,84-0,89 (m, 9H), 1,13-1,39 (m, 6H), 1,43 (s, 9H), 2,25 (dd, 1H, J = 8,4 Hz, 15,6 Hz), 2,35 (dd, 1H, J = 4,4 Hz, 15,6 Hz), 2,79 (s, br, 2H), 3,25-3,35 (m, 1H).
MS, m/z, 244,2 (M + 1)+.
Hidroklorid (S)-3-amino-5,5-dimetiloktanske kiseline
Prema Primjeru 1, tert-butilni ester 3-amino-5,5-dimetiloktanske kiseline obradi se s 3 N HCl kako bi se dobilo 286 mg naslovnog spoja u obliku krutine.
1H-NMR (400 MHz; CD3OD): 0,87-0,93 (m, 9H), 1,18-1,31 (m, 4H), 1,51 (dd, 1H, J = 4 Hz, 14,4 Hz), 1,62 (dd, 1H, J = 6,8 Hz, 14,4 Hz), 2,60 (dd, 1H, J = 8 Hz, 17,6 Hz), 2,73 (dd, 1H, J = 4 Hz, 7,6 Hz), 3,55-3,60 (m, 1H).
MS (APCI), m/z 188,1 (M + 1)+, 186,1 (M – 1)+.
[image] α = +20° (MeOH (metil-alkohol)).
Talište = 194,2-195,2°C.
Primjer 7
2-aminometil-3-(1-metilciklopropil)propionska kiselina
Etilni ester 2-cijano-3-(1-metilciklopropil)akrilne kiseline
1-metilciklopropan-metanolu (Aldrich, 1,13 ml, 11,6mmol) u 50 ml CH2Cl2 doda se neutralni aluminijev oksid (2,5 g), te PCC (2,5 g, 11,6 mmol), a smjesu miješa 3 sata na temperaturi okoliša. Smjesu se filtrira kroz 1 cm debeli čep od silikagela u vakuumu, te ispere s Et2O. Filtrat se koncentrira do ukupnog volumena od približno 5 ml. Ostatku se doda THF (10 ml), etil-cijanoacetat (1,2 ml, 11,3 mmol), piperidin (5 kapi), te konačno octena kiselina (5 kapi). Sve zajedno miješa se preko noći na temperaturi okoliša, te razdijeli između Et2O i zasićene vodene otopine NaHCO3. Faze se razdvoji, a organsku ispere slanom vodom, osuši (MgSO4), te koncentrira. Flash-kromatografija ostatka (10→15 % smjesa EtOAc/heksani) daje 0,53 g (25 %) estera u obliku bezbojnog ulja, koje kristalizira prilikom stajanja.
Talište = 35-37 °C.
1H-NMR (CDCl3) δ 6,99 (s, 1H), 4,27 (q, J = 7,3 Hz, 2H), 1,55 (s, 3H), 1,32 (t, J = 7,3 Hz, 3H), 1,14 (s, 2H), 1,07 (s, 2H).
13C-NMR δ 170,44, 162,90, 115,17, 103,69, 62,52, 21,24, 21,07 (2C), 20,71, 14,35.
[image]
Etilni ester 2-aminometil-3-(1-metilciklopropil)propionske kiseline
Etilnom esteru 2-cijano-3-(1-metilciklopropil)akrilne kiseline (0,45 g, 2,51 mmol) u 16 ml smjese EtOH:THF (1:1) doda se Raneyev nikal (0,4 g), a smjesu hidrogenira u Parrovoj tresilici, pod tlakom od 331 kPa (48 psi), u trajanju od 15,5 sati. Zatim se doda Pearlmanov katalizator (0,5 g), a s hidrogenacijom nastavi još 15 sati. Smjesu se filtrira i koncentrira. Flash-kromatografija ostatka 2→3→4→5→6→8 % MeOH/CH2Cl2 daje 0,25 g (54 %) aminoestera u obliku bezbojnog ulja.
1H-NMR (CDCl3) δ 3,97 (m, 2H), 2,67 (m, 2H), 2,46 (m, 1H), 1,28 (d, J = 7,3Hz, 2H), 1,19 (bs, 2H), 1,09 (t, J = 7,3 Hz, 3H), 0,85 (s, 3H), 0,04 (m, 4H).
LRMS: m/z 186,1 (M + 1).
2-aminometil-3-(1-metilciklopropil)propionska kiselina
U otopinu etilnog estera 2-aminometil-3-(1-metilciklopropil)propionske kiseline (0,25 g, 1,35 mmol) u 10 ml metanola na 0°C doda se 10 % vodene otopine NaOH (10 ml). Smjesu se miješa na temperaturi okoliša preko noći, te koncentrira kako bi se uklonilo metanol. Ostatak se ohladi do 0°C, te koncentriranom HCl zakiseli do pH 2. Nakon što je se pusti da se zagrije do temperature okoliša smjesu se izlije na ionskoizmjenjivačku smolu DOWEX-50WX8-100, te eluira s H2O dok lakmus-papir ne pokaže neutralnu rekciju. Eluiranje se nastavi s 5 % vodenom otopinom NH4OH (100 ml), a alkalne frakcije koncentrira kako bi se dobilo 0,15 g (71 %) aminokiseline u obliku bezbojne krutine.
1H-NMR (CDCl3) δ 2,72 (m, 2H), 2,42 (m, 1H), 1,34 (dd, J = 8,5, 13,9 Hz, 1H), 1,19 (dd, J = 6,1, 13,9 Hz, 1H), 0,82 (s, 3H), 0,05 (m, 4H).
LRMS: m/z 158,0 (M + 1).
Primjer 8
(3S,5R)-3-amino-5-metiloktanska kiselina
tert-butilni ester (5S)-5-metilokta-2,6-dienske kiseline
U otopinu etilnog estera (S)-3-metilheks-4-enske kiseline* (1,0 g, 6,4mmol) u 30 ml toluena na -78°C ukapava se DIBAH (diizobutilaluminijev hidrid) (1,0 M u THF, 6,4 ml) u trajanju od 5 minuta. Smjesu se 45 minuta miješa na -78°C, za koje vrijeme se doda 5 kapi metanola, što rezultira snažnim razvijanjem H2. Metanol se dodaje dok se ne opazi da se plin prestao razvijati (približno 5 ml). Za to vrijeme se ukloni hladnu kupelj, te se doda približno 5 ml zasićene vodene otopine Na+K+ tartarata. Kada smjesa dođe na sobnu temperaturu, doda se još zasićene vodene otopine Na+K+ tartarata i Et2O, a s miješanjem nastavi dok se faze praktički ne izbistre (približno 1 sat). Faze se razdvoji, a organsku ispere slanom vodom, osuši (MgSO4), te koncentrira do približno 10 ml ukupnog volumena zahvaljujući njihovoj hlapivosti. Sirovu smjesu pomiješa se s još jednom šaržom aldehida, dobivenog iz 10 mmol estera gore opisanim postupkom, a sve zajedno upotrijebi bez pročišćavanja. U suspenziju natrijevog hidrida (60 % disperzija u mineralnom ulju) u 25 ml THF-a ukapava se t-butil-P,P-dimetil-fosfonoacetat (3,0 ml, 15 mmol) u trajanju od 1 sata, tako da razvijanje H2 bude pod kontrolom. Kada se s dodavanjem završi, brzo se ukapa sirovi aldehid u toluenu (približno 20 ml ukupnog volumena), a smjesu preko noći miješa na temperaturi okoliša. Smjesu se razdijeli između Et2O i zasićene vodene otopine NH4Cl, faze razdvoji, organsku ispere slanom vodom, osuši (MgSO4), te koncentrira. Flash-kromatografijom ostatka (0→3→5 % smjesa EtOAc/heksani) dobije se 1,0 g (29 %, dva koraka) nezasićenog estera u obliku blijedožutog ulja. ;1H-NMR (CDCl3) δ 6,75 (m, 1H), 5,66 (m, 1H), 5,30 (m, 2H), 2,03-2,29 (m, 3H), 1,58 (d, J = 6,1 Hz, 3H), 1,41 (s, 9H), 0,91 (d, J = 6,6Hz, 3H). ;* Etilni ester (S)-3-metilheks-4-enske kiseline dobije se iz (S)-trans-3-penten-2-ola [J. Liang, D.W. Hoard, V. Van Khau, M.J. Martinelli, E.D. Moher, R.E. Moore, M.A. Tius: J. Org. Chem., 64, 1459, (1999.)] Johnson-Claisenovom pregradnjom uz trietil-ortoacetat, prema protokolu iz literature [R.K. Hill, R. Soman, S. Sawada: J. Org. Chem., 37, 3737, (1972.)].
tert-butilni ester (3R,5S)-3-[benzil(1-feniletil)amino]-5-metilokt-6-enske kiseline
U otopinu (S)-(–)-N-benzil-α-metilbenzilamina (0,60 ml, 2,85 mmol) u 9,0 ml THF na -78°C brzo se ukapava n-butillitij (1,6 M u heksanima, 1,6 ml), što rezultira intenzivno ružičastom bojom. Smjesu se 30 minuta miješa na -78°C, za koje vrijeme se polako ukapava tert-butilni ester (5S)-5-metilokta-2,6-dienske kiseline (0,5 g, 2,38 mmol) u 1,0 ml THF-a, što rezultira blijedosmećkastožutom bojom, koja potamni tijekom 3 sata. Smjesu se miješa 3 sata na -78°C, te ugasi zasićenom vodenom otopinom NH4Cl. Smjesu se pusti neka se zagrije do sobne temperature, te miješa preko noći, zatim razdijeli između EtOAc i zasićene vodene otopine NH4Cl. Faze se koncentrira, a organsku osuši (MgSO4), te koncentrira. Flash-kromatografijom ostatka (3→5 % smjesa EtOAc/heksani) dobije se 0,52 g (52 %) aminoestera u obliku žutog ulja.
1H-NMR (CDCl3) δ 7,34 (m, 2H), 7,20 (m, 8H), 5,27 (m, 2H), 3,74 (m, 1H), 3,72 (d, J = 15,9 Hz, 1H), 3,41 (d, J = 14,9 Hz, 1H), 3,27 (m, 1H), 2,38 (m, 1H), 1,98 (dd, J = 3,7, 14,2 Hz, 1H), 1,81 (dd, J = 9,3, 14,4 Hz, 1H), 1,54 (d, J = 4,9 Hz, 3H), 1,32 (s, 9H), 1,24 (d, J = 7,1 Hz, 3H), 0,99 (m, 2H), 0,74 (d, J = 6,6 Hz, 3H).
(3S,5R)-3-amino-5-metiloktanska kiselina
U otopinu tert-butilnog estera (3R,5S)-3-[benzil(1-feniletil)amino]-5-metilokt-6-enske kiseline (0,92 g, 2,18 mmol) u 50 ml MeOH doda se 20 % Pd/C (0,20 g), a smjesu hidrogenira u Parrovoj tresilici pod tlakom od 331 kPa (48 psi) u trajanju od 23 sata. Smjesu se filtrira i koncentrira. Sirovom aminoesteru u 10 ml CH2Cl2 doda se 1,0 ml trifluoroctene kiseline, a otopinu preko noći miješa na temperaturi okoliša. Smjesu se koncentrira, a ostatak otopi u minimalnoj količini H2O, te izlije na ionskoizmjenjivačku smolu DOWEX-50WX8-100. Stupac se eluira s H2O dok lakmus-papir ne pokaže neutralnu reakciju, te se nastavi s 5 % vodenom otopinom NH4OH (100 ml). Alkalne frakcije se koncentrira kako bi se dobilo 0,25 g (66 %, dva koraka) aminokiseline u obliku prljavo bijele krutine.
1H-NMR (CD3OD) δ 3,41 (m, 1H), 2,36 (dd, J = 5,1, 16,6 Hz, 1H), 2,25 (dd, J = 8,1, 16,6 Hz, 1H), 1,42 (m, 2H), 1,24 (m, 1H), 1,12 (m, 2H), 1,00 (m, 1H), 0,73 (d, J = 6,4 Hz, 3H), 0,68 (t, J = 6,8 Hz, 3H).
LRMS: m/z 172,1 (M – 1).
Primjer 9
2-aminometil-8-metilnonanska kiselina
Za dobivanje 2-aminometil-8-metilnonanske kiseline iz 6-metil-1-heptanola upotrijebljen je postupak sličan onom za 2-aminometil-4,4,8-trimetilnonansku kiselinu.
m/z 202,1 (M+).
2-aminometil-4,8-dimetilnonanska kiselina
(R)-2,6-dimetilheptan-1-ol
Magnezijevi opiljci (2,04 g, 84 mmol) i kristal joda suspendira se u 5 ml THF-a radi dodavanja 1-brom-3-metilbutana (0,3 ml, čist). Smjesu se grije kako bi se započelo tvorbu Grignardovog reagensa. Preostali 1-brom-3-metilbutan (8,63 ml, 72 mmol) razrijedi se u THF-u (60 ml), te ukapava. Smjesu se miješa 2 sata na temperaturi okoliša, te ohladi do -5°C. Zatim se ukapava otopina bakrenog klorida (1,21 g, 9 mmol) i LiCl (0,76 g, 18 mmol) u THF-u (50 ml), uz održavanje temperature ispod 0°C. Nastalu smjesu miješa se 20 minuta, te se ukapava (R)-3-brom-2-metilpropanol u THF-u (20 ml), uz odražavanje temperature ispod 0°C. Smjesu se pusti da polako preko noći dođe na temperaturu okoliša. Reakcijsku smjesu ugasi amonijevim hidroksidom i vodom. Smjesu se razrijedi s EtOAc, te 3 × ekstrahira s 20 ml EtOAc. Organske tvari ispere se slanom vodom, osuši (MgSO4), filtrira, te koncentrira. Preostalo ulje pročisti se kromatografijom na silikagelu (90/10 smjesa heksan/EtOAc) kako bi se dobilo 2,67 g (R)-2,6-dimetilheptan-1-ola.
(R)-1-jod-2,6-dimetilheptan
U smjesu trifenilfosfina na nosaču (6,55 g, 19,67 mmol) u CH2Cl2 na 0°C doda se jod (4,99 g, 19,67 mmol) i imidazol (1,33 g, 19,67 mmol). Smjesu se zagrije na temperaturu okoliša, miješa 1 sat, te ohladi do 0°C radi ukapavanja (R)-2,6-dimetilheptan-1-ola u CH2Cl2 (5 ml). Smjesu se pusti da dođe na temperaturu okoliša, te miješa 1 sat, za koje vrijeme je se filtrira kroz jastučić od celita, a krutine ispere s CH2Cl2. Filtrat se koncentrira, a sirovi produkt pročisti kromatografijom na silikagelu kako bi se dobilo (R)-1-jod-2,6-dimetilheptan (2,44 g).
t-butilni ester (4R)-4,8-dimetilnonanske kiseline
Diizopropilaminu (0,827 ml, 5,9 mmol) u THF-u (8 ml) na -78°C doda se nBuLi (n-butillitij) (2,65 ml 2,6 M otopine u pentanu). Otopinu se miješa 30 minuta na -78°C, a zatim se doda t-butil-acetat (0,8 ml, 5,9 mmol). Smjesu se miješa na -78°C 2 sata, zatim se doda (R)-1-jod-2,6-dimetilheptan (0,3 g, 1,18 mmol) i HMPA (1,5 ml) u THF-u (1 ml). Reakcijsku smjesu miješa se na -78°C, te pusti da polako preko noći dođe na temperaturu okoliša, te zagrije na 35°C da se reakciju dovede do završetka. Reakcijsku smjesu ugasi se dodavanjem amonijevog klorida (zasićena vodena otopina), a smjesu ekstrahira s EtOAc (2 × 10 ml). Organske tvari se pomiješa, ispere vodom, osuši (MgSO4), filtrira, te koncentrira. Kromatografijom na silikagelu (98/2 smjesa heksan/EtOAc) dobije se 0,25 g t-butilnog estera (4R)-4,8-dimetilnonanske kiseline.
(4R)-4,8-dimetilnonanska kiselina
t-butilni ester (4R)-4,8-dimetilnonanske kiseline u 25 ml CH2Cl2 na 0°C obradi se TFA-om (6 ml). Smjesu se pusti da dođe na temperaturu okoliša, te miješa preko noći. Otapalo se ukloni u rotacijskom otparivaču, a smjesu pročisti kromatografijom na silikagelu (95/5 smjesa heksan/EtOAc) kako bi se dobilo 0,962 g (4R)-4,8-dimetilnonanska kiselina.
m/z 185 (M–).
3-(4R,8-dimetilnonanoil)-4(S)-metil-5(R)-feniloksazolidin-2-on
Kako bi se dobilo 3-(4R,8-dimetilnonanoil)-4(S)-metil-5(R)-feniloksazolidin-2-on (1,35 g) upotrijebi se postupak sličan onom za (4R,5S)-4-metil-3-(R)-4-metilheptanoil)-5-oksazolidin-2-on.
m/z 346,5 (M+).
Benzilni ester [4R,8-dimetil-2R-(4R-metil-2-okso-5R-feniloksazolidin-3-karbonil)nonil]karbaminske kiseline
U otopinu 3-(4(R),8-dimetilnonanoil)-4(S)-metil-5(R)-feniloksazolidin-2-ona (1,05 g, 3,04 mmol) u CH2Cl2 (12 ml) i TiCl4 (3,04 ml 1 M otopine u CH2Cl2) doda se diizopropiletilamin (0,55 ml, 3,19 mmol) na -20°C. Nastalu tamnocrevenu otopinu miješa se 30 minuta na -20°C prije dodavanja otopine N-metoksimetilbenzil-karbamata (0,652 g, 3,34 mmol) u CH2Cl2 (3,5 ml) i TiCl4 (3,34 ml). Smjesu se miješa 4 sata na 0 °C. Reakcijsku smjesu ugasi se dodavanjem zasićene vodene otopine amonijevog klorida. Smjesu se ekstrahira s CH2Cl2 (3 × 15 ml). Organske tvari se pomiješa, ispere s 1 N HCl, neutralizira s NaOH, te ispere slanom vodom. Organske tvari se osuši (MgSO4), filtrira, koncentrira, te pročisti kromatografijom na silikagelu (95/5 smjesa heksan/EtOAc) kako bi se dobilo 0,555 g benzilnog estera [4R,8-dimetil-2R-(4R-metil-2-okso-5R-feniloksazolidin-3-karbonil)nonil]karbaminske kiseline.
2(R)-(benziloksikarbonilaminometil)-4(R),8-dimetilnonanska kiselina
Kako bi se dobilo 0,198 g 2(R)-(benziloksikarbonilaminometil)-4(R),8-dimetilnonansku kiselinu upotrijebi se postupak sličan onom za t-butilni ester (S)-2-((R)-2-metilpentil)jantarne kiseline.
2-aminometil-4,8-dimetilnonanska kiselina
2(R)-(benziloksikarbonilaminometil)-4(R),8-dimetilnonansku kiselinu (0,148 g, 0,566 mmol) obradi se vodikom, u prisustvu 20 % Pd/C, kako bi se nakon filtracije i pročišćavanja kromatografijom na silikagelu (85/15 smjesa CH2Cl2/MeOH) dobilo 0,082 g 2-aminometil-4,8-dimetilnonanske kiseline.
m/z 216,3 (M+).
Primjer 10
2-aminometil-4,4,8-trimetilnonanska kiselina
Metilni ester 2,2,6-trimetilheptanske kiseline
Diizopropilaminu (1,54 ml, 11,03 mmol) u THF-u (22 ml) na -78°C doda se nBuLi (6,89 ml 1,6 M otopine u heksanu). Otopinu se miješa 30 minuta na -78°C, a zatim se doda metil-izobutirat (0,97 ml, 8,48 mmol). Smjesu se miješa 2 sata na -78°C, zatim se doda 1-jod-4-metilpentan (1,8 g, 8,48 mmol) i DMPU (0,55 ml, 4,24 mmol) u THF-u (6 ml). Reakcijsku smjesu miješa se na -78°C, te pusti neka polako u trajanju od 16 sati dođe na temperaturu okoliša. Reakcijsku smjesu ugasi se dodavanjem amonijevog klorida (zasićena vodena otopina), a smjesu ekstrahira s EtOAc (2 × 10 ml). Organske tvari se pomiješa, ispere vodom, osuši (MgSO4), filtrira, te koncentrira. Kromatografijom na silikagelu (99/1 heksan/EtOAc) dobije se 1,57 g metilnog estera 2,2,6-trimetilheptanske kiseline.
2,2,6-trimetilheptan-1-ol
Metilni ester 2,2,6-trimetilheptanske kiseline (1,97 g, 10,6 mmol) preuzme se u toluenu (65 ml), te ohladi do -78°C. Zatim se ukapa DiBALH (diizobutilaluminijev hidrid) (12,7 ml 1 N otopina u toluenu). Nakon 45 minuta doda se 1,5 ml DiBALH. Nakon 2 sata reakcijsku smjesu se ugasi dodavanjem 15 ml MeOH na -78°C. Smjesu se zagrije do temperature okoliša, zatim ponovno ohladi -78°C radi dodavanja 10 ml 1 N HCl. Smjesu se ekstrahira s EtOAc (3 × 15 ml). Pomiješane organske tvari ispere se slanom vodom, osuši (MgSO4), filtrira, te koncentrira. Preostalo ulje pročisti se kromatografijom na silikagelu (95/5 smjesa heksan/EtOAc) kako bi se dobilo 2,2,6-trimetilheptan-1-ol (0,88 g).
m/z 159 (M+).
2,2,6-trimetilheptanal
Piridinijev klorokromat ((pyridinium chlorochromate) PCC, 4,17 g, 19,4 mmol) pomiješa se s neutralnim aluminijevim oksidom (14,6 g) u CH2Cl2, te miješa 15 minuta na temperaturi okoliša. Alkohol se razrijedi u CH2Cl2, a smjesu miješa 2 sata na temperaturi okoliša. Otopinu se filtrira kroz jastučić od silicijevog dioksida, a krutine ispere s CH2Cl2. Filtrat se otpari kako bi se dobilo 1,05 g 2,2,6-trimetilheptanala, što se provede bez daljnjeg pročišćavanja.
m/z 157 (M+).
Benzilni ester 2-cijano-4,4,8-trimetilnon-2-enske kiseline
U smjesu 2,2,6-trimetilheptanala (1,05 g, 6,73 mmol), piperidina (0,19 ml, 2,01 mmol) i benzil-cijanoacetata (1,29 g, 7,4 mmol) u toluenu (50 ml) doda se ledena octena kiselina (0,72 g, 12,1 mmol). Tikvicu se opremi Dean-Starkovom zamkom, a smjesu grije na refluksu 18. Smjesu se ohladi, obradi razrijeđenom HCl, a slojeve razdvoji. Organske tvari ispere se zasićenom otopinom natrijevog bikarbonata, te slanom vodom, osuši (MgSO4), filtrira, te koncentrira. Preostalo ulje pročisti se kromatografijom na silikagelu (98/2 smjesa heksan/EtOAc) kako bi se dobilo 1,3 g benzilnog estera 2-cijano-4,4,8-trimetilnon-2-enske kiseline.
m/z 314 (M+).
2-aminometil-4,4,8-trimetilnonanska kiselina
Benzilni ester 2-cijano-4,4,8-trimetilnon-2-enske kiseline (1,3 g, 4,14 mmol) u THF-u (50 ml) obradi se vodikom u prisustvu 20 % Pd/C kako bi se dobilo smjesu cijano kiseline i cijano metilnog estera. Smjesu se pročisti kromatografijom na silikagelu kako bi se dobilo 278 mg 80105x41-1-2. Kiselinu se zatim obradi vodikom u prisustvu Raneyevog nikla u smjesi MeOH/NH4OH kako bi se dobilo 0,16 g 2-aminometil-4,4,8-trimetilnonanske kiseline.
m/z 230,3 (M+).
Primjer 11
2-aminometil-4-etiloktanska kiselina
Postupak sličan onom za 2-aminometil-4,4,8-trimetilnonansku kiselinu upotrijebljen je za dobivanje 2-aminometil-4-etiloktanske kiseline iz 2-etilheksanala.
m/z 202,1 (M+).
Primjer 12
2-aminometil-4-etil-8-metilnonanska kiselina
Postupak sličan onom za 2-aminometil-4,4,8-trimetilnonansku kiselinu upotrijebljen je za dobivanje 2-aminometil-8-metilnonanske kiseline iz 2,6-di-t-butil-4-metilfenil-ciklopropilkarboksilata.
m/z 230,2 (M+).
Primjer 13
3-amino-2-[1-(4-metilpentil)ciklopropilmetil]propionska kiselina
Postupak sličan onom za 2-aminometil-4,4,8-trimetilnonansku kiselinu upotrijebljen je za dobivanje 2-aminometil-8-metilnonanske kiseline iz 2,6-di-t-butil-4-metilfenil-ciklopropilkarboksilata.
m/z 228,2 (M+).
Primjer 14
2-aminometil-4-etilheksanska kiselina
Postupak sličan onom za 2-aminometil-4,8-dimetilnonanska kiselina upotrijebljen je za dobivanje 2-aminometil-4-etilheksanske kiseline iz 4-etilheksanske kiseline.
m/z 174,1.
Primjer 15
3(S)-amino-3,5-dimetilheptanska kiselina
(1,3-dimetilpentiliden)amid 2-metilpropan-2(S)-sulfinske kiseline
Otopinu (S)-(–)-2-metil-2-propansulfonamida (500 mg, 4,1 mmol), 4-metil-2-heksanona (470 mg, 4,1 mmol), i titanijevog(IV) etoksida (1,7 ml, 8,3 mmol) grije se 18 sati na refluksu. Reakcijsku smjesu izlije se u 20 ml slane vode, uz brzo miješanje. Nastalu otopinu filtrira se kroz Celite, a organski sloj odvoji. Vodeni sloj ekstrahira se etil-acetatom (2 × 20 ml). Pomiješane organske tvari se osuši (Na2SO4), filtrira, te koncentrira. Nastalo ulje pročisti se kromatografijom na silikagelu (25 % EtOAc u heksanu) kako bi se dobilo 575 mg (1,3-dimetilpentiliden)amida 2-metilpropan-2(S)-sulfinske kiseline u obliku žutog ulja.
3,5-metilni ester dimetil-3-(2-metilpropan-2(S)-sulfinilamino)heptanske kiseline
U otopinu litijevog bis(trimetilsilil)amida na -78°C (5,1 ml 1 M otopine u THF-u) u THF-u (6 ml) ukapava se metil-acetat ((0,41 ml, 5,1 mmol). Nakon 20 minuta miješanja, ukapava se otopina klorotitanijevog triizopropoksida (2,5 ml, 10 mmol) u THF-u (3 ml). Nakon 1 sata ukapava se (1,3-dimetilpentiliden)amid 2-metilpropan-2(S)-sulfinske kiseline (560 mg, 2,6 mmol) u THF-u (3 ml) na -78°C. Reakcijsku smjesu miješa se 5 sati na -78°C, te ugasi dodavanjem 10 ml otopine amonijevog klorida, te zagrije do sobne temperature. Smjesu se razrijedi s 10 ml vode, te filtrira. Vodeni sloj ekstrahira se etil-acetatom (2 × 20 ml). Pomiješane organske tvari ispere se slanom vodom, osuši (Na2SO4), filtrira, te koncentrira. Nastalo ulje pročisti se kromatografijom na silikagelu (30 % EtOAc u heksanu) kako bi se dobilo 360 mg 3,5-metilnog estera dimetil-3-(2-metilpropan-2(S)-sulfinilamino)heptanske kiseline.
3(S)-amino-3,5-dimetilheptanska kiselina
3,5-metilni ester dimetil-3-(2-metilpropan-2(S)-sulfinilamino)heptanske kiseline (360 mg, 1,2 mmol) otopi se u 6 N HCl (2 ml) i dioksanu (2 ml), te grije 6 sati na 100°C. Smjesu se ohladi do sobne temperature, razrijedi vodom, te ekstrahira s EtOAc (15 ml). Organske tvari pročisti se ionskoizmjenjivačkom kromatografijom kako bi se dobilo 3(S)-amino-3,5-dimetilheptansku kiselinu (270 mg), te ponovno pročisti kromatografijom na silikagelu (70:25:5 smjesa CH2Cl2/MeOH/NH4OH) kako bi se dobilo 203 mg 3(S)-amino-3,5-dimetilheptanske kiseline u obliku bijele krutine.
m/z 174 (C9H19NO2 + H).
Primjer 16
3(S)-amino-3,5-dimetilnonanska kiselina
Postupak sličan onom za 3(S)-amino-3,5-dimetilheptansku kiselinu upotrijebljen je za dobivanje 3(S)-amino-3,5-dimetilnonansku kiselinu.
m/z 202,1 (C11H23NO2 + H).
Primjer 17
3(S)-amino-3,5-dimetiloktanska kiselina
Postupak sličan onom za 3(S)-amino-3,5-dimetilheptansku kiselinu upotrijebljen je za dobivanje 3(S)-amino-3,5-dimetilnonanske kiseline.
m/z 188,1 (C10H21NO2 + H).
Claims (14)
1. Ovaj izum odnosi se na spojeve formule I
[image]
,
naznačene time što
R1 je vodik ili (C1-C6)alkil, izborno supstituiran s 1 do 5 atoma fluora;
R2 je vodik ili (C1-C6)alkil, izborno supstituiran s 1 do 5 atoma fluora; ili
R1 i R2, zajedno s ugljikom na koji su vezani, tvore 3- do 6- člani cikloalkilni prsten;
R3 je (C1-C6)alkil, (C3-C6)cikloalkil, (C3-C6)cikloalkil(C1-C3)alkil, fenil, fenil-(C1-C3)alkil, piridil, piridil-(C1-C3)alkil, fenil-N(H)-, ili piridil-N(H)-, gdje svaki od gore navedenih alkilnih ostataka može izborno biti supstituiran s 1 do 5 atoma fluora, po mogućnosti s 0 do 3 atoma fluora, gdje navedeni fenilni i navedeni piridilni, te fenilni i piridilni ostaci u navedenom fenil-(C1-C3)alkilu, odnosno navedenom piridil-(C1-C3) alkilu, mogu izborno biti supstituirani s 1 do 3 supstituenta, po mogućnosti s 0 do 2 supstituenta, koje se neovisno bira između klora, fluora, amino, nitro, cijano, (C1-C3)alkilamino, (C1-C3)alkila, izborno supstituiranog s 1 do 3 atoma fluora i (C1-C3)alkoksi, izborno supstituiranog s 1 do 3 atoma fluora;
R4 je vodik ili (C1-C6)alkil, izborno supstituiran s 1 do 5 atoma fluora;
R5 je vodik ili (C1-C6)alkil, izborno supstituiran s 1 do 5 atoma fluora; a
R6 je vodik ili (C1-C6)alkil;
ili farmaceutski prihvatljiva sol takvog spoja.
2. Spoj prema zahtjevu 1, naznačen time što mu je formula IA
[image]
,
gdje
R1 je vodik ili (C1-C3)alkil, izborno supstituiran s 1 do 5 atoma fluora;
R2 je vodik ili (C1-C3)alkil, izborno supstituiran s 1 do 5 atoma fluora; a
R3 je (C1-C6)alkil, (C3-C6)cikloalkil, (C3-C6)cikloalkil-(C1-C3)alkil, fenil, fenil-(C1-C3)alkil, piridil, piridil-(C1-C3)alkil, fenil-N(H)-, ili piridil-N(H)-, gdje svaki od gore navedenih alkilnih ostataka može izborno biti supstituiran s 1 do 5 atoma fluora, po mogućnosti s 0 do 3 atoma fluora, gdje navedeni fenilni i navedeni piridilni, te fenilni i piridilni ostaci u navedenom fenil-(C1-C3)alkilu, odnosno navedenom piridil-(C1-C3) alkilu, mogu izborno biti supstituiran s 1 do 3 supstituenta, po mogućnosti s 0 do 2 supstituenta, koje se neovisna bira između klora, fluora, amino, nitro, cijano, (C1-C3)alkilamino, (C1-C3)alkila, izborno supstituiranog s 1 do 3 atoma fluora i (C1-C3)alkoksi, izborno supstituiranog s 1 do 3 atoma fluora;
uz uvjet da kada R1 je vodik, tada R2 nije vodik;
ili farmaceutski prihvatljiva sol takvog spoja.
3. Spoj formule II
[image]
,
naznačen time što
R1 je vodik ili (C1-C3)alkil, izborno supstituiran s 1 do 5 atoma fluora;
R2 je vodik ili (C1-C3)alkil, izborno supstituiran s 1 do 5 atoma fluora;
R3 je (C1-C6)alkil, (C3-C6)cikloalkil, (C3-C6)cikloalkil-(C1-C3)alkil, fenil, fenil-(C1-C3)alkil, piridil, piridil-(C1-C3)lkil, fenil-N(H)-, ili piridil-N(H)-, gdje svaki od gore navedenih alkilnih ostataka može izborno biti supstituiran s 1 do 5 atoma fluora, po mogućnosti s 0 do 3 atoma fluora, gdje navedeni fenil i navedeni piridil i fenil i piridil ostaci u navedenom fenil-(C1-C3)alkilu, odnosno navedenom piridil-(C1-C3)alkilu, mogu izborno biti supstituirani s 1 do 3 supstituenta, po mogućnosti s 0 do 2 supstituenta, koje se neovisno bira između klora, fluora, amino, nitro, cijano, (C1-C3)alkilamino, (C1-C3)alkila, izborno supstituiranog s 1 do 3 atoma fluora i (C1-C3)alkoksi, izborno supstituiranog s 1 do 3 atoma fluora;
uz uvjet da kada R1 je vodik, tada R2 nije vodik;
ili farmaceutski prihvatljiva sol takvog spoja.
4. Spoj prema zahtjevu 2, naznačen time što mu je formula IA-1
[image]
,
gdje
R3 je (C1-C6)alkil, (C3-C6)cikloalkil, (C3-C6)cikloalkil-(C1-C3)alkil, fenil, fenil-(C1-C3)alkil, piridil, piridil-(C1-C3)alkil, fenil-N(H)-, ili piridil-N(H)-, gdje svaki od gore navedenih alkilnih ostataka može izborno biti supstituiran s 1 do 5 atoma fluora, po mogućnosti s 0 do 3 atoma fluora, gdje navedeni fenilni i navedeni piridilni, te fenilni i piridilni ostaci u navedenom fenil-(C1-C3)alkilu, odnosno navedenom piridil-(C1-C3) alkilu, mogu izborno biti supstituirani s 1 do 3 supstituenta, po mogućnosti s 0 do 2 supstituenta, koje se bira između klora, fluora, amino, nitro, cijano, (C1-C3)alkilamino, (C1-C3)alkila, izborno supstituiranog s 1 do 3 atoma fluora i (C1-C3)alkoksi, izborno supstituiranog s 1 do 3 atoma fluora;
ili farmaceutski prihvatljiva sol takvog spoja.
5. Spoj prema zahtjevu 3, naznačen time što mu je formula IIA
[image]
,
gdje
R3 je (C1-C6)alkil, (C3-C6)cikloalkil, (C3-C6)cikloalkil-(C1-C3)alkil, fenil, fenil-(C1-C3)alkil, piridil, piridil-(C1-C3)alkil, fenil-N(H)-, ili piridil-N(H)-, gdje svaki od gore navedenih alkilnih ostataka može izborno biti supstituiran s 1 do 5 atoma fluora, po mogućnosti s 0 do 3 atoma fluora, gdje navedeni fenilni i navedeni piridilni, te fenilni i piridilni ostaci u navedenom fenil-(C1-C3)alkilu, odnosno navedenom piridil-(C1-C3) alkilu, mogu izborno biti supstituirani s 1 do 3 supstituenta, po mogućnosti s 0 do 2 supstituenta, koje se bira između klora, fluora, amino, nitro, cijano, (C1-C3)alkilamino, (C1-C3)alkila, izborno supstituiranog s 1 do 3 atoma fluora i (C1-C3)alkoksi, izborno supstituiranog s 1 do 3 atoma fluora;
ili farmaceutski prihvatljiva sol takvog spoja.
6. Spoj prema zahtjevu 2, naznačen time što mu je formula IA-2,
[image]
,
gdje
R1 je vodik ili (C1-C3)alkil, izborno supstituiran s 1 do 5 atoma fluora;
R2 je vodik ili (C1-C3)alkil, izborno supstituiran s 1 do 5 atoma fluora; a
R3 je (C1-C6)alkil, (C3-C6)cikloalkil, (C3-C6)cikloalkil-(C1-C3)alkil, fenil, fenil-(C1-C3)alkil, piridil, piridil-(C1-C3)alkil, fenil-N(H)-, ili piridil-N(H)-, gdje svaki od gore navedenih alkilnih ostataka može izborno biti supstituiran s 1 do 5 atoma fluora, po mogućnosti s 0 do 3 atoma fluora, gdje navedeni fenilni i navedeni piridilni, te fenilni i piridilni ostaci u navedenom fenil-(C1-C3)alkilu, odnosno navedenom piridil-(C1-C3) alkilu, mogu izborno biti supstituirani s 1 do 3 supstituenta, po mogućnosti s 0 do 2 supstituenta, koje se neovisno bira između klora, fluora, amino, nitro, cijano, (C1-C3)alkilamino, (C1-C3)alkila, izborno supstituiranog s 1 do 3 atoma fluora i (C1-C3)alkoksi, izborno supstituiranog s 1 do 3 atoma fluora;
uz uvjet da kada R1 je vodik, tada R2 nije vodik;
ili farmaceutski prihvatljiva sol takvog spoja.
7. Spoj formule III
[image]
,
naznačen time što
R3 je (C1-C6)alkil, (C3-C6)cikloalkil, (C3-C6)cikloalkil-(C1-C3)alkil, fenil, fenil-(C1-C3)alkil, piridil, piridil-(C1-C3)alkil, fenil-N(H)-, ili piridil-N(H)-, gdje svaki od gore navedenih alkilnih ostataka može izborno biti supstituiran s 1 do 5 atoma fluora, po mogućnosti s 0 do 3 atoma fluora, gdje navedeni fenilni i navedeni piridilni, te fenilni i piridilni ostaci u navedenom fenil-(C1-C3)alkilu, odnosno navedenom piridil-(C1-C3) alkilu, mogu izborno biti supstituirani s 1 do 3 supstituenta, po mogućnosti s 0 do 2 supstituenta, koje se bira između klora, fluora, amino, nitro, cijano, (C1-C3)alkilamino, (C1-C3)alkila, izborno supstituiranog s 1 do 3 atoma fluora i (C1-C3)alkoksi, izborno supstituiranog s 1 do 3 atoma fluora;
ili njegova farmaceutski prihvatljiva sol.
8. Spoj formule IV
[image]
,
naznačen time što
R1 je vodik ili (C1-C6)alkil, izborno supstituiran s 1 do 5 atoma fluora; a
R3 je (C1-C6)alkil, (C3-C6)cikloalkil, (C3-C6)cikloalkil-(C1-C3)alkil, fenil, fenil-(C1-C3)alkil, piridil, piridil-(C1-C3)alkil, fenil-N(H)-, ili piridil-N(H)-, gdje svaki od gore navedenih alkilnih ostataka može izborno biti supstituiran s 1 do 5 atoma fluora, po mogućnosti s 0 do 3 atoma fluora, gdje navedeni fenilni i navedeni piridilni, te fenilni i piridilni ostaci u navedenom fenil-(C1-C3)alkilu, odnosno navedenom piridil-(C1-C3) alkilu, mogu izborno biti supstituirani s 1 do 3 supstituenta, po mogućnosti s 0 do 2 supstituenta, koje se bira između klora, fluora, amino, nitro, cijano, (C1-C3)alkilamino, (C1-C3)alkila, izborno supstituiranog s 1 do 3 atoma fluora i (C1-C3)alkoksi, izborno supstituiranog s 1 do 3 atoma fluora;
ili farmaceutski prihvatljiva sol takvog spoja.
9. Farmaceutski pripravak, naznačen time što sadrži terapijski djelotvornu količinu spoja prema bilo kojem od zahtjeva 1 do 8, ili njegove farmaceutski prihvatljive sol, te farmaceutski prihvatljivu podlogu.
10. Postupak liječenja poremećaja ili stanja koje se bira između napadaja nesvjestice, fibromialgije, hipokinezije, kranijalnih poremećaja, napadaja vrućine, esencijalnog tremora, navike i ovisnosti o kemijskim sredstvima, (npr. navike ili ovisnosti o alkoholu, amfetaminima (ili tvarima sličnim amfetaminima) kofeinu, kanabisu, kokainu, heroinu, halucinogenima, duhanu, inhalansima i pogonskim plinovima za aerosole, nikotin, opioidima, fenilglicidinskim derivatima, sedativima, hipnoticima, benzodiazepinima i drugim anksioliticima), i simptoma ustezanja povezanih s takvima navikama ili ovisnostima, ovisničkog ponašanja, poput kockanja; migrene, spazama, artritisa, sindroma iritabilnog crijeva (IBS), kronične boli, akutne boli, neuropatske boli, vaskularne glavobolje, sinusne glavobolje, upalnih poremećaja (npr. reumatoidnog artritisa, osteoartritisa, psorijaze), mokrenja, predmenstrualnog sindroma, predmenstrualnog disforičnog poremećaja, tinitusa, i oštećenja želuca kod sisavca, uključujući čuvjeka, naznačen time što se sastoji u primjeni na sisavcu kojem je potrebno takvo liječenje terapijski djelotvorne količine spoja prema bilo kojem od zahtjeva 1 do 8 ili njegove farmaceutski prihvatljive soli.
11. Postupak liječenja poremećaja ili stanja koje se bira iz grupe koju čine delirij, demencija, te amnestički i drugi kognitivni ili neurodegenerativni poremećaji, poput Parkinsonove bolesti (PD), Huntingtonove bolesti (HD), Alzheimerove bolesti, senilne demencije, demencije Alzheimerovog tipa, poremećaj pamćenja, vaskularne demencije, te drugih demencija, primjerice, uzrokovanih HIV-bolešću, ozljedom glave, Parkinsonovom bolešću, Huntingtonovom bolešću, Pickovom bolešću, Creutzfeldt-Jakobovom bolešću, ili uzrokovanih višestrukom etiologijom; poremećaji kretanja, poput akinezije, diskinezije, uključujući porodične paroksizmalne diskinezije, spazme, Touretteov sindrom, Scottov sindrom, PALSYS i akinetički rigidni sindrom; ekstrapiramidalni poremećaji kretanja, poput poremećaja kretanja uzrokovanih primjenom lijekova, primjerice, Parkinsonizma uzrokovanog neurolepticima, neuroleptičnog malignog sindroma, akutne distonije uzrokovane neurolepticima, akutne akatizije uzrokovane neurolepticima, tardivne diskinezije uzrokovane neurolepticima i posturalnog tremora uzrokovanog primjenom lijekova; Downov sindrom; demijelinizirajuće bolesti, poput multiple skleroze (MS) i amiolateralne skleroze (ALS), periferne neuropatije, primjerice dijabetične i neuropatije uzrokovane kemoterapijom, i postherpetične neuralgije, trigeminalne neuralgije, segmentalne ili interkostalne neuralgije i drugih neuralgija; i cerebrovaskularne poremećaje uzrokovane akutnim ili kroničnim oštećenjem cerebralne vaskulature, poput cerebralnog infarkta, subarahnoidalnog krvarenja ili cerebralnog edema kod sisavca, uključujući čovjeka, naznačen time što se sastoji u primjeni na navedenom sisavcu količine spoja prema bilo kojem od patentnih zahtjeva 1 do 8, ili njegove farmaceutski prihvatljive soli, djelotvorne u liječenju takvog poremećaja ili stanja.
12. Postupak liječenja poremećaja ili stanja, koje se bira iz grupe koju čine poremećaji spavanja (npr. nesanica, nesanica povezana s upotrebom lijekova, poremećaji REM-sna, hipersomnija, narkolepsija, poremećaji ciklusa sna i budnosti, sindromi apneje u snu, parasomnije, te poremećaji spavanja povezani s radom u smjenama i nepravilnim radnim vremenom) kod sisavca, uključujući čovjeka, naznačen time što se sastoji u primjeni na navedenom sisavcu količine spoja prema bilo kojem od patentnih zahtjeva 1 do 8, ili njegove farmaceutski prihvatljive soli, djelotvorne u liječenju takvog poremećaja ili stanja.
13. Postupak liječenja poremećaja ili stanja, koje se bira između poremećaja raspoloženja, poput depresije, ili preciznije, depresivnih poremećaja, primjerice jedne epizode ili povratnih velikih depresivnih poremećaja, distimičnih poremećaja, depresivne neuroze i neurotične depresije, melankolične depresije, uključujući anoreksiju, gubitak na težini, nesanicu, ranojutarnje buđenje i psihomotoričku retardaciju, atipičnu depresiju (ili reaktivnu depresiju), uključujući pojačani tek, hipersomniju, psihomotoričku agitaciju ili razdražljivost, sezonski afektivni poremećaj i pedijatrijsku depresiju; ili bipolarnih poremećaja ili manične depresije, primjerice bipolarni poremećaj I, bipolarni poremećaj II i ciklotimični poremećaj; poremećaja ponašanja i poremećaja anarhoidnog ponašanja; anksioznih poremećaja, poput paničnog poremećaja, uz ili bez agorafobiju, agorafobiju bez paničnog poremećaja u anamnezi, specifičnih fobija, primjerice specifičnih animalnih fobija, socijalne anksioznosti, socijalne fobije, opsesivno-kompulzivnog poremećaja, stresnih poremećaja, uključujući posttraumatski stresni poremećaj i akutni stresni poremećaj, te generaliziranih anksioznih poremećaja; poremećaja granične osobnosti; shizofrenije i drugih psihotičnih poremećaja, primjerice shizofreniformnih poremećaja, shizoafektivnih poremećaja, sumanutih poremećaja, kratkotrajnih psihotičnih poremećaja, podijeljenih psihotičnih poremećaja, psihotičnih poremećaja s obmanama ili halucinacijama, psihotične epizode anksioznosti, anksioznosti povezane s psihozom, psihotičnih poremećaje raspoloženja, poput teškog velikog depresivnog poremećaja; poremećaja raspoloženja povezanih s psihotičnim poremećajima poput akutne manije i depresije povezane s bipolarnim poremećajem, poremećaja raspoloženja povezanih sa shizofrenijom; poremećaja ponašanja povezanih s mentalnom retardacijom, autističnim poremećajem, te poremećajem ponašanja kod sisavca, uključujući čovjeka, naznačen time što se sastoji u primjeni na navedenom sisavcu količine spoja prema bilo kojem od zahtjeva 1 do 8, ili njegove farmaceutski prihvatljive soli, djelotvorne u liječenju takvog poremećaja ili stanja.
14. Spoj ili sol, naznačeni time što ih se bira između sljedećih spojeva i njihovih farmaceutski prihvatljivih soli:
3-amino-5-metiloktanske kiseline;
3-amino-5-metilnonanske kiseline;
(3S,5R)-3-amino-5-metilheptanske kiseline;
(3S,5R)-3-amino-5-metiloktanske kiseline;
(3S,5R)-3-amino-5-metilnonanske kiseline;
3-amino-7-ciklopentil-5-metilheptanske kiseline;
3-amino-7-cikloheksil-5-metilheptanske kiseline;
(3S,5R)-3-amino-7-ciklopentil-5-metilheptanske kiseline;
(3S,5R)-3-amino-7-cikloheksil-5-metilheptanske kiseline;
3-amino-5-metil-7-fenilheptanske kiseline;
3-amino-5-metil-7-(2,4-difluorfenil)heptanske kiseline;
3-amino-8-(2,3-difluorfenil)-5-metiloktanske kiseline;
3-amino-8-(2,4-difluorfenil)-5-metiloktanske kiseline;
2-aminometil-4-metilheptanske kiseline;
(2R,4R)-2-aminometil-4-metilheptanske kiseline;
(2R,4S)-2-aminometil-4-metilheptanske kiseline;
2-aminometil-3-[1-(4-metilpentil)ciklopropil]propionske kiseline;
2-aminometil-4-etil-8-metilnonanske kiseline;
2-aminometil-3-(1-metilciklopropil)propionske kiseline;
2-aminometil-4,4-dimetil-8-metilnonanske kiseline;
2-aminometil-4-cikloheksil-3-metilmaslačne kiseline; i
2-aminometil-4,6-dimetilheptanske kiseline.
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US36841302P | 2002-03-28 | 2002-03-28 | |
PCT/IB2003/000976 WO2003082807A2 (en) | 2002-03-28 | 2003-03-17 | Amino acids with affinity for the alpha-2-delta-protein |
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