NO330612B1 - Tetrahydroquinoline derivatives, pharmaceutical compositions comprising such, such compounds for use in therapy and the use thereof for the manufacture of drugs for fertility regulation - Google Patents
Tetrahydroquinoline derivatives, pharmaceutical compositions comprising such, such compounds for use in therapy and the use thereof for the manufacture of drugs for fertility regulation Download PDFInfo
- Publication number
- NO330612B1 NO330612B1 NO20052727A NO20052727A NO330612B1 NO 330612 B1 NO330612 B1 NO 330612B1 NO 20052727 A NO20052727 A NO 20052727A NO 20052727 A NO20052727 A NO 20052727A NO 330612 B1 NO330612 B1 NO 330612B1
- Authority
- NO
- Norway
- Prior art keywords
- alkoxy
- phenyl
- trimethyl
- compounds
- yield
- Prior art date
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- 239000003814 drug Substances 0.000 title claims description 8
- 230000035558 fertility Effects 0.000 title claims description 7
- 230000033228 biological regulation Effects 0.000 title claims description 4
- 229940079593 drug Drugs 0.000 title claims description 4
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 238000002560 therapeutic procedure Methods 0.000 title claims description 3
- 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 title claims 6
- 150000001875 compounds Chemical class 0.000 title description 279
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 125000003545 alkoxy group Chemical group 0.000 claims description 77
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- -1 furylcarbonylamino Chemical group 0.000 claims description 36
- 125000003282 alkyl amino group Chemical group 0.000 claims description 22
- 125000002541 furyl group Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 239000000654 additive Substances 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 4
- 238000000034 method Methods 0.000 description 174
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 72
- 239000000460 chlorine Substances 0.000 description 70
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 58
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 49
- 239000000203 mixture Substances 0.000 description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 239000000243 solution Substances 0.000 description 39
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 36
- 238000004587 chromatography analysis Methods 0.000 description 36
- 239000000741 silica gel Substances 0.000 description 36
- 229910002027 silica gel Inorganic materials 0.000 description 36
- 239000003480 eluent Substances 0.000 description 35
- 238000002953 preparative HPLC Methods 0.000 description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 239000007821 HATU Substances 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 229910001868 water Inorganic materials 0.000 description 24
- 125000004432 carbon atom Chemical group C* 0.000 description 22
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 19
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- 229940028334 follicle stimulating hormone Drugs 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 15
- NNJMFJSKMRYHSR-UHFFFAOYSA-N 4-phenylbenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 102000005962 receptors Human genes 0.000 description 15
- 108020003175 receptors Proteins 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- 229960000583 acetic acid Drugs 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 235000011054 acetic acid Nutrition 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical class O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 238000006722 reduction reaction Methods 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 238000010520 demethylation reaction Methods 0.000 description 11
- 230000009467 reduction Effects 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- VCNGNQLPFHVODE-UHFFFAOYSA-N 5-methylthiophene-2-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)S1 VCNGNQLPFHVODE-UHFFFAOYSA-N 0.000 description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 10
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 10
- 108010060374 FSH Receptors Proteins 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 150000003530 tetrahydroquinolines Chemical class 0.000 description 9
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 8
- 102000008175 FSH Receptors Human genes 0.000 description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 8
- 238000005917 acylation reaction Methods 0.000 description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
- 230000017858 demethylation Effects 0.000 description 8
- 238000004108 freeze drying Methods 0.000 description 8
- 230000014509 gene expression Effects 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 238000006396 nitration reaction Methods 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 7
- 238000006640 acetylation reaction Methods 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
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- 125000000592 heterocycloalkyl group Chemical group 0.000 description 7
- 150000003840 hydrochlorides Chemical class 0.000 description 7
- 230000000638 stimulation Effects 0.000 description 7
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 150000001555 benzenes Chemical class 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 150000002367 halogens Chemical group 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- SFTFNJZWZHASAQ-UHFFFAOYSA-N 3,5-dibromobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC(Br)=C1 SFTFNJZWZHASAQ-UHFFFAOYSA-N 0.000 description 5
- QZLSBOVWPHXCLT-UHFFFAOYSA-N 5-chlorothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)S1 QZLSBOVWPHXCLT-UHFFFAOYSA-N 0.000 description 5
- 102000006771 Gonadotropins Human genes 0.000 description 5
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- 239000002585 base Substances 0.000 description 5
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Description
Foreliggende oppfinnelse omhandler et tetrahydrokinolinderivat, et farmasøytisk preparat som inneholder dette, så vel som anvendelse av nevnte forbindelse i medisinsk terapi. The present invention relates to a tetrahydroquinoline derivative, a pharmaceutical preparation containing this, as well as the use of said compound in medical therapy.
Gonadotropiner tjener viktige funksjoner i en rekke kroppsfunksjoner som inkluderer metabolisme, temperaturregulering og reproduksjonsprosessen. Gonadotropiner virker på spesifikke gonadale celletyper for å initiere eggstokk- og tes-tikkel-differensiering og steroidogenese. Det hypofyseale gonadotropin FSH (fol-likkelstimulerende hormon) spiller for eksempel en sentral rolle i stimuleringen av follikkelutvikling og modning mens LH (luteiniserende hormon) induserer eggløs-ning (Sharp, R.M. Clin Endocrinol. 33:787-807, 1990; Dorrington og Armstrong, Recent Prog. Horm. Res. 35:301-342,1979). På det nåværende tidspunkt, blir FSH anvendt klinisk, i kombinasjon med LH eller hCG, for eggstokk- stimulering dvs. eggstokk-hyperstimulering for in vitro befruktning (IVF) og induksjon av eggløsning hos infertile anovulatoriske kvinner (Insler, V., Int. J. Fertility 33:85-97, 1988, Navot og Rosenwaks, J. Vitro Fert. Embryo Transfer 5:3-13, 1988), så vel som for mannlig hypogonadisme og mannlig infertilitet. Gonadotropins serve important functions in a variety of bodily functions that include metabolism, temperature regulation, and the reproductive process. Gonadotropins act on specific gonadal cell types to initiate ovarian and testicular differentiation and steroidogenesis. For example, the pituitary gonadotropin FSH (follicle-stimulating hormone) plays a central role in stimulating follicle development and maturation while LH (luteinizing hormone) induces ovulation (Sharp, R.M. Clin Endocrinol. 33:787-807, 1990; Dorrington and Armstrong , Recent Prog. Horm. Res. 35:301-342, 1979). At present, FSH is used clinically, in combination with LH or hCG, for ovarian stimulation ie ovarian hyperstimulation for in vitro fertilization (IVF) and induction of ovulation in infertile anovulatory women (Insler, V., Int. J . Fertility 33:85-97, 1988, Navot and Rosenwaks, J. Vitro Fert. Embryo Transfer 5:3-13, 1988), as well as for male hypogonadism and male infertility.
Gonadotropinet FSH frigis fra den fremre hypofyse- under påvirkningen av gonadotropin-frigjørende hormon og østrogener og fra placenta under graviditet. Hos kvinnen, virker FSH på eggstokkene og fremmer utvikling av follikler og er det viktigste hormonet for å regulere sekresjon av østrogener. Hos mannen, er FSH ansvarlig for integriteten av tubili seminiferi og virker på Sertoli celler for å støtte gametogenese. Renset FSH anvendes klinisk for å behandle infertilitet hos kvinner og for noen typer av spermatogenesesvikt hos menn. Gonadotropiner bestemt for terapeutiske formål kan isoleres fra humane urinkilder og har lav renhet (Morse et al, Amer. J. Reproduct. Immunol. og Microbiology 17:143,1988). Alternativt, kan de fremstilles som rekombinante gonadotropiner. Rekombinant human FSH er tilgjengelig kommersielt og anvendes i assistert reproduksjon (Olijve et al. Mol. Hum. Reprod. 2:371, 1996; Devroey et al. Lancet 339:1170, 1992). The gonadotropin FSH is released from the anterior pituitary under the influence of gonadotropin-releasing hormone and estrogens and from the placenta during pregnancy. In the female, FSH acts on the ovaries and promotes the development of follicles and is the most important hormone in regulating the secretion of estrogens. In the male, FSH is responsible for the integrity of the seminiferous tubules and acts on Sertoli cells to support gametogenesis. Purified FSH is used clinically to treat infertility in women and for some types of spermatogenesis failure in men. Gonadotropins intended for therapeutic purposes can be isolated from human urine sources and are of low purity (Morse et al, Amer. J. Reproduct. Immunol. and Microbiology 17:143,1988). Alternatively, they can be prepared as recombinant gonadotropins. Recombinant human FSH is available commercially and is used in assisted reproduction (Olijve et al. Mol. Hum. Reprod. 2:371, 1996; Devroey et al. Lancet 339:1170, 1992).
Virkningene av FSH hormonet medieres av en spesifikk plasmamembran-reseptor som er et element i den store familien av G-protein koblede reseptorer. Disse reseptorene består av et enkelt polypeptid med syv transmembran domener og er i stand til å vekselvirke med Gs proteinet, og fører f.eks. til aktivering av adenylatcyklase. The effects of the FSH hormone are mediated by a specific plasma membrane receptor which is an element of the large family of G-protein coupled receptors. These receptors consist of a single polypeptide with seven transmembrane domains and are capable of interacting with the Gs protein, leading e.g. to the activation of adenylate cyclase.
FSH reseptoren er et meget spesifikt mål i eggstokk-follikkelvekst proses-sen og blir utelukkende uttrykt i eggstokken. Blokkering av denne reseptoren eller inhibering av signaleringen som normalt induseres etter FSH-mediert reseptorakti-vering vil forstyrre follikkelutvikling og således eggløsning og fertilitet. FSH antagonister med lav molekylvekt kunne derfor danne basis for nye prevensjonsmidler. Slike FSH antagonister kunne gi opphav til redusert follikkelutvikling (ingen egg-løsning) med fortsatt tilstrekkelig gjenværende østrogenproduksjon for å unngå ugunstige effekter på f.eks. benmasse. På den annen side, kan forbindelser som stimulerer FSH reseptoraktiviteten tjene til å etterligne den gonadotropiske effek-ten av den naturlige liganden. The FSH receptor is a very specific target in the ovary-follicle growth process and is exclusively expressed in the ovary. Blocking this receptor or inhibiting the signaling that is normally induced after FSH-mediated receptor activation will disrupt follicle development and thus ovulation and fertility. FSH antagonists with low molecular weight could therefore form the basis for new contraceptives. Such FSH antagonists could give rise to reduced follicle development (no ovulation) with still sufficient residual estrogen production to avoid adverse effects on e.g. bone mass. On the other hand, compounds that stimulate FSH receptor activity may serve to mimic the gonadotropic effect of the natural ligand.
Foreliggende oppfinnelse beskriver tetrahydrokinolinderivat med lav molekylvekt som selektivt har fruktbarhetsregulerende effekt. The present invention describes a low molecular weight tetrahydroquinoline derivative which selectively has a fertility-regulating effect.
Oppfinnelsen omfatter tetrahydrokinolinforbindelser med formel I eller farmasøytisk akseptable salter derav The invention encompasses tetrahydroquinoline compounds of formula I or pharmaceutically acceptable salts thereof
hvor where
R<1>og R<2>er Me; R<1> and R<2> are Me;
R3 er H, hydroksy eller (1-4C)alkoksy; R 3 is H, hydroxy or (1-4C) alkoxy;
R4 er H, OH, (1-4C)alkoksy eller R<7;>R4 is H, OH, (1-4C) alkoxy or R<7;>
R<5>er H, OH, (1-4C)alkoksy eller R<7;>R<5> is H, OH, (1-4C) alkoxy or R<7;>
med det forbehold at hvis R<4>er H, er R<5>ikke H, OH eller (1-4C)alkoksy og at hvis R5 er H, er R<4>ikke H, OH eller (1-4C)alkoksy; with the proviso that if R<4> is H, R<5> is not H, OH or (1-4C) alkoxy and that if R5 is H, R<4> is not H, OH or (1-4C) alkoxy;
R6 er (1-6C)alkyl, (3-7C)cykloalkyl, R6 is (1-6C)alkyl, (3-7C)cycloalkyl,
fenyl eventuelt substituert med halogen, (1-6C)alkoksy eller (1-6C)alkyl, phenyl optionally substituted with halogen, (1-6C) alkoxy or (1-6C) alkyl,
furyl eventuelt substituert med (1-6C)alkyl, furyl optionally substituted with (1-6C)alkyl,
tienyl eventuelt substituert med halogen eller (1-6C)alkyl eller bifenyl; thienyl optionally substituted with halogen or (1-6C)alkyl or biphenyl;
R<7>er (1-6C)alkylamino, (di)(1-6C)alkylamino, fenyl(1-4C)alkylamino, pyridyl(1-4C)alkylamino, furylkarbonylamino, morfolinyl(1-4C)alkoksy, (di)(1-6C)alkylaminokarbonyl(1-6C)alkoksy, piperidinyl(1-4C)alkoksy, pyridyl(1-4C)alkoksy, karbamoyl(1-4C)alkoksy, morfolinylkarbonylamino(1-4C)alkoksy, amino(1-4C)alkoksy, (1-6C)alkoksykarbonyl(1-4C)alkoksy, furyl(1-4C)alkoksy, pyrrolidinyl(1-4C)alkoksy eller isoksazolyl(1-4C)alkoksy eventuelt substituert med (1-6C)alkyl. R<7> is (1-6C)alkylamino, (di)(1-6C)alkylamino, phenyl(1-4C)alkylamino, pyridyl(1-4C)alkylamino, furylcarbonylamino, morpholinyl(1-4C)alkoxy, (di )(1-6C)Alkylaminocarbonyl(1-6C)Alkoxy, Piperidinyl(1-4C)Alkoxy, Pyridyl(1-4C)Alkoxy, Carbamoyl(1-4C)Alkoxy, Morpholinylcarbonylamino(1-4C)Alkoxy, Amino(1- 4C) alkoxy, (1-6C) alkoxycarbonyl (1-4C) alkoxy, furyl (1-4C) alkoxy, pyrrolidinyl (1-4C) alkoxy or isoxazolyl (1-4C) alkoxy optionally substituted with (1-6C) alkyl.
Forbindelsene over modulerer FSH reseptorfunksjonen og kan anvendes for de samme kliniske formål som naturlig FSH hvis de opptrer som agonister, med den fordelen at de viser endrede stabilitetsegenskaper og kan administreres på forskjellig måte. Hvis de blokkerer FSH reseptoren kan de anvendes f.eks. som et prevensjonsmiddel. The compounds above modulate FSH receptor function and can be used for the same clinical purposes as natural FSH if they act as agonists, with the advantage that they show altered stability properties and can be administered in different ways. If they block the FSH receptor, they can be used e.g. as a contraceptive.
Således, kan tetrahydrokinolinderivatet ifølge foreliggende oppfinnelse anvendes for fruktbarhetsregulering. Thus, the tetrahydroquinoline derivative according to the present invention can be used for fertility regulation.
De følgende betegnelser skal ha de angitte betydninger gitt nedenfor om ikke på annen måte definert i kravene. The following designations shall have the specified meanings given below unless otherwise defined in the requirements.
Betegnelsen (1-4C)alkyl som anvendt her betyr en forgrenet eller uforgrenet alkylgruppe som har 1-4 karbonatomer, foreksempel metyl, etyl, propyl, isopropyl, butyl, sek-butyl og tert-butyl. The term (1-4C)alkyl as used herein means a branched or unbranched alkyl group having 1-4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.
Betegnelsen (1-6C)alkyl som anvendt her betyr en forgrenet eller uforgrenet alkylgruppe som har 1-6 karbonatomer, foreksempel metyl, etyl, propyl, isopropyl, butyl, sek-butyl, tert-butyl og heksyl. (1-5C)Alkylgrupper er foretrukket, (1-4C)alkyl er den mest foretrukne. The term (1-6C)alkyl as used herein means a branched or unbranched alkyl group having 1-6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and hexyl. (1-5C)Alkyl groups are preferred, (1-4C)alkyl is the most preferred.
Betegnelsen (3-8C)cykloalkyl betyr en cykloalkylgruppe som har 3-8 karbonatomer, og er cyklopropyl, cyklobutyl, cyklopentyl, cykloheksyl, cykloheptyl og cyklooktyl. (3-6C)cykloalkylgrupper er foretrukket. The term (3-8C)cycloalkyl means a cycloalkyl group having 3-8 carbon atoms, and is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. (3-6C) cycloalkyl groups are preferred.
Betegnelsen (2-6C)heterocykloalkyl betyr en heterocykloalkylgruppe som har 2-6 karbonatomer, fortrinnsvis 3-5 karbonatomer og inkluderer minst ett heteroatom valgt fra N, O og/eller S, som kan være tilknyttet via et heteroatom hvis mulig eller et karbonatom. Foretrukne heteroatomer er N eller O. Mest foretrukket er piperidinyl, piperazinyl, morfolinyl og pyrrolidinyl. The term (2-6C)heterocycloalkyl means a heterocycloalkyl group having 2-6 carbon atoms, preferably 3-5 carbon atoms and including at least one heteroatom selected from N, O and/or S, which may be attached via a heteroatom if possible or a carbon atom. Preferred heteroatoms are N or O. Most preferred are piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl.
Betegnelsen (1-4C)alkoksy betyr en alkoksygruppe som har 1-4 karbonatomer, alkylgruppen har samme betydning som tidligere definert. (1-2C)alkoksygrupper er foretrukket. The term (1-4C) alkoxy means an alkoxy group which has 1-4 carbon atoms, the alkyl group has the same meaning as previously defined. (1-2C)Alkoxy groups are preferred.
Betegnelsen (2-4C)alkoksy betyr en alkoksygruppe som har 2-4 karbonatomer, alkylgruppen har samme betydning som tidligere definert. The term (2-4C) alkoxy means an alkoxy group that has 2-4 carbon atoms, the alkyl group has the same meaning as previously defined.
Betegnelsen (di)(1-4C)alkylamino som anvendt her betyr en aminogruppe, monosubstituert eller disubstituert med alkylgrupper som hver inneholder 1-4 karbonatomer og har samme betydning som tidligere definert. The term (di)(1-4C)alkylamino as used herein means an amino group, monosubstituted or disubstituted with alkyl groups each containing 1-4 carbon atoms and has the same meaning as previously defined.
Betegnelsen (6C)aryl som anvendt her betyr en fenylgruppe, som eventuelt kan være substituert med én eller flere substituenter valgt fra hydroksy, amino, jod, brom, klor, fluor, nitro, trifluormetyl, cyano, fenyl, (1-4C)alkyl, (1-4C)alkoksy, (1-4C)(di)alkylamino; alkyl, alkoksy og (di)alkylaminogruppene har samme betydning som tidligere definert, for eksempel fenyl, 3,5-dibromfenyl, 4-bifenyl, 3,5-diklorfenyl, 3-brom-6-metylamino-fenyl, 3-klor-2,6-dimetoksyfenyl og 3,5-dimetyl-fenyl. The term (6C)aryl as used here means a phenyl group, which may optionally be substituted with one or more substituents selected from hydroxy, amino, iodo, bromine, chlorine, fluorine, nitro, trifluoromethyl, cyano, phenyl, (1-4C)alkyl , (1-4C)alkoxy, (1-4C)(di)alkylamino; the alkyl, alkoxy and (di)alkylamino groups have the same meaning as previously defined, for example phenyl, 3,5-dibromophenyl, 4-biphenyl, 3,5-dichlorophenyl, 3-bromo-6-methylamino-phenyl, 3-chloro-2 ,6-dimethoxyphenyl and 3,5-dimethyl-phenyl.
Betegnelsen (2-5C)heteroaryl betyr en substituert eller usubstituert aroma-tisk gruppe som har 2-5 karbonatomer, som minst inkluderer ett heteroatom valgt fra N, O og/eller S, slik som imidazolyl, pyridyl, pyrimidyl, tienyl eller furyl. Substi-tuentene på heteroarylgruppen kan velges fra substituentgruppen listet opp for (6C)arylgruppen. Heteroarylgruppen kan være tilknyttet via et karbonatom eller et heteroatom, hvis mulig. Foretrukne heteroarylgrupper er tienyl, furyl og pyridyl. The term (2-5C)heteroaryl means a substituted or unsubstituted aromatic group having 2-5 carbon atoms, which includes at least one heteroatom selected from N, O and/or S, such as imidazolyl, pyridyl, pyrimidyl, thienyl or furyl. The substituents on the heteroaryl group can be selected from the substituent group listed for the (6C)aryl group. The heteroaryl group may be attached via a carbon atom or a heteroatom, if possible. Preferred heteroaryl groups are thienyl, furyl and pyridyl.
Betegnelsen di(1-4C)alkylamino(2-4C)alkoksy som anvendt her betyr en (di)alkylaminogruppe, alkylgruppen eller alkylgruppene av denne inneholder 1-4 karbonatomer, forbundet via aminogruppen til alkylgruppen med en alkoksygruppe som har 2-4 karbonatomer, hvor (di)alkylaminogruppen og alkoksy-gruppen har samme betydning som tidligere definert. The term di(1-4C)alkylamino(2-4C)alkoxy as used herein means a (di)alkylamino group, the alkyl group or alkyl groups thereof containing 1-4 carbon atoms, connected via the amino group to the alkyl group with an alkoxy group having 2-4 carbon atoms, where the (di)alkylamino group and the alkoxy group have the same meaning as previously defined.
Betegnelsen (2-6C)heterocykloalkyl(2-4C)alkoksy som anvendt her betyr en heterocykloalkylgruppe som har 2-6 karbonatomer, forbundet til alkylgruppen av en alkoksygruppe som har 2-4 karbonatomer, hvor alkoksy-gruppen og heterocykloalkylgruppen har samme betydning som tidligere definert. The term (2-6C)heterocycloalkyl(2-4C)alkoxy as used herein means a heterocycloalkyl group having 2-6 carbon atoms, connected to the alkyl group by an alkoxy group having 2-4 carbon atoms, where the alkoxy group and the heterocycloalkyl group have the same meaning as before defined.
Betegnelsen (6C)arylkarbonylamino som anvendt her betyr en fenylgruppe, eventuelt substituert med én eller flere substituenter valgt fra substituentgruppen listet opp for (6C)arylgruppen, forbundet til karbonylgruppen av en karbonylaminogruppe, (6C)arylgruppen har samme betydning som tidligere definert. The term (6C)arylcarbonylamino as used herein means a phenyl group, optionally substituted with one or more substituents selected from the group of substituents listed for the (6C)aryl group, connected to the carbonyl group by a carbonylamino group, the (6C)aryl group having the same meaning as previously defined.
Betegnelsen (6C)arylkarbonyloksy som anvendt her betyr en fenylgruppe, eventuelt substituert med én eller flere substituenter valgt fra substituentgruppen listet opp for (6C)arylgruppen, forbundet til karbonylgruppen av en karbonyloksygruppe, (6C)arylgruppen har samme betydning som tidligere definert. The term (6C)arylcarbonyloxy as used herein means a phenyl group, optionally substituted with one or more substituents selected from the group of substituents listed for the (6C)aryl group, connected to the carbonyl group by a carbonyloxy group, the (6C)aryl group having the same meaning as previously defined.
Betegnelsen (2-5C)heteroarylkarbonylamino som anvendt her betyr en he-teroarylgruppe som inneholder 2-5 karbonatomer, eventuelt substituert med én eller flere substituenter valgt fra substituentgruppen listet opp for (6C)arylgruppen, forbundet til karbonylgruppen av en karbonylaminogruppe. Heteroarylgruppen i heteroarylkarbonylaminogruppen har samme betydning som tidligere definert. The term (2-5C)heteroarylcarbonylamino as used herein means a heteroaryl group containing 2-5 carbon atoms, optionally substituted with one or more substituents selected from the group of substituents listed for the (6C)aryl group, attached to the carbonyl group of a carbonylamino group. The heteroaryl group in the heteroarylcarbonylamino group has the same meaning as previously defined.
Betegnelsen (2-5C)heteroarylkarbonyloksy som anvendt her betyr en hete-roarylgruppe som inneholder 2-5 karbonatomer, eventuelt substituert med én eller flere substituenter valgt fra substituentgruppen listet opp for (6C)arylgruppen, forbundet til karbonylgruppen av en karbonyloksygruppe. Heteroarylgruppen i hete-roarylkarbonyloksygruppen har samme betydning som tidligere definert. The term (2-5C)heteroarylcarbonyloxy as used herein means a heteroaryl group containing 2-5 carbon atoms, optionally substituted with one or more substituents selected from the group of substituents listed for the (6C)aryl group, attached to the carbonyl group by a carbonyloxy group. The heteroaryl group in the heteroarylcarbonyloxy group has the same meaning as previously defined.
Betegnelsen (2-6C)heterocykloalkylkarbonylamino som anvendt her betyr en heterocykloalkylgruppe som har 2-6 karbonatomer, forbundet til karbonylgruppen av en karbonylaminogruppe, heterocykloalkylgruppen har samme betydning som tidligere definert. The term (2-6C)heterocycloalkylcarbonylamino as used herein means a heterocycloalkyl group having 2-6 carbon atoms, connected to the carbonyl group by a carbonylamino group, the heterocycloalkyl group having the same meaning as previously defined.
Betegnelsen (di)(1-4C)alkylaminokarbonyl som anvendt her betyr en (di)-alkylaminogruppe, alkylgruppen(e) av denne har 1-4 karbonatomer, forbundet via aminogruppen til en karbonylgruppe, (di)alkylaminogruppen har samme betydning som tidligere definert. The term (di)(1-4C)alkylaminocarbonyl as used here means a (di)-alkylamino group, the alkyl group(s) of which have 1-4 carbon atoms, connected via the amino group to a carbonyl group, the (di)alkylamino group has the same meaning as previously defined .
Betegnelsen (di)(1-4C)alkylaminokarbonylamino som anvendt her betyr en (di)alkylaminogruppe, alkylgruppen(e) av denne har 1-4 karbonatomer, forbundet via aminogruppen til karbonylgruppen av en karbonylaminogruppe, og tilveiebringer således en ureafunksjonalitet, (di)alkylaminogruppen har samme betydning som tidligere definert. The term (di)(1-4C)alkylaminocarbonylamino as used herein means a (di)alkylamino group, the alkyl group(s) of which have 1-4 carbon atoms, connected via the amino group to the carbonyl group of a carbonylamino group, thus providing a urea functionality, (di) the alkylamino group has the same meaning as previously defined.
Betegnelsen (1-4C)alkoksykarbonylamino som anvendt her betyr en alkoksygruppe som har 1-4 karbonatomer, bundet til karbonylgruppe med en karbonylaminogruppe, og tilveiebringer således en karbamatfunksjonalitet, alkoksygruppen har samme betydning som tidligere definert. The term (1-4C) alkoxycarbonylamino as used here means an alkoxy group having 1-4 carbon atoms, bonded to the carbonyl group with a carbonylamino group, thus providing a carbamate functionality, the alkoxy group having the same meaning as previously defined.
Betegnelsen R<8->(2-4C)alkylamino som anvendt her betyr en R<8>gruppe bundet til alkylgruppen av en (2-4C)alkylaminogruppe, som har samme betydning som tidligere definert. The term R<8>(2-4C)alkylamino as used here means an R<8> group attached to the alkyl group of a (2-4C)alkylamino group, which has the same meaning as previously defined.
Betegnelsen R<8->(2-4C)alkoksy som anvendt her betyr en R<8>gruppe bundet til alkylgruppen av en (2-4C) alkoksygruppe, som har samme betydning som tidligere definert. The term R<8>(2-4C) alkoxy as used here means an R<8> group attached to the alkyl group of a (2-4C) alkoxy group, which has the same meaning as previously defined.
Betegnelsen R<9->metylamino som anvendt her betyr en R<9>gruppe bundet til metylgruppen av en metylaminogruppe. The term R<9>methylamino as used herein means an R<9> group attached to the methyl group of a methylamino group.
Betegnelsen R<9->metoksy som anvendt her betyr en R<9>gruppe bundet til metylgruppen av en metoksygruppe. The term R<9>methoxy as used herein means an R<9> group attached to the methyl group of a methoxy group.
Betegnelsen farmasøytisk akseptabelt salt representerer de salter som er, innenfor omfanget av medisinsk bedømmelse, egnet for anvendelse i kontakt for vevet av mennesker og lavere dyr uten unødvendig toksisitet, irritasjon, allergisk respons og lignende og er i samsvar med et rimelig nytte/risiko forhold. Farma-søytisk akseptable salter er velkjent på området. De kan oppnås under den ende-lige isolering og rensning av forbindelsene ifølge oppfinnelsen eller separat ved omsetning av en fri base funksjon, hvis til stede, med en egnet mineralsyre slik som saltsyre, fosforsyre eller svovelsyre eller med en organisk syre slik som for eksempel askorbinsyre, sitronsyre, vinsyre, melkesyre, maleinsyre, malonsyre, fumarsyre, glykolsyre, ravsyre, propionsyre, eddiksyre og. Hvis til stede, kan en syrefunksjon omsettes med en organisk- eller en mineralbase, slik som natriumhydroksid, kaliumhydroksid eller litiumhydroksid. The designation pharmaceutically acceptable salt represents those salts which are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and lower animals without unnecessary toxicity, irritation, allergic response and the like and are in accordance with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. They can be obtained during the final isolation and purification of the compounds according to the invention or separately by reaction of a free base function, if present, with a suitable mineral acid such as hydrochloric acid, phosphoric acid or sulfuric acid or with an organic acid such as for example ascorbic acid , citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid and. If present, an acid function can be reacted with an organic or a mineral base, such as sodium hydroxide, potassium hydroxide or lithium hydroxide.
Oppfinnelsen omhandler således forbindelsene med formel I som definert her ovenfor. The invention thus deals with the compounds of formula I as defined here above.
Oppfinnelsen omhandler også forbindelser med formel I, hvor R<4>er H, OH eller (1-4C)alkoksy. The invention also relates to compounds of formula I, where R<4> is H, OH or (1-4C) alkoxy.
I en annen utførelsesform tilveiebringer oppfinnelsen forbindelser med formel I hvor R<5>er OH, (1-4C)alkoksy eller R<7>. In another embodiment, the invention provides compounds of formula I where R<5> is OH, (1-4C) alkoxy or R<7>.
I en annen utførelsesform tilveiebringer oppfinnelsen forbindelser med formel I hvor R6 er fenyl eventuelt substituert med halogen, (1-6C)alkoksy eller (1-6C)alkyl, furyl eventuelt substituert med (1-6C)alkyl, tienyl eventuelt substituert med halogen eller (1-6C)alkyl, bifenyl eller (1-6C)alkyl. In another embodiment, the invention provides compounds of formula I where R6 is phenyl optionally substituted with halogen, (1-6C) alkoxy or (1-6C) alkyl, furyl optionally substituted with (1-6C) alkyl, thienyl optionally substituted with halogen or (1-6C)alkyl, biphenyl or (1-6C)alkyl.
I et annet aspekt omhandler oppfinnelsen forbindelser med formel I hvor R<6>er fenyl eventuelt substituert med halogen, (1-6C)alkoksy eller (1-6C)alkyl, furyl eventuelt substituert med (1-6C)alkyl, tienyl eventuelt substituert med halogen eller (1-6C)alkyl eller bifenyl. In another aspect, the invention deals with compounds of formula I where R<6> is phenyl optionally substituted with halogen, (1-6C) alkoxy or (1-6C) alkyl, furyl optionally substituted with (1-6C) alkyl, thienyl optionally substituted with halogen or (1-6C)alkyl or biphenyl.
Oppfinnelsen omhandler også forbindelser med formel I hvor R7 er (di)(1-4C)alkylamino, furylkarbonylamino, morfolinyl(1-4C)alkoksy, piperidinyl(1-4C)alkoksy, pyridyl(1-4C)alkoksy, karbamoyl(1-4C)alkoksy, morfolinylkarbonylamino(1-4C)alkoksy, furyl(1-4C)alkoksy, pyrrolidinyl(1-4C)alkoksy eller isoksazolyl(1-4C)alkoksy. The invention also relates to compounds of formula I where R 7 is (di)(1-4C)alkylamino, furylcarbonylamino, morpholinyl(1-4C) alkoxy, piperidinyl(1-4C) alkoxy, pyridyl(1-4C) alkoxy, carbamoyl(1- 4C) alkoxy, morpholinylcarbonylamino(1-4C) alkoxy, furyl(1-4C) alkoxy, pyrrolidinyl(1-4C) alkoxy or isoxazolyl(1-4C) alkoxy.
Et annet aspekt ved oppfinnelsen er forbindelser med formel I hvor R7 er (di)(1-4C)alkylamino, morfolinyl(1-4C)alkoksy, piperidinyl(1-4C)alkoksy, pyridyl(1-4C)alkoksy, karbamoyl(1 -4C)alkoksy, morfolinylkarbonylamino(1 -4C)alkoksy, furyl(1-4C)alkoksy, pyrrolidinyl(1-4C)alkoksy eller isoksazolyl(1-4C)alkoksy. Another aspect of the invention are compounds of formula I where R 7 is (di)(1-4C)alkylamino, morpholinyl(1-4C) alkoxy, piperidinyl(1-4C) alkoxy, pyridyl(1-4C) alkoxy, carbamoyl(1 -4C) alkoxy, morpholinylcarbonylamino(1-4C) alkoxy, furyl(1-4C) alkoxy, pyrrolidinyl(1-4C) alkoxy or isoxazolyl(1-4C) alkoxy.
I enda et annet aspekt omhandler oppfinnelsen forbindelser med formel I hvor R7 er (di)(1-4C)alkylamino. In yet another aspect, the invention relates to compounds of formula I where R7 is (di)(1-4C)alkylamino.
Enda et annet aspekt av oppfinnelsen omhandler forbindelser hvor alle spesifikke definisjoner av gruppene R<1>til R<7>som definert her ovenfor kombineres i forbindelsen med formel I. Yet another aspect of the invention deals with compounds where all specific definitions of the groups R<1> to R<7> as defined here above are combined in the compound of formula I.
Egnede metoder for fremstilling av forbindelsene ifølge oppfinnelsen er beskrevet nedenfor. Suitable methods for producing the compounds according to the invention are described below.
Forbindelsene ifølge foreliggende oppfinnelse hvor R<4>og R<5>er (1-4C)alk-oksy, R<1>og R<2>er metyl og R<6>er som tidligere definert kan fremstilles ved å starte fra passende substituerte aniliner med den generelle formel II, ved hjelp av den veldokumentert Skraup reaksjon, som gir 2,2,4-trimetyl-1,2-dihydrokinolinderivater med formel lll-a. The compounds according to the present invention where R<4> and R<5> are (1-4C)alkoxy, R<1> and R<2> are methyl and R<6> as previously defined can be prepared by starting from suitably substituted anilines of the general formula II, by means of the well-documented Skraup reaction, which gives 2,2,4-trimethyl-1,2-dihydroquinoline derivatives of formula III-a.
Relaterte Skraup cyklokondenseringer finnes i litteratur: A. Knoevenagel, Chem. Ber. 54:1726, 1921; R.L. Atkins og D.E. Bliss, J. Org. Chem. 43:1975, 1978; J.V. Johnson, B.S. Rauckman, D.P. Baccanari og B. Roth, J. Med. Chem. 32:1942, 1989; W.C. Lin, S.-T. Huang og S.-T. Lin, J. Chin. Chem. Soc. 43:497, 1996; J.P. Edwards, S.J. West, K.B. Marschke, D.E. Mais, M.M. Gottardis og T.K. Jones, J. Med. Chem. 41:303, 1998. Related Skraup cyclocondensations can be found in the literature: A. Knoevenagel, Chem. Pray. 54:1726, 1921; R. L. Atkins and D.E. Bliss, J. Org. Chem. 43:1975, 1978; J.V. Johnson, B.S. Rauckman, D.P. Baccanari and B. Roth, J. Med. Chem. 32:1942, 1989; W.C. Lin, S.-T. Huang and S.-T. Lin, J. Chin. Chem. Soc. 43:497, 1996; J. P. Edwards, S.J. West, K.B. Marschke, D.E. Mais, M.M. Gottardis and T.K. Jones, J. Med. Chem. 41:303, 1998.
Den ovennevnte reaksjonen blir typisk utført ved forhøyet temperatur i aceton eller mesityloksid i nærvær av jod eller protisk syre så som saltsyre, p-tolu-ensulfonsyre eller vandig hydrogenjodid. Alternativt, kan 1,2-dihydro-2,2,4-tri-metylkinoliner med formel lll-a fremstilles ved omsetning av det tilsvarende anilin med formel II med aceton i nærvær av MgS04, 4-tert-butylkatekol og jod (L.G. Hamann, R.l. Higuchi, L. Zhi, J.P. Edwards og X.-N. Wang, J. Med. Chem, 41:623, 1998). I enda en annen prosedyre, kan reaksjonen utføres i aceton ved anvendelse av lantanidtriflater (f.eks. skandiumtriflat) som katalysatorer. I dette tilfellet, kan reaksjonen kjøres ved romtemperatur eller ved forhøyede temperaturer ved anvendelse av konvensjonell oppvarming eller mikrobølge bestråling (M. E. Theoclitou og L. A. Robinson, Tetrahedron Lett. 43:3907, 2002). The above reaction is typically carried out at elevated temperature in acetone or mesityl oxide in the presence of iodine or protic acid such as hydrochloric acid, p-toluenesulfonic acid or aqueous hydrogen iodide. Alternatively, 1,2-dihydro-2,2,4-tri-methylquinolines of formula III-a can be prepared by reacting the corresponding aniline of formula II with acetone in the presence of MgSO 4 , 4-tert-butylcatechol and iodine (L.G. Hamann , R. L. Higuchi, L. Zhi, J. P. Edwards and X.-N. Wang, J. Med. Chem, 41:623, 1998). In yet another procedure, the reaction can be carried out in acetone using lanthanide triflates (eg, scandium triflate) as catalysts. In this case, the reaction can be run at room temperature or at elevated temperatures using conventional heating or microwave irradiation (M. E. Theoclitou and L. A. Robinson, Tetrahedron Lett. 43:3907, 2002).
Utgangsmaterialer kan enten oppnås direkte fra kommersielle kilder eller enkelt fremstilles av fagfolk på området. Starting materials can either be obtained directly from commercial sources or easily prepared by those skilled in the art.
Forbindelser med formel lll-b kan fremstilles fra aniliner med den generelle formel II ved omsetning med metylvinylketon. Relaterte cykliseringer er beskrevet i United States Patent 2.686.182 (Badische Anilin- & Soda-Fabrik Aktiengesell-schaft). Compounds of formula III-b can be prepared from anilines of the general formula II by reaction with methyl vinyl ketone. Related cyclizations are described in United States Patent 2,686,182 (Badische Anilin- & Soda-Fabrik Aktiengesell-schaft).
Påfølgende 1-A/-acetylering av forbindelser med formel lll-a-b hvor R<1>og R<2>er som tidligere definert, kan utføres ved anvendelse av standard betingelser. I et typisk forsøk, blir forbindelser med formel III oppvarmet under tilbakeløp i eddiksyreanhydrid eller omsatt i et løsemiddel slik som diklormetan, tetrahydrofuran, toluen eller pyridin med acetylklorid i nærvær av en base slik som A/,A/-diisopro- pyletylamin, trietylamin eller natriumhydrid, for å gi /V-acetylerte 4-metyl-1,2-di-hydrokinolinderivater med formel IV-a-b. Subsequent 1-A/-acetylation of compounds of formula III-a-b where R<1> and R<2> are as previously defined can be carried out using standard conditions. In a typical experiment, compounds of formula III are heated under reflux in acetic anhydride or reacted in a solvent such as dichloromethane, tetrahydrofuran, toluene or pyridine with acetyl chloride in the presence of a base such as A/,A/-diisopropylethylamine, triethylamine or sodium hydride, to give /V-acetylated 4-methyl-1,2-dihydroquinoline derivatives of formula IV-a-b.
Relaterte A/-acyleringer av en dihydrokinolinramme er funnet i litteraturen: G. Reddelien og A. Thurm, Chem. Ber. 65:1511,1932; Zh. V. Shmyreva, Kh. S. Shikhaliev og E.B. Shpanig, Izv. Vyssh. Uchebn. Zaved., Khim. Khim. Technol. 31:45, 1988; Zh. V. Shmyreva, Kh. S. Shikhaliev, L.P. Zalukaev, Y.A. Ivanov, Y.S. Ryabokobylko og DVS. Pokrovskaya, Zh. Obshch. Khim. 59:1391, 1989. Related A/-acylations of a dihydroquinoline framework are found in the literature: G. Reddelien and A. Thurm, Chem. Pray. 65:1511, 1932; Zh. V. Shmyreva, Kh. S. Shikhaliev and E.B. Shpanig, Izv. Vyssh. Uchebn. Zaved., Khim. Kim. Technol. 31:45, 1988; Zh. V. Shmyreva, Kh. S. Shikhaliev, L.P. Zalukaev, Y.A. Ivanov, Y.S. Ryabokobylko and DVS. Pokrovskaya, Zh. Obshch. Kim. 59:1391, 1989.
Innføring av den nødvendige (substituerte) fenylgruppe i stilling 4 av di-hydrokinolinrammen kan gjennomføres via Friedel-Crafts alkylering av benzen eller et passende substituert benzen med forbindelsene med generell struktur IV-a-b. Denne reaksjonen blir typisk utført ved forhøyede temperaturer enten i ublan-det benzen eller det passende substituerte benzen eller i et passende inert løse-middel slik som heptan eller heksan med benzen eller det passende substituerte benzen som reagens, under katalyse av en Lewis-syre (f.eks. AICI3, AIBr3, FeCb eller SnCU). Friedel-Crafts alkyleringer med 2,2,4-trimetyl-1,2-dihydrokinoliner er beskrevet i litteratur av B.A. Lugovik, L.G. Yudin og A.N. Kost, Dokl. Akad. Nauk SSSR, 170:340, 1966; B.A. Lugovik, L.G. Yudin, S.M. Vinogradova og A.N. Kost, Khim. Geterosikl. Soedin, 7:795, 1971. Introduction of the required (substituted) phenyl group in position 4 of the dihydroquinoline framework can be accomplished via Friedel-Crafts alkylation of benzene or an appropriately substituted benzene with the compounds of general structure IV-a-b. This reaction is typically carried out at elevated temperatures either in unmixed benzene or the suitably substituted benzene or in a suitable inert solvent such as heptane or hexane with benzene or the suitably substituted benzene as reagent, under catalysis by a Lewis acid ( eg AICI3, AIBr3, FeCb or SnCU). Friedel-Crafts alkylations with 2,2,4-trimethyl-1,2-dihydroquinolines are described in the literature by B.A. Lugovik, L.G. Yudin and A.N. Kost, Dokl. Acad. Nauk SSSR, 170:340, 1966; B.A. Lugovik, L.G. Yudin, S.M. Vinogradova and A.N. Diet, Khim. Goat cycle. Soedin, 7:795, 1971.
Alternativt, kan aniliner med generell struktur II omsettes med et passende substituert 1 -metylstyren derivat og formaldehyd i acetonitril ved omgivelses- eller forhøyet temperatur, for å gi forbindelser med generell struktur V-b. Relaterte cykliseringer er beskrevet i litteratur: J.M. Mellorog G.D. Merriman, Tetrahedron, 51:6115, 1995. Alternatively, anilines of general structure II can be reacted with an appropriately substituted 1-methylstyrene derivative and formaldehyde in acetonitrile at ambient or elevated temperature to give compounds of general structure V-b. Related cyclizations are described in literature: J.M. Mellorog G.D. Merriman, Tetrahedron, 51:6115, 1995.
Forbindelser med generell struktur V-a-b kan deretter nitreres regioselektivt i stilling 6 av tetrahydrokinolinrammen, for å gi forbindelser med generell struktur Vl-a-b. Denne reaksjonen blir typisk utført ved temperaturer i området -10°C til romtemperatur i diklormetan ved anvendelse av en blanding av salpetersyre og eddiksyreanhydrid som en nitreringsreagens. Alternativt, kan salpetersyre tilsettes til en løsning av forbindelsene med generell struktur V-a-b i iseddik eller i en blanding av eddiksyre og diklormetan. Relaterte regioselektive nitreringer av tetrahyd-rokinoliner er beskrevet i litteratur: B. Golankiewicz, Pol. J. Chem., 54:355, 1980; Zh. V. Shmyreva, Kh. S. Shikhaliev, L.P. Zalukaev, Y.A. Ivanov, Y.S. Ryabokobylko og DVS. Pokrovskaya, Zh. Obshch. Khim. 59:1391, 1989. Compounds of general structure V-a-b can then be regioselectively nitrated at position 6 of the tetrahydroquinoline framework, to give compounds of general structure Vl-a-b. This reaction is typically carried out at temperatures in the range of -10°C to room temperature in dichloromethane using a mixture of nitric acid and acetic anhydride as a nitration reagent. Alternatively, nitric acid can be added to a solution of the compounds of general structure V-a-b in glacial acetic acid or in a mixture of acetic acid and dichloromethane. Related regioselective nitrations of tetrahydroquinolines are described in the literature: B. Golankiewicz, Pol. J. Chem., 54:355, 1980; Zh. V. Shmyreva, Kh. S. Shikhaliev, L.P. Zalukaev, Y.A. Ivanov, Y.S. Ryabokobylko and DVS. Pokrovskaya, Zh. Obshch. Kim. 59:1391, 1989.
Reduksjon av nitrogruppen av forbindelsene med generell struktur Vl-a-b kan oppnås ved et mangfold av metoder velkjent på området for reduksjon av aromatiske nitroforbindelser så som overgangsmetallkatalysert hydrogenering, behandling med sulfider, behandling med jern eller andre metaller og (mild) syre, behandling med tinndiklorid under sure betingelser og lignende. Mer spesifikt, kan reduksjonen av nitrogruppen av forbindelsene med den generelle formel Vl-a-b gjennomføres ved behandling med sinkstøv og eddiksyre i THF eller 1,4-dioksan i temperatur-området på 0°C til 100°C. Reduction of the nitro group of the compounds of general structure Vl-a-b can be achieved by a variety of methods well known in the field for the reduction of aromatic nitro compounds such as transition metal catalyzed hydrogenation, treatment with sulphides, treatment with iron or other metals and (mild) acid, treatment with tin dichloride under acidic conditions and the like. More specifically, the reduction of the nitro group of the compounds of the general formula Vl-a-b can be carried out by treatment with zinc dust and acetic acid in THF or 1,4-dioxane in the temperature range of 0°C to 100°C.
Påfølgende 6-A/-acylering av forbindelser med formel Vll-a-b kan utføres ved anvendelse av standardbetingelser, velkjent for fagfolk på området, for å gi Subsequent 6-A/-acylation of compounds of formula VIII-a-b can be carried out using standard conditions, well known to those skilled in the art, to give
forbindelser med generell struktur l-a-b. For eksempel blir forbindelser med formel VII omsatt i et løsemiddel så som diklormetan, tetrahydrofuran, toluen eller pyridin med et acylhalogenid (R<6->C(0)-Cl) eller syreanhydrid (R<6->C(0)-0-C(0)-R<6>) i nærvær av en base compounds with general structure l-a-b. For example, compounds of formula VII are reacted in a solvent such as dichloromethane, tetrahydrofuran, toluene or pyridine with an acyl halide (R<6->C(0)-Cl) or acid anhydride (R<6->C(0)-0 -C(0)-R<6>) in the presence of a base
slik som A/,A/-diisopropyletylamin, trietylamin, pyridin eller natriumhydrid for å gi 6-/V-acylerte-1,2,3,4-tetrahydrokinolinderivater med formel l-a-b. Alternativt, kan acylering av forbindelser med generell formel Vll-a-b, for å gi forbindelser med generell formel l-a-b også utføres ved omsetning med en passende karboksylsyre (R<6->C02H) i nærvær av en koblingsreagens slik som 0-(benzotriazol-1-yl)-/V,/V,/V',/V-tetrametyluronium tetrafluorborat (TBTU), 0-(7-azabenzotriazol-1-yl)-A/,A/,A/',A/-tetrametyluronium heksafluorfosfat (HATU) eller bromtripyrrolidinofosfo-nium heksafluorfosfat (PyBrOP) og en tertiær base, f.eks. A/,/V-diisopropyletylamin, such as N,N-diisopropylethylamine, triethylamine, pyridine or sodium hydride to give 6-N-acylated-1,2,3,4-tetrahydroquinoline derivatives of formula 1-a-b. Alternatively, acylation of compounds of general formula VIII-a-b to give compounds of general formula I-a-b can also be carried out by reaction with an appropriate carboxylic acid (R<6->CO 2 H) in the presence of a coupling reagent such as O-(benzotriazole-1 -yl)-/V,/V,/V',/V-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-A/,A/,A/',A/-tetramethyluronium hexafluorophosphate (HATU) or bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP) and a tertiary base, e.g. A/,/V-diisopropylethylamine,
i et løsemiddel slik som /V,/V-dimetylformamid eller diklormetan ved omgivelses-eller forhøyet temperatur. in a solvent such as /V,/V-dimethylformamide or dichloromethane at ambient or elevated temperature.
Forbindelser ifølge foreliggende oppfinnelse hvor R<3>= H, OH eller (1-4C) alkoksy, R<4>= OH, R<5>= OH eller (1-4C)alkoksy og R<1>, R2 og R<6>er som tidligere beskrevet kan fremstilles ved demetyleringsreaksjoner av forbindelser med generell formel l-c-d. Demetyleringsreaksjoner av aromatiske metyletere er velkjent for fagfolk på området. I et typisk forsøk, blir demetylering oppnådd etter reaksjon av en forbindelse med formel l-c-d med BBr3i et inert løsemiddel så som diklormetan ved lav til omgivelsestemperatur, for å gi demetylerte forbindelser med generell formel l-e-i. Alternativt, kan demetylering gjennomføres etter reaksjon av forbindelser med formel l-c-d med BF3 Me2S kompleks ved omgivelsestemperatur. Gra-den av demetylering kan kontrolleres i noe utstrekning ved forsiktig å kontrollere reaksjonstemperaturen og mengden av demetyleringsreagensen. Generelt, blir blandinger av mono-, di- og, hvis relevant, trihydroksyforbindelser med den generelle formel l-e-i oppnådd, som kan separeres ved kromatografi. Demetylerings-reaksjonen forløper generelt med en moderat grad av selektivitet, med foretrukket demetylering i stilling 5 av tetrahydrokinolinrammen. Reaksjonshastigheten for demetylering (dealkylering) av forbindelser med generell formel l-c-d er 5-OMe > 4-(p-OAIk-fenyl) > 7-OMe. Compounds according to the present invention where R<3>= H, OH or (1-4C) alkoxy, R<4>= OH, R<5>= OH or (1-4C) alkoxy and R<1>, R2 and R <6>'s as previously described can be prepared by demethylation reactions of compounds of general formula 1-c-d. Demethylation reactions of aromatic methyl ethers are well known to those skilled in the art. In a typical experiment, demethylation is achieved after reaction of a compound of formula 1-c-d with BBr 3 in an inert solvent such as dichloromethane at low to ambient temperature to give demethylated compounds of general formula 1-e-i. Alternatively, demethylation can be carried out after reaction of compounds of formula 1-c-d with BF 3 Me 2 S complex at ambient temperature. The degree of demethylation can be controlled to some extent by carefully controlling the reaction temperature and the amount of the demethylation reagent. In general, mixtures of mono-, di- and, if relevant, trihydroxy compounds of the general formula 1-e-i are obtained, which can be separated by chromatography. The demethylation reaction generally proceeds with a moderate degree of selectivity, with preferred demethylation in position 5 of the tetrahydroquinoline framework. The reaction rate for demethylation (dealkylation) of compounds of general formula 1-c-d is 5-OMe > 4-(p-OAIk-phenyl) > 7-OMe.
Forbindelser ifølge foreliggende oppfinnelse hvor R<3>er H eller en (funksjonalisert) alkoksygruppe og R4 og/eller R5 er (funksjonaliserte) alkoksygrupper eller acyloksygrupper kan fremstilles ved realkylerings- eller acyleringsreaksjoner av hydroksylgruppene av forbindelser med generell formel l-e-i med henholdsvis (funksjonaliserte) alkylhalogenider (f.eks. kloretylpyrrolidin) eller acylhalogenider (f.eks. 2-furoylklorid eller metylklorformiat), under standardbetingelser. Compounds according to the present invention where R<3> is H or a (functionalized) alkoxy group and R4 and/or R5 are (functionalized) alkoxy groups or acyloxy groups can be prepared by realkylation or acylation reactions of the hydroxyl groups of compounds of general formula l-e-i with respectively (functionalized) alkyl halides (eg chloroethyl pyrrolidine) or acyl halides (eg 2-furoyl chloride or methyl chloroformate), under standard conditions.
Forbindelsene ifølge foreliggende oppfinnelse hvor R<4>= H og R5 er forbundet til tetrahydrokinolinrammen via et nitrogenatom og R<1>, R<2>og R<6>er som tidligere definert kan fremstilles ved å starte fra A/-Boc-1,4-fenylen diamin (VIII). Re-aksjonssekvensen (a) Skraup reaksjon, (b) acetylering og (c) Friedel-Crafts alkylering av benzen eller en substituert benzen som beskrevet før fører til dannelsen av forbindelser med generell formel X-a. Det skal bemerkes at den Boc-beskyttende gruppen blir spaltet av under reaksjonsbetingelsene av Friedel-Crafts reaksjonen. The compounds according to the present invention where R<4>= H and R5 are connected to the tetrahydroquinoline framework via a nitrogen atom and R<1>, R<2> and R<6> are as previously defined can be prepared by starting from A/-Boc- 1,4-phenylene diamine (VIII). The reaction sequence (a) Skraup reaction, (b) acetylation and (c) Friedel-Crafts alkylation of benzene or a substituted benzene as described before leads to the formation of compounds of general formula X-a. It should be noted that the Boc protecting group is cleaved off under the reaction conditions of the Friedel-Crafts reaction.
Alternativt kan A/-Boc-1,4-fenylen diamin behandles med metylvinylketon, fulgt av acetylering og Friedel-Crafts reaksjon som beskrevet før, for å gi forbindelser med den generelle formel X-b. Alternatively, N -Boc-1,4-phenylene diamine can be treated with methyl vinyl ketone, followed by acetylation and the Friedel-Crafts reaction as described above, to give compounds of the general formula X-b.
I enda en annen prosedyre, kan forbindelser med generell formel X-b oppnås ved å starte med partialreduksjonen av 4-metylkinolin (XI) med BH3 THF kompleks og natrium bis(2-metoksy-etoksy)aluminium dihydrid, for å gi 4-metyl-1,2-dihydrokinolin, fulgt av acetylering som beskrevet før, for å gi forbindelse XII. Reduksjoner av relaterte kinoliner til 1,2-dihydrokinoliner er beskrevet i litteratur: se for eksempel: D. Roberts og J. A. Joule, J. Org. Chem. 62:568, 1997; R. F. Heier, L. A. Dolak, J. N. Duncan, D. K. Hyslop, M. F. Lipton, I. J. Martin, M. A. Mauragis, M. F. Piercey, N. F. Nichols, P. J. K. D. Schreur, M. W. Smith og M. W. Moon, J. Med. Chem. 40: 639, 1997. Friedel-Crafts omsetning av XII med benzen eller en passende substituert benzen gir forbindelser med generell formel XIII, som kan omsettes til forbindelser med generell formel X-b ved den regioselektive 6-nitrering og reduksjon til det tilsvarende 6-amino derivat ved anvendelse av tidligere beskrevne betingelser. Regioselektive nitreringsreaksjoner på lignende rammer er rapportert i litteratur, se for eksempel: Zh. V. Shmyreva et al., J. Gen. Chem. USSR (Eng. Overs.) 59: 1234, 1989. In yet another procedure, compounds of general formula X-b can be obtained by starting with the partial reduction of 4-methylquinoline (XI) with BH3 THF complex and sodium bis(2-methoxy-ethoxy)aluminum dihydride, to give 4-methyl-1 ,2-dihydroquinoline, followed by acetylation as described before, to give compound XII. Reductions of related quinolines to 1,2-dihydroquinolines are described in the literature: see, for example: D. Roberts and J. A. Joule, J. Org. Chem. 62:568, 1997; R. F. Heier, L. A. Dolak, J. N. Duncan, D. K. Hyslop, M. F. Lipton, I. J. Martin, M. A. Mauragis, M. F. Piercey, N. F. Nichols, P. J. K. D. Schreur, M. W. Smith, and M. W. Moon, J. Med. Chem. 40: 639, 1997. Friedel-Crafts reaction of XII with benzene or an appropriately substituted benzene gives compounds of general formula XIII, which can be converted to compounds of general formula X-b by the regioselective 6-nitration and reduction to the corresponding 6-amino derivative by applying previously described conditions. Regioselective nitration reactions on similar frameworks have been reported in the literature, see for example: Zh. V. Shmyreva et al., J. Gen. Chem. USSR (Eng. Trans.) 59: 1234, 1989.
Forbindelser med generell formel X-a-b kan deretter beskyttes med den faglig kjente 9-fluorenylmetyloksykarbonylgruppe (Fmoc-gruppe), se for eksempel: T. W. Greene og P. M. Wuts, Protective Groups in Organic Synthesis (3. utg., John Wiley & Sons, Inc., 1999, se spesielt p. 506.). Den ovennevnte beskyttelse blir hensiktsmessig utført ved anvendelse av FmocCI i THF med pyridin som en base. Compounds of general formula X-a-b can then be protected with the art-known 9-fluorenylmethyloxycarbonyl group (Fmoc group), see, for example: T. W. Greene and P. M. Wuts, Protective Groups in Organic Synthesis (3rd ed., John Wiley & Sons, Inc., 1999, see especially p. 506.). The above protection is conveniently carried out using FmocCl in THF with pyridine as a base.
Regioselektiv nitrering i stilling 7 av tetrahydrokinolinrammen av forbindelser med generell formel XIV-a-b, fulgt av reduksjon av nitrogruppen (wcte supra), gir 7-amino-1,2,3,4-tetrahydrokinolinderivater med generell formel XV-a-b. Regioselektive nitreringer på relaterte rammer med et lignende substitusjonsmønster kan finnes i litteratur; se for eksempel: S. H. Reich, M. A. M. Fuhry, D. Nguyen, M. J. Pino et. al., J. Med. Chem. 35: 847, 1992; A. Ivobe, M. Uchida, K. Kamata, Y. Hotei, H. Kusama, H. Harada, Chem. Pharm. Bull. 49: 822, 2001. Nitreringsbe-tingelsene er lignende de beskrevet tidligere. Regioselective nitration at position 7 of the tetrahydroquinoline framework of compounds of general formula XIV-a-b, followed by reduction of the nitro group (wcte supra), gives 7-amino-1,2,3,4-tetrahydroquinoline derivatives of general formula XV-a-b. Regioselective nitrations on related frameworks with a similar substitution pattern can be found in the literature; see for example: S. H. Reich, M. A. M. Fuhry, D. Nguyen, M. J. Pino et. al., J. Med. Chem. 35: 847, 1992; A. Ivobe, M. Uchida, K. Kamata, Y. Hotei, H. Kusama, H. Harada, Chem. Pharm. Bull. 49: 822, 2001. The nitration conditions are similar to those described previously.
Reduktiv alkylering av aminogruppen i stilling 7 av tetrahydrokinolinderivater med generell formel XV-a-b ved anvendelse av passende substituerte aldehy der og et egnet reduksjonsmiddel (f.eks. natriumcyanoborhydrid eller natrium tri-acetoksy borhydrid) i et egnet løsemiddel slik som metanol eller /V,A/-dimetylform-amid fører til dannelsen av forbindelser med generell formel XVIa-b. Generelt, fø-rer formaldehyd til den dominerende dannelse av 7-dimetylamino tetrahydrokinolinderivater (D = E =Me), mens andre aldehyder gir opphav til den dominerende dannelse av monoalkylerte forbindelser med generell formel XVIa-b (D = H, E = Reductive alkylation of the amino group in position 7 of tetrahydroquinoline derivatives of general formula XV-a-b using suitable substituted aldehydes and a suitable reducing agent (e.g. sodium cyanoborohydride or sodium triacetoxy borohydride) in a suitable solvent such as methanol or /V, N-dimethylformamide leads to the formation of compounds of general formula XVIa-b. In general, formaldehyde leads to the dominant formation of 7-dimethylamino tetrahydroquinoline derivatives (D = E = Me), while other aldehydes give rise to the dominant formation of monoalkylated compounds of general formula XVIa-b (D = H, E =
(funksjonalisert) alkyl). Reduktive alkyleringer av aromatiske aminer er velkjent for fagfolk på området. (functionalized) alkyl). Reductive alkylations of aromatic amines are well known to those skilled in the art.
Standard spalting av den Fmoc beskyttende gruppen ved anvendelse av piperidin i diklormetan fører til 6-amino tetrahydrokinolinderivater med generell formel XVI l-a-b som kan acyleres selektivt i stilling 6 som beskrevet før, for å gi forbindelser ifølge foreliggende oppfinnelse med generell formel l-j-k. Standard cleavage of the Fmoc protecting group using piperidine in dichloromethane leads to 6-amino tetrahydroquinoline derivatives of general formula XVI l-a-b which can be selectively acylated in position 6 as described above, to give compounds according to the present invention of general formula l-j-k.
I en annen prosedyre, kan aminogruppen i stilling 7 av tetrahydrokinolinderivater med generell formel XV-a-b acyleres med (hetero)aryl karboksylsyrer (G-CO2H) eller acylklorider (G-C(O)-CI) som ble beskrevet tidligere. I de påfølgende trinn, fører samme avbeskyttelse-acyleringsstrategi (avbeskyttelse av 6-N-Fmoc og acylering av det resulterende 6-NH2) som ble beskrevet tidligere, deretter til forbindelser ifølge foreliggende oppfinnelse med generell formel l-l-m. In another procedure, the amino group in position 7 of tetrahydroquinoline derivatives of general formula XV-a-b can be acylated with (hetero)aryl carboxylic acids (G-CO 2 H) or acyl chlorides (G-C(O)-CI) as described previously. In the subsequent steps, the same deprotection-acylation strategy (deprotection of 6-N-Fmoc and acylation of the resulting 6-NH 2 ) as described previously, then leads to compounds according to the present invention of general formula 1-1-m.
Forbindelsene ifølge foreliggende oppfinnelse hvor R4 = H og R<5>er forbundet til tetrahydrokinolinrammen via et oksygenatom og R<1>, R2 og R6 er som tidligere definert, kan fremstilles ved å starte fra 2-metoksy-4-nitroanilin (XVII). Reak-sjonssekvensen (a) Fmoc-beskyttelse, for å gi XIX, (b) reduksjon av nitrogruppen, for å gi XX, fulgt av (c) regioselektiv Skraup reaksjon, (d) acetylering og (e) Fmoc- avbeskyttelse som beskrevet før fører til dannelsen av forbindelser med generell formel XXI-a. The compounds according to the present invention where R4 = H and R<5> are connected to the tetrahydroquinoline framework via an oxygen atom and R<1>, R2 and R6 are as previously defined, can be prepared by starting from 2-methoxy-4-nitroaniline (XVII) . The reaction sequence (a) Fmoc protection, to give XIX, (b) reduction of the nitro group, to give XX, followed by (c) regioselective Skraup reaction, (d) acetylation and (e) Fmoc deprotection as described before leads to the formation of compounds of general formula XXI-a.
Forbindelser med generell formel XXI-b kan oppnås ved behandling av forbindelse XX med metylvinylketon ved anvendelse av betingelsene beskrevet tidligere for omsetningen av forbindelser med formel II til lll-b, fulgt av 1 -/V-acetylering og Fmoc avbeskyttelse som beskrevet før. Compounds of general formula XXI-b can be obtained by treating compound XX with methyl vinyl ketone using the conditions described earlier for the reaction of compounds of formula II to III-b, followed by 1 -/V-acetylation and Fmoc deprotection as described before.
Påfølgende omsetning av forbindelser med generell formel XXI til XXIII kan utføres ved acylering av 6-aminogruppen ved anvendelse av et passende acyle-ringsmiddel, for eksempel acylklorid R<6->C(0)-Cl, fulgt av Friedel-Crafts omsetning med benzen eller et passende benzenderivat ved anvendelse av betingelser beskrevet tidligere. Under de Lewis-sure betingelsene av Friedel-Crafts reaksjonen forekommer ledsagende demetylering av 7-OMe funksjonen i forbindelser med generell formel XXII. Den slik oppnådde frie 7-OH gruppen i forbindelser med generell formel XXIII kan realkyleres eller acyleres med henholdsvis (funksjonaliserte) alkylhalogenider (f.eks. kloretylpyrrolidin) eller acylhalogenider (f.eks. 2-furoylklorid eller metylklorformiat), under standardbetingelser for å gi forbindelser med generell formel l-n-o (E = funksjonalisert alkyl, acyl eller karbamat). Subsequent reaction of compounds of general formula XXI to XXIII can be carried out by acylation of the 6-amino group using a suitable acylating agent, for example acyl chloride R<6->C(O)-Cl, followed by Friedel-Crafts reaction with benzene or a suitable benzene derivative using conditions previously described. Under the Lewis acidic conditions of the Friedel-Crafts reaction, accompanying demethylation of the 7-OMe function occurs in compounds of general formula XXII. The thus obtained free 7-OH group in compounds of general formula XXIII can be realkylated or acylated with (functionalized) alkyl halides (e.g. chloroethylpyrrolidine) or acyl halides (e.g. 2-furoyl chloride or methyl chloroformate), respectively, under standard conditions to give compounds of general formula 1-n-o (E = functionalized alkyl, acyl or carbamate).
Forbindelser ifølge foreliggende oppfinnelse hvor R<4>og R<5>er forbundet via et nitrogenatom til tetrahydrokinolinrammen kan fremstilles fra forbindelser med generell formel XXIV, hvor PG er en nitrogenbeskyttende gruppe, f.eks. Boe, acetyl, metylkarbamat eller Fmoc, via de tidligere beskrevne reaksjoner f.eks.: Skraup reaksjon eller cyklokondensering med metylvinylketon, 1-A/-acetylering, spalting av den beskyttende gruppen, A/-alkylering, Friedel-Crafts reaksjon, nitrering, nitro-reduksjon og acylering ( vide supra). Compounds according to the present invention where R<4> and R<5> are connected via a nitrogen atom to the tetrahydroquinoline framework can be prepared from compounds of general formula XXIV, where PG is a nitrogen protecting group, e.g. Boe, acetyl, methylcarbamate or Fmoc, via the previously described reactions, e.g.: Skraup reaction or cyclocondensation with methyl vinyl ketone, 1-A/-acetylation, cleavage of the protecting group, A/-alkylation, Friedel-Crafts reaction, nitration, nitro-reduction and acylation (vide supra).
Skraup reaksjoner med aceton eller mesityloksid på forbindelser med generell formel XXV kan føre til to forskjellige regioisomere produkter med henholdsvis generell formel XXVI-a og XXVI l-a. Omsetning av forbindelser med generell formel XXV ved anvendelse av metylvinylketon under tidligere beskrevne betingelser kan gi regioisomere produkter med henholdsvis generell formel XXVI-b en XXVII-b. Generelt, kan disse regioisomere dihydrokinoliner separeres ved anvendelse av kromatografiske teknikker (silikagel, HPLC) eller krystallisering og kan deretter omsettes til forbindelser Scrap reactions with acetone or mesityl oxide on compounds of general formula XXV can lead to two different regioisomeric products of general formula XXVI-a and XXVI l-a, respectively. Reaction of compounds of general formula XXV using methyl vinyl ketone under previously described conditions can give regioisomeric products of general formula XXVI-b and XXVII-b, respectively. In general, these regioisomeric dihydroquinolines can be separated using chromatographic techniques (silica gel, HPLC) or crystallization and can then be converted into compounds
ifølge foreliggende oppfinnelse via de tidligere beskrevne ruter. according to the present invention via the previously described routes.
Forbindelser ifølge foreliggende oppfinnelse hvor R<5>= H kan fremstilles ved reduktiv 7-deoksygenering av forbindelser med generell formel XXVIII eller XXXI (L og/eller M er passende (substituert) alkyl, acyl alkyloksykarbonyl eller alkylami-nokarbonyl) via selektiv 7-O-triflatiering og påfølgende reduksjon av 7-OTf (Tf = trifluormetylsulfonyl) gruppen. De nødvendige forbindelser med generell formel XXXI er tilgjengelige fra derivater av generell formel XXVII ved anvendelse av tidligere beskrevne betingelser. Den (regioselektive) triflatieringsreaksjonen kan utfø-res under kontrollerte betingelser ved anvendelse av Tf2N-fenyl og A/,/V-diisopro-pyletylamin i DM F ved romtemperatur. Generelt, forekommer preferensiell triflatiering av 7-OH gruppen. Den påfølgende reduksjon kan gjennomføres ved anvendelse av en blanding av trifenylfosfin, trietylamin, maursyre og palladium(ll) acetat som beskrevet i litteraturen. Se for eksempel K.A. Parker, Q. Ding, Tetrahedron 56:10249, 2000. Omsetning av de således oppnådde forbindelser med generell formel XXX eller XXXII ved anvendelse av tidligere beskrevne betingelser fører deretter til forbindelser med den generelle formel l-p-q, hvor R<5>= H. Compounds according to the present invention where R<5>= H can be prepared by reductive 7-deoxygenation of compounds of general formula XXVIII or XXXI (L and/or M is suitably (substituted) alkyl, acyl alkyloxycarbonyl or alkylaminocarbonyl) via selective 7- O-triflation and subsequent reduction of the 7-OTf (Tf = trifluoromethylsulfonyl) group. The required compounds of general formula XXXI are available from derivatives of general formula XXVII using previously described conditions. The (regioselective) triflation reaction can be carried out under controlled conditions using Tf 2 N-phenyl and A/,/V-diisopropylethylamine in DM F at room temperature. In general, preferential triflation of the 7-OH group occurs. The subsequent reduction can be carried out using a mixture of triphenylphosphine, triethylamine, formic acid and palladium(II) acetate as described in the literature. See for example K.A. Parker, Q. Ding, Tetrahedron 56:10249, 2000. Reaction of the thus obtained compounds of general formula XXX or XXXII using previously described conditions then leads to compounds of the general formula l-p-q, where R<5>= H.
Noen av forbindelsene ifølge oppfinnelsen, som kan være i form av en fri base, kan isoleres fra reaksjonsblandingen i form av et farmasøytisk akseptabelt salt. De farmasøytisk akseptable salter kan også oppnås ved behandling av den frie basen med formel I med en organisk eller uorganisk syre slik som hydrogen-klorid, hydrogenbromid, hydrogenjodid, svovelsyre, fosforsyre, eddiksyre, propionsyre, glykolsyre, maleinsyre, malonsyre, metansulfonsyre, fumarsyre, ravsyre, vinsyre, sitronsyre, benzosyre og askorbinsyre. Some of the compounds according to the invention, which may be in the form of a free base, can be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts can also be obtained by treating the free base of formula I with an organic or inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid and ascorbic acid.
Forbindelsene ifølge foreliggende oppfinnelse har minst ett chiralt karbonatom og kan derfor oppnås som rene enantiomerer eller som en blanding av enantiomerer eller som en blanding av diastereomerer. Metoder for å oppnå de rene enantiomerene er velkjent på området, f.eks. krystallisering av salter som oppnås fra optisk aktive syrer og den racemiske blanding eller kromatografi ved anvendelse av chirale kolonner. For diastereomerer, kan normal fase eller om-vendt fase kolonner anvendes. The compounds according to the present invention have at least one chiral carbon atom and can therefore be obtained as pure enantiomers or as a mixture of enantiomers or as a mixture of diastereomers. Methods for obtaining the pure enantiomers are well known in the art, e.g. crystallization of salts obtained from optically active acids and the racemic mixture or chromatography using chiral columns. For diastereomers, normal phase or reversed phase columns can be used.
Forbindelsene ifølge oppfinnelsen kan danne hydrater eller solvater. Det er kjent for fagfolk på området at ladede forbindelser danner hydratiserte spesier når de lyofiliseres med vann eller danner solvatiserte spesier når de konsentreres i en løsning med et passende organisk løsemiddel. Forbindelsene ifølge foreliggende oppfinnelse inkluderer hydrater eller solvater av de listede forbindelsene. The compounds according to the invention can form hydrates or solvates. It is known to those skilled in the art that charged compounds form hydrated species when lyophilized with water or form solvated species when concentrated in solution with a suitable organic solvent. The compounds of the present invention include hydrates or solvates of the listed compounds.
For selektering av aktive forbindelser må testing ved 10"<5>M resultere i en aktivitet på mer enn 20% av den maksimale aktiviteten når FSH blir anvendt som en referanse. Et annet kriterium kunne være EC5overdien som må være < 10"<5>M, fortrinnsvis < 10"7 M. For the selection of active compounds, testing at 10"<5>M must result in an activity of more than 20% of the maximum activity when FSH is used as a reference. Another criterion could be the EC5o value which must be < 10"<5> M, preferably < 10"7 M.
Fagfolk vil forstå at ønskelige EC50verdier er avhengig av den testede forbindelsen. For eksempel blir en forbindelse med en EC50som er mindre enn 10"<5>M generelt betraktet som en kandidat for medikamentseleksjon. Fortrinnsvis er denne verdien lavere enn 10"<7>M. Imidlertid, kan en forbindelse som har en høyere EC50, men er selektiv for den spesielle reseptor, være en enda bedre kandidat. Those skilled in the art will appreciate that desirable EC50 values are dependent on the compound tested. For example, a compound with an EC50 less than 10"<5>M is generally considered a candidate for drug selection. Preferably, this value is lower than 10"<7>M. However, a compound that has a higher EC50 but is selective for that particular receptor may be an even better candidate.
Metoder for å bestemme reseptorbinding, så vel som in vitro og in vivo for-søk for å bestemme biologisk aktivitet, av gonadotropiner er velkjent. Generelt, blir den uttrykte reseptor brakt i kontakt med forbindelsen som skal testes og binding eller stimulering eller inhibering av en funksjonell respons blir målt. Methods for determining receptor binding, as well as in vitro and in vivo assays for determining biological activity, of gonadotropins are well known. Generally, the expressed receptor is contacted with the compound to be tested and binding or stimulation or inhibition of a functional response is measured.
For å måle en funksjonell respons, blir isolert DNA som koder for FSH re-septorgenet, fortrinnsvis den humane reseptor, uttrykt i egnede vertsceller. En slik celle kunne være eggstokkcelle fra kinesisk hamster, men andre celler er også egnet. Fortrinnsvis er cellene av pattedyropprinnelse (Jia et al, Mol.Endokrin., 5:759-776, 1991). To measure a functional response, isolated DNA encoding the FSH receptor gene, preferably the human receptor, is expressed in suitable host cells. Such a cell could be a Chinese hamster ovary cell, but other cells are also suitable. Preferably, the cells are of mammalian origin (Jia et al, Mol. Endokrin., 5:759-776, 1991).
Metoder for å konstruere rekombinant FSH som uttrykker cellelinjer er velkjent på området (Sambrook et al., Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, siste utgave). Reseptor-ekspresjon oppnås ved ekspresjon av DNA-et som koder for det ønskede protein. Teknikker for setestyrt mutagenese, ligering av ytterligere sekvenser, PCR og konstruksjon av egnede ekspresjonssystemer er alle, på nåværende tidspunkt, velkjent på området. Porsjoner eller alt, av DNA-et som koder for det ønskede protein kan konstrueres syntetisk ved anvendelse av standard fastfase teknikker, fortrinnsvis for å inkludere restriksjonsseter for enkel ligering. Egnede kontrollele-menter for transkripsjon og translasjon av den inkluderte kodende sekvensen kan tilveiebringes til de DNA-kodende sekvensene. Som det er velkjent, er det nå tilgjengelig ekspresjonssystemer som er kompatible med en rekke verter, inkludert prokaryote verter slik som bakterier og eukaryote verter slik som gjær, plantecel-ler, insektceller, pattedyrceller, fugleceller og lignende. Methods for constructing recombinant FSH expressing cell lines are well known in the art (Sambrook et al., Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, latest edition). Receptor expression is achieved by expression of the DNA that codes for the desired protein. Techniques for site-directed mutagenesis, ligation of additional sequences, PCR and construction of suitable expression systems are all, by now, well known in the art. Portions, or all, of the DNA encoding the desired protein can be synthetically constructed using standard solid phase techniques, preferably to include restriction sites for easy ligation. Suitable control elements for transcription and translation of the included coding sequence can be provided to the DNA coding sequences. As is well known, expression systems are now available that are compatible with a variety of hosts, including prokaryotic hosts such as bacteria and eukaryotic hosts such as yeast, plant cells, insect cells, mammalian cells, avian cells and the like.
Celler som uttrykker reseptoren blir deretter brakt i kontakt med testforbindelsen for å observere binding eller stimulering eller inhibering av en funksjonell respons. Cells expressing the receptor are then contacted with the test compound to observe binding or stimulation or inhibition of a functional response.
Alternativt kan isolerte cellemembraner som inneholder den uttrykte reseptoren anvendes for å måle binding av forbindelse. Alternatively, isolated cell membranes containing the expressed receptor can be used to measure compound binding.
For måling av binding, kan radioaktivt merkede eller fluorescerent merkede forbindelser anvendes. Konkurransebindingsforsøk kan også utføres. For measurement of binding, radioactively labeled or fluorescently labeled compounds can be used. Competitive binding attempts can also be performed.
Et annet forsøk involverer screening for FSH reseptoragonist forbindelser ved å bestemme stimulering av reseptormediert cAMP akkumulering. Således involverer en slik metode ekspresjon av reseptoren på celleoverflaten av en verts-celle og eksponering av cellen overfor testforbindelsen. Mengden cAMP blir deretter målt. Nivået av cAMP kan reduseres eller økes, avhengig av den inhiberende eller stimulerende effekt av testforbindelsen etter binding til reseptoren. Another experiment involves screening for FSH receptor agonist compounds by determining stimulation of receptor-mediated cAMP accumulation. Thus, such a method involves expression of the receptor on the cell surface of a host cell and exposure of the cell to the test compound. The amount of cAMP is then measured. The level of cAMP can be decreased or increased, depending on the inhibitory or stimulatory effect of the test compound after binding to the receptor.
Screening for FSH reseptorantagonister involverer inkubering av FSH reseptor-uttrykkende celler med et konsentrasjonsområde av testforbindelsen i nær vær av en fiksert, submaksimalt effektiv, FSH konsentrasjon (dvs. en FSH konsentrasjon som induserer omtrent 80% av den maksimale stimulering av cAMP akkumulering i fravær av testforbindelse). Fra konsentrasjon-effekt kurvene, kan IC50verdien og prosentdelen av inhibering av FSH-indusert cAMP akkumulering bestemmes for hver av testforbindelsene. Screening for FSH receptor antagonists involves incubating FSH receptor-expressing cells with a concentration range of the test compound in close proximity to a fixed, submaximal effective, FSH concentration (ie, an FSH concentration that induces approximately 80% of the maximal stimulation of cAMP accumulation in the absence of test connection). From the concentration-effect curves, the IC50 value and the percentage of inhibition of FSH-induced cAMP accumulation can be determined for each of the test compounds.
I tillegg til direkte måling av f.eks. cAMP nivåer i den eksponerte cellen, kan cellelinjer anvendes som i tillegg til transfeksjon med reseptor som koder for DNA også er transfektert med et annet DNA som koder for et rapportørgen, ekspresjonen av dette responderer til nivået av cAMP. Slike rapportørgener kunne være cAMP induserbare eller kunne være konstruert på en slik måte at de er forbundet med nye cAMP mottagelige elementer. Generelt, kunne rapportørgenekspresjon kontrolleres ved ethvert responselement som reagerer på endrede nivåer av cAMP. Egnede rapportørgener er f.eks. genene som koder for P-galaktosidase, alkalisk fosfatase, ildflue luciferase og grønt fluorescens protein. Prinsippene av slike transaktiveringsforsøk er velkjent på området og er beskrevet f.eks. i Stra-towa, Ch., Himmler, A. og Czernilofsky, A.P., (1995) Curr.Opin.Biotechnol. 6:574. Som referanseforbindelse kan humant rekombinant FSH anvendes. Alternativt kan også konkurranseforsøk utføres In addition to direct measurement of e.g. cAMP levels in the exposed cell, cell lines can be used which, in addition to transfection with a receptor that codes for DNA, are also transfected with another DNA that codes for a reporter gene, the expression of which responds to the level of cAMP. Such reporter genes could be cAMP inducible or could be engineered in such a way that they are linked to new cAMP responsive elements. In general, reporter gene expression could be controlled by any response element that responds to changing levels of cAMP. Suitable reporter genes are e.g. the genes that code for P-galactosidase, alkaline phosphatase, firefly luciferase and green fluorescence protein. The principles of such transactivation experiments are well known in the field and are described e.g. in Stratowa, Ch., Himmler, A. and Czernilofsky, A.P., (1995) Curr.Opin.Biotechnol. 6:574. Human recombinant FSH can be used as a reference compound. Alternatively, competitive trials can also be carried out
Foreliggende oppfinnelse omhandler også et farmasøytisk preparat som omfatter et tertrahydrokinolinderivat eller farmasøytisk akseptable salter derav som har den generelle formel I i blanding med farmasøytisk akseptable tilsetningsmidler og eventuelt andre terapeutiske midler. Tilsetningsmidlene må være "akseptable" i betydningen av å være kompatible med de andre bestanddelene i preparatet og ikke skadelig for mottagerne derav. The present invention also relates to a pharmaceutical preparation comprising a tetrahydroquinoline derivative or pharmaceutically acceptable salts thereof which have the general formula I in admixture with pharmaceutically acceptable additives and possibly other therapeutic agents. The additives must be "acceptable" in the sense of being compatible with the other components of the preparation and not harmful to the recipients thereof.
Preparater inkluderer f.eks. de egnet for oral, sublingual, subkutan, intrave-nøs, intramuskulær, lokal eller rektal administrering og lignende, alle i enhets-doseformer for administrering. Preparations include e.g. those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, local or rectal administration and the like, all in unit dosage forms for administration.
For oral administrering, kan den aktive bestanddelen presenteres som at-skilte enheter, slik som tabletter, kapsler, pulvere, granulater, løsninger og suspensjoner. For oral administration, the active ingredient can be presented as discrete units, such as tablets, capsules, powders, granules, solutions and suspensions.
For parenteral administrering, kan det farmasøytiske preparatet ifølge oppfinnelsen presenteres i enhetsdose eller multidose beholdere, f.eks. injeksjons-væsker i forutbestemte mengder, for eksempel i forseglede medisinglass og am- puller og kan også lagres i en frysetørket (lyofilisert) tilstand som bare krever tilsetning av steril flytende bærer, f.eks. vann, før anvendelse. For parenteral administration, the pharmaceutical preparation according to the invention can be presented in unit dose or multidose containers, e.g. injection fluids in predetermined quantities, for example in sealed vials and ampoules and can also be stored in a freeze-dried (lyophilized) state that only requires the addition of a sterile liquid carrier, e.g. water, before use.
Blandet med slike farmasøytisk akseptable tilsetningsmidler, f.eks. som beskrevet i standardreferansen, Gennaro, A.R. et al., Remington: The Science and Practice of Pharmacy (20. Utgave., Lippincott Williams & Wilkins, 2000, se spesielt Del 5: Pharmaceutical Manufacturing), kan det aktive midlet komprimeres til faste doseenheter, så som piller, tabletter eller prosesseres til kapsler eller sup-positorier. Ved hjelp av farmasøytisk akseptable væsker kan det aktive midlet anvendes som en fluid sammensetning, f.eks. som et injeksjonspreparat, i form av en løsning, suspensjon, emulsjon eller som en spray, f.eks. en nesespray. Mixed with such pharmaceutically acceptable additives, e.g. as described in the standard reference, Gennaro, A.R. et al., Remington: The Science and Practice of Pharmacy (20th Ed., Lippincott Williams & Wilkins, 2000, see especially Section 5: Pharmaceutical Manufacturing), the active agent may be compressed into fixed dosage units, such as pills, tablets, or processed for capsules or suppositories. By means of pharmaceutically acceptable liquids, the active agent can be used as a fluid composition, e.g. as an injection preparation, in the form of a solution, suspension, emulsion or as a spray, e.g. a nasal spray.
For å fremstille faste doseenheter, er det tenkt anvendelse av konvensjo-nelle additiver slik som fyllmidler, fargemidler og polymere bindemidler. Generelt kan hvilket som helst farmasøytisk akseptabelt additiv som ikke forstyrrer funksjonen av de aktive forbindelsene anvendes. Egnede bærere som det aktive midlet ifølge oppfinnelsen kan administreres med som faste preparater inkludert laktose, stivelse, cellulosederivater og lignende eller blandinger derav, anvendt i egnede mengder. For parenteral administrering, kan vandige suspensjoner, isoto-niske saltløsninger og sterile injiserbare løsninger anvendes, som inneholder far-masøytisk akseptable dispergeringsmidler og/eller fuktemidler, slik som propylen-glykol eller butylenglykol. In order to produce fixed dose units, the use of conventional additives such as fillers, coloring agents and polymeric binders is envisaged. In general, any pharmaceutically acceptable additive which does not interfere with the function of the active compounds may be used. Suitable carriers with which the active agent according to the invention can be administered as solid preparations including lactose, starch, cellulose derivatives and the like or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions, and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol.
Oppfinnelsen inkluderer videre et farmasøytisk preparat, som beskrevet tidligere heri, i kombinasjon med pakningsmateriale som er egnet for nevnte preparat, nevnte pakningsmateriale inkluderer bruksinstruksjoner for preparatet for anvendelsen som ovenfor beskrevet. The invention further includes a pharmaceutical preparation, as described earlier herein, in combination with packaging material which is suitable for said preparation, said packaging material includes instructions for use of the preparation for the application as described above.
Tetrahydrokinolinderivatene ifølge oppfinnelsen kan også administreres i form av implanterbare farmasøytiske anordninger, bestående av en kjerne av ak-tivt materiale, innkapslet av en frigjøringshastighetsregulerende membran. Slike implantater skal benyttes subkutant eller lokalt og vil frigi den aktive bestanddelen ved en omtrent konstant hastighet over relativt store tidsrom, for eksempel fra uker til år. Metoder for fremstilling av implanterbare farmasøytiske anordninger som sådanne er kjent på området, for eksempel som beskrevet i Europeisk Patent 0.303.306 (AKZO Nobel N.V.). The tetrahydroquinoline derivatives according to the invention can also be administered in the form of implantable pharmaceutical devices, consisting of a core of active material, encapsulated by a release rate-regulating membrane. Such implants are to be used subcutaneously or locally and will release the active ingredient at an approximately constant rate over relatively large periods of time, for example from weeks to years. Methods for producing implantable pharmaceutical devices as such are known in the field, for example as described in European Patent 0.303.306 (AKZO Nobel N.V.).
Den nøyaktige dosen og regimet for administrering av den aktive bestanddelen eller et farmasøytisk preparat derav, vil nødvendigvis være avhengig av den terapeutiske effekt som skal oppnås (behandling av infertilitet; prevensjon) og kan variere med den spesielle forbindelse, administreringsveien og alderen og tilstan-den av den individuelle pasient som medikamentet skal administreres til. The exact dose and regimen of administration of the active ingredient or a pharmaceutical preparation thereof will necessarily depend on the therapeutic effect to be achieved (treatment of infertility; contraception) and may vary with the particular compound, route of administration and age and condition. of the individual patient to whom the drug is to be administered.
Generelt krever parenteral administrering lavere doser enn andre administ-reringsmetoder som er mer avhengig av absorpsjon. Imidlertid, inneholder en dose for mennesker fortrinnsvis 0,0001-25 mg pr. kg kroppsvekt. Den ønskede dose kan presenteres som én dose eller som flere underdoser administrert med passende intervaller gjennom hele dagen, eller, i tilfelle kvinnelige mottagere, som doser som skal administreres ved passende daglige intervaller gjennom hele menstruasjonssyklusen. Dosen så vel som administreringsregimet kan avvike mellom en kvinnelig og en mannlig mottager. In general, parenteral administration requires lower doses than other administration methods that are more dependent on absorption. However, a dose for humans preferably contains 0.0001-25 mg per kg body weight. The desired dose may be presented as a single dose or as multiple subdoses administered at appropriate intervals throughout the day, or, in the case of female recipients, as doses to be administered at appropriate daily intervals throughout the menstrual cycle. The dose as well as the administration regimen may differ between a female and a male recipient.
Således, kan forbindelsene ifølge oppfinnelsen anvendes i terapi. Thus, the compounds according to the invention can be used in therapy.
I et annet aspekt tilhører oppfinnelsen anvendelsen av en tetrahydrokinolin-derivatforbindelse som har den generelle formel I for fremstillingen av et medikament som skal anvendes for fertililtetskontroll. In another aspect, the invention relates to the use of a tetrahydroquinoline derivative compound having the general formula I for the preparation of a medicament to be used for fertility control.
I enda et annet aspekt tilhører oppfinnelsen anvendelsen av en tetrahydro-kinolinderivatforbindelse som har den generelle formel I for fremstillingen av et medikament som skal anvendes for behandling av infertilitet. In yet another aspect, the invention relates to the use of a tetrahydroquinoline derivative compound having the general formula I for the preparation of a medicament to be used for the treatment of infertility.
I enda et annet aspekt tilhører oppfinnelsen anvendelsen av en tetrahydro-kinolinderivatforbindelse som har den generelle formel I for fremstilling av et medikament som skal anvendes for å forhindre fruktbarhet. In yet another aspect, the invention relates to the use of a tetrahydroquinoline derivative compound having the general formula I for the preparation of a medicament to be used to prevent fertility.
Oppfinnelsen er illustrert ved de følgende eksempler. The invention is illustrated by the following examples.
Eksempler Examples
Generelle kommentarer: General comments:
De følgende forkortelser blir anvendt i eksemplene: DMA = A/,/V-dimetylani-lin, DIPEA = A/,/V-diisopropyletylamin, TFA = trifluoreddiksyre, DtBAD = di-fert-butyl-azodikarboksylat, HATU = 0-(7-azabenzotriazol-1-yl)-A/,A/,A/',A/-tetrametyluro-nium heksafluorfosfat, Fmoc = 9-fluorenylmetoksykarbonyl, Fmoc-CI = 9-fluor-enylmetoksykarbonylklorid, DMF = /V,/V-dimetylformamid, DMAP = 4-dimetylami-nopyridin, THF = tetrahydrofuran. The following abbreviations are used in the examples: DMA = A/,/V-dimethylaniline, DIPEA = A/,/V-diisopropylethylamine, TFA = trifluoroacetic acid, DtBAD = di-tert-butyl-azodicarboxylate, HATU = 0-(7 -azabenzotriazol-1-yl)-A/,A/,A/',A/-tetramethyluronium hexafluorophosphate, Fmoc = 9-fluorenylmethoxycarbonyl, Fmoc-CI = 9-fluoroenylmethoxycarbonyl chloride, DMF = /V,/V- dimethylformamide, DMAP = 4-dimethylaminopyridine, THF = tetrahydrofuran.
Hvis ikke angitt på annen måte, blir alle sluttprodukter fra eksemplene nedenfor lyofilisert fra vann/1,4-dioksanblandinger eller vann/acetonitrilblandinger. Hvis forbindelsen ble fremstilt som et HCI- eller TFA salt, ble de respektive syrer tilsatt i passende mengder til løsemiddelblandingen før lyofilisering. Unless otherwise indicated, all final products from the examples below are lyophilized from water/1,4-dioxane mixtures or water/acetonitrile mixtures. If the compound was prepared as an HCl or TFA salt, the respective acids were added in appropriate amounts to the solvent mixture prior to lyophilization.
Navnene av sluttproduktene beskrevet i eksemplene blir generert ved anvendelse av Beilstein Autonome programmet (versjon: 2.02.119). The names of the final products described in the examples are generated using the Beilstein Autonomous program (version: 2.02.119).
De følgende analytiske HPLC metoder anvendes for bestemmelse av re-tensjonstider: Metode 1: Kolonne: 5 um Luna C-18(2) 150x4,6 mm; strøm: 1 ml/min; deteksjon: 210 nm; kolonnetemperatur: 40°C; løsemiddel A: CH3CN/H20 = 1/9 (volum/volum); løsemiddel B: CH3CN; løsemiddel C: 0,1 M vandig trifluoreddiksyre; gradient: løsemiddel A/B/C = 65/30/5 til 10/85/5 (volum/volum/v) i 30,00 min, deretter konstant i ytterligere 10,00 min ved A/B/C = 10/85/5 (volum/volum/v). The following analytical HPLC methods are used for determining retention times: Method 1: Column: 5 µm Luna C-18(2) 150x4.6 mm; flow: 1 ml/min; detection: 210 nm; column temperature: 40°C; solvent A: CH3CN/H2O = 1/9 (v/v); solvent B: CH3CN; solvent C: 0.1 M aqueous trifluoroacetic acid; gradient: solvent A/B/C = 65/30/5 to 10/85/5 (vol/vol/v) for 30.00 min, then constant for another 10.00 min at A/B/C = 10/ 85/5 (volume/volume/v).
Metode 2: Identisk med metode 1, bortsett fra den anvendte gradienten: Gradient: løsemiddel A/B/C = 75/20/5 til 15/80/5 (volum/volum/v) i 30,00 min, deretter konstant i ytterligere 10,00 min ved A/B/C = 15/80/5 (volum/volum/v). Method 2: Identical to Method 1, except for the gradient used: Gradient: solvent A/B/C = 75/20/5 to 15/80/5 (vol/vol/v) for 30.00 min, then constant for another 10.00 min at A/B/C = 15/80/5 (volume/volume/v).
Metode 3: Identisk med metode 1, bortsett fra den anvendte gradienten: Gradient: løsemiddel A/B/C = 35/60/5 til 10/85/5 (volum/volum/v) i 30,00 min, deretter konstant i ytterligere 10,00 min ved A/B/C = 10/85/5 (volum/volum/v). Method 3: Identical to Method 1, except for the gradient used: Gradient: solvent A/B/C = 35/60/5 to 10/85/5 (vol/vol/v) for 30.00 min, then constant for another 10.00 min at A/B/C = 10/85/5 (volume/volume/v).
Metode 4: Kolonne: 3 pm Luna C-18(2) 100*2mm; strøm: 0,25 ml/min; deteksjon: 210 nm; kolonnetemperatur: 40°C; løsemiddel A: H20; løsemiddel B: CH3CN; gradient: løsemiddel A/B = 75/25 til 0/100 (volum/volum) i 20,00 min, deretter konstant i ytterligere 10,00 min ved A/B = 0/100 (volum/volum). Method 4: Column: 3 pm Luna C-18(2) 100*2mm; flow: 0.25 ml/min; detection: 210 nm; column temperature: 40°C; solvent A: H 2 O; solvent B: CH3CN; gradient: solvent A/B = 75/25 to 0/100 (v/v) for 20.00 min, then constant for another 10.00 min at A/B = 0/100 (v/v).
Metode 5: Kolonne: 3 um Luna C-18(2) 100*2 mm; strøm: 0,25 ml/min; deteksjon: 210 nm; kolonnetemperatur: 40°C; løsemiddel A: H20; løsemiddel B: CH3CN; løsemiddel C: 50 mM fosfatbuffer, pH 2,1; gradient: løsemiddel A/B/C = 70/20/10 til 10/80/10 (volum/volum/v) i 20,00 min, deretter konstant i ytterligere 10,00 min ved A/B/C = 10/80/10 (volum/volum/v). Method 5: Column: 3 um Luna C-18(2) 100*2 mm; flow: 0.25 ml/min; detection: 210 nm; column temperature: 40°C; solvent A: H 2 O; solvent B: CH3CN; solvent C: 50 mM phosphate buffer, pH 2.1; gradient: solvent A/B/C = 70/20/10 to 10/80/10 (v/v/v) for 20.00 min, then constant for another 10.00 min at A/B/C = 10/ 80/10 (volume/volume/v).
Metode 6: Identisk med metode 5, bortsett fra den anvendte gradienten: Gradient: løsemiddel A/B/C = 65/30/5 til 10/85/5 (volum/volum/v) i 20,00 min, deretter konstant i ytterligere 10,00 min ved A/B/C = 10/85/5 (volum/volum/v). Method 6: Identical to Method 5, except for the gradient used: Gradient: solvent A/B/C = 65/30/5 to 10/85/5 (vol/vol/v) for 20.00 min, then constant for another 10.00 min at A/B/C = 10/85/5 (volume/volume/v).
De følgende metoder blir anvendt for preparative HPLC-rensinger: Metode A: Kolonne = Luna C-18. Gradient: 0,1% trifluoreddiksyre i H20/CH3CN (9/1, volum/volum)/CH3CN = 80/20 til 0/100 (volum/volum) i 30-45 min, avhengig av separeringsenkelheten. Deteksjon: 210 nm. The following methods are used for preparative HPLC purifications: Method A: Column = Luna C-18. Gradient: 0.1% trifluoroacetic acid in H2O/CH3CN (9/1, v/v)/CH3CN = 80/20 to 0/100 (v/v) for 30-45 min, depending on ease of separation. Detection: 210 nm.
Metode B: Kolonne = Luna C-18. Gradient: H20/CH3CN (9/1, volum/volum)/ CH3CN = 80/20 til 0/100 (volum/volum) i 30-45 min, avhengig av separeringsenkelheten. Deteksjon: 210 nm. Method B: Column = Luna C-18. Gradient: H20/CH3CN (9/1, v/v)/CH3CN = 80/20 to 0/100 (v/v) for 30-45 min, depending on ease of separation. Detection: 210 nm.
Eksempel 1 Example 1
A/- ri- acetvl- 5, 7- dimetoksv- 4-( 4- metoksv- fenvl)- 2, 2, 4- trimetvl- 1, 2, 3, 4- tetrahvdrokinolin- 6- vn- 3- klor- 2, 6- dimetoksv- benzamid A/- ri- acetvl- 5, 7- dimethoxysv- 4-( 4- methoxysv- phenyl)- 2, 2, 4- trimethvl- 1, 2, 3, 4- tetrahydroquinoline- 6- vn- 3- chloro- 2 , 6-dimethoxybenzamide
(a) . 5, 7- dimetoksv- 2, 2, 4- trimetvl- 1, 2- dihvdrokinolin (a) . 5, 7- dimethoxysv- 2, 2, 4- trimethovl- 1, 2- dihydroquinoline
En løsning av 3,5-dimetoksyanilin (50 g) i aceton (800 ml) ble satt dråpevis til en blanding av MgS04(100 g) og Sc(OTf)3(8,0 g) i 1 I aceton ved romtemperatur. Etter 5 timer ble en annen porsjon av Sc(OTf)3(3,2 g) tilsatt og reaksjonsblandingen ble omrørt inntil intet utgangsmateriale var tilbake. Etter filtrering, ble ace-tonen delvis inndampet i vakuum som forårsaker krystallisering av tittelforbindelsen som ble samlet opp ved filtrering, for å gi 22 g etter tørking in vakuum. Den gjenværende moderluten ble konsentrert i vakuum og residuet ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/ volum) som elueringsmidlet, for å gi ytterligere 19,4 g av tittelforbindelsen. Utbytte: 42 g. A solution of 3,5-dimethoxyaniline (50 g) in acetone (800 ml) was added dropwise to a mixture of MgSO 4 (100 g) and Sc(OTf) 3 (8.0 g) in 1 L of acetone at room temperature. After 5 hours, another portion of Sc(OTf)3 (3.2 g) was added and the reaction mixture was stirred until no starting material remained. After filtration, the acetone was partially evaporated in vacuo causing crystallization of the title compound which was collected by filtration to give 22 g after drying in vacuo. The remaining mother liquor was concentrated in vacuo and the residue was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent to give an additional 19.4 g of the title compound. Yield: 42 g.
(b) . 1 - acetyl- 5, 7- dimetoksv- 2, 2, 4- trimetyl- 1, 2- dihydrokinolin (b) . 1 - acetyl- 5, 7- dimethoxy- 2, 2, 4- trimethyl- 1, 2- dihydroquinoline
En blanding av forbindelsen beskrevet i eksempel 1a (42 g) og eddiksyreanhydrid (100 ml) ble omrørt ved 100°C i 20 timer. Reaksjonsblandingen ble tømt i 500 ml is-vann under omrøring. De utfelte faststoffer ble samlet opp ved filtrering og tørket in vakuum ved 40°C i 2 dager. Det gjenværende brune faststoffet kunne anvendes ubearbeidet for ytterligere syntetiske transformasjoner. A mixture of the compound described in Example 1a (42 g) and acetic anhydride (100 ml) was stirred at 100°C for 20 hours. The reaction mixture was poured into 500 ml of ice-water with stirring. The precipitated solids were collected by filtration and dried in vacuum at 40°C for 2 days. The remaining brown solid could be used unprocessed for further synthetic transformations.
Utbytte: 45 g. Yield: 45 g.
(c) . 1- acetvl- 5, 7- dimetoksv- 4-( 4- metoksvfenvl)- 2, 2, 4- trimetvl- 1, 2, 3, 4- tetrahydrokinolin (c) . 1- Acetyl- 5, 7- Dimethoxy- 4-( 4- Methoxyphenyl)- 2, 2, 4- Trimethyl- 1, 2, 3, 4- Tetrahydroquinoline
En blanding av forbindelsen beskrevet i eksempel 1b (30 g) og AICI3(44 g) i anisol (500 ml) ble omrørt ved 50°C i 18 timer. Reaksjonsblandingen ble avkjølt (0°C) og behandlet med vann og etylacetat ble tilsatt. Blandingen ble omrørt natten over. Det organiske laget ble separert, tørket over MgSCvt, filtrert og konsentrert in va kuum. Residuet ble kromatografert på silikagel ved anvendelse av heptan/etylacetat = 8/2 (volum/volum) som elueringsmidlet. A mixture of the compound described in Example 1b (30 g) and AlCl 3 (44 g) in anisole (500 ml) was stirred at 50°C for 18 hours. The reaction mixture was cooled (0°C) and treated with water and ethyl acetate was added. The mixture was stirred overnight. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel using heptane/ethyl acetate = 8/2 (volume/volume) as the eluent.
Utbytte: 15 g. Yield: 15 g.
(d) . 1- acetvl- 5, 7- dimetoksv- 4-( 4- metoksvfenvl)- 2, 2, 4- trimetyl- 6- nitro- 1, 2, 3, 4- tetrahvdrokinolin (d) . 1- Acetyl- 5, 7- Dimethoxy- 4-( 4- Methoxyphenyl)- 2, 2, 4- Trimethyl- 6- Nitro- 1, 2, 3, 4- Tetrahydroquinoline
En løsning av eddiksyreanhydrid (450 ul) i rykende salpetersyre (22,5 ml) ble satt dråpevis til en løsning av forbindelsen beskrevet i eksempel 1c (15 g) i CH2CI2(500 ml) ved 0°C. Etter fullstendig addisjon ble reaksjonsblandingen omrørt ved romtemperatur i 3 timer. Vann ble tilsatt og det organiske laget ble separert, tørket over MgSCv, filtrert og konsentrert in vakuum. Residuet ble krystallisert fra etanol, for å gi tittelforbindelsen som et krystallinsk, fast stoff. A solution of acetic anhydride (450 µl) in fuming nitric acid (22.5 mL) was added dropwise to a solution of the compound described in Example 1c (15 g) in CH 2 Cl 2 (500 mL) at 0°C. After complete addition, the reaction mixture was stirred at room temperature for 3 hours. Water was added and the organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue was crystallized from ethanol to give the title compound as a crystalline solid.
Utbytte: 10 g. Yield: 10 g.
(e) . 1- acetvl- 6- amino- 5, 7- dimetoksv- 4-( 4- metoksvfenyl)- 2, 2, 4- trimetvl- 1, 2, 3, 4-tetrahydrokinolin (e) . 1- Acetyl- 6- amino- 5, 7- dimethoxy- 4-( 4- methoxyphenyl)- 2, 2, 4- trimethyl- 1, 2, 3, 4-tetrahydroquinoline
En løsning av forbindelsen beskrevet i eksempel 1d (11,75 g) og eddiksyre (15,5 ml) i THF (600 ml) ble avkjølt til 0°C. Sinkstøv (36 g) ble tilsatt i porsjoner og is-badet fjernet. Temperaturen steg raskt til 30°C, etter som reaksjonsblandingen fikk avkjøles ned til romtemperatur. Overskuddet av sink ble fjernet ved filtrering og til filtratet ble det satt CH2CI2og en mettet vandig løsning av Na2C03. Det organiske laget ble separert, tørket over MgS04, filtrert og konsentrert i vakuum. Produktet ble anvendt ubearbeidet i det neste trinnet. A solution of the compound described in Example 1d (11.75 g) and acetic acid (15.5 mL) in THF (600 mL) was cooled to 0°C. Zinc dust (36 g) was added in portions and the ice bath removed. The temperature rose rapidly to 30°C, after which the reaction mixture was allowed to cool down to room temperature. The excess zinc was removed by filtration and to the filtrate was added CH 2 Cl 2 and a saturated aqueous solution of Na 2 CO 3 . The organic layer was separated, dried over MgSO 4 , filtered and concentrated in vacuo. The product was used unprocessed in the next step.
Utbytte: 10,9 g. Yield: 10.9 g.
(f) . A/- ri- acetvl- 5. 7- dimetoksv- 4-( 4- metoksv- fenvl)- 2, 2, 4- trimetvl- 1, 2, 3, 4- tetrahvdro- kinolin- 6- vn- 3- klor- 2, 6- dimetoksv- benzamid (f) . A/- ri- acetvl- 5. 7- dimethoxy- 4-( 4- methoxy- phenyl)- 2, 2, 4- trimethvl- 1, 2, 3, 4- tetrahydro- quinolin- 6- vn- 3- chloro - 2, 6- dimethoxybenzamide
Generell prosedyre A: Til en løsning av forbindelsen beskrevet i eksempel 1e (100 mg), 3-klor-2,6-dimetoksybenzosyre (60 mg) og DIPEA (132 ul) i CH2CI2(2 ml) ble det tilsatt HATU (143 mg) ved romtemperatur. Hvis reaksjonen ikke nådde fullførelse etter 18 timer, ble mer HATU og DIPEA tilsatt. Etter fullføring av reaksjonen ble en mettet, vandig løsning av NaHC03tilsatt, det organiske laget ble separert, tørket (MgS04) og konsentrert in vakuum. Tittelforbindelsen ble renset ved preparativ HPLC (metode A). General Procedure A: To a solution of the compound described in Example 1e (100 mg), 3-chloro-2,6-dimethoxybenzoic acid (60 mg) and DIPEA (132 µl) in CH 2 Cl 2 (2 mL) was added HATU (143 mg ) at room temperature. If the reaction did not reach completion after 18 hours, more HATU and DIPEA were added. After completion of the reaction, a saturated aqueous solution of NaHCO 3 was added, the organic layer was separated, dried (MgSO 4 ) and concentrated in vacuo. The title compound was purified by preparative HPLC (Method A).
Utbytte: 87 mg. MS-ESI: [M+H]<+>= 597,4 Yield: 87 mg. MS-ESI: [M+H]<+>= 597.4
HPLC: Rt = 17,98 min (metode 1). HPLC: Rt = 17.98 min (method 1).
Eksempel 2 Example 2
4, 5- dimetyl- furan- 2- karboksvlsyre [ 1- acetvl- 5, 7- dimetoksv- 4-( 4- metoksv- fenyl)-2. 2, 4- trimetvl- 1. 2, 3, 4- tetrahvdro- kinolin- 6- vn- amid 4, 5- dimethyl- furan- 2- carboxylic acid [ 1- acetyl- 5, 7- dimethoxy- 4-(4- methoxy- phenyl)-2. 2, 4- trimethyl- 1. 2, 3, 4- tetrahydroquinoline- 6- vn- amide
Generell prosedyre B: Til en løsning av forbindelsen beskrevet i eksempel 1e (800 mg), 4,5-dimetylfuran-2-karboksylsyre (308 mg) og DMA (768 ul) i DMF (10 ml) ble det tilsatt HATU (1,1 g) ved romtemperatur. Hvis reaksjonen ikke nådde fullførelse etter 18 timer, ble reaksjonsblandingen varmet opp til 50°C. Etter fullfø-ring av reaksjonen, ble vann og etylacetat tilsatt, det organiske laget ble separert, tørket (MgSCv) og konsentrert in vakuum. Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/ volum) som elueringsmidlet. General Procedure B: To a solution of the compound described in Example 1e (800 mg), 4,5-dimethylfuran-2-carboxylic acid (308 mg) and DMA (768 µl) in DMF (10 ml) was added HATU (1, 1 g) at room temperature. If the reaction did not reach completion after 18 hours, the reaction mixture was heated to 50°C. After completion of the reaction, water and ethyl acetate were added, the organic layer was separated, dried (MgSO4) and concentrated in vacuo. The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.
Utbytte: 444 mg. MS-ESI: [M+H]<+>= 521,4 Yield: 444 mg. MS-ESI: [M+H]<+>= 521.4
HPLC: Rt = 16,96 min (metode 1). HPLC: Rt = 16.96 min (method 1).
Eksempel 3 Example 3
5- brom- tiofen- 2- karboksvlsyre f1- acetvl- 5, 7- dimetoksv- 4-( 4- metoksv- fenyl)- 2, 2, 4-trimetvl- 1, 2, 3, 4- tetrahydro- kinolin- 6- vn- amid 5- bromo-thiophene- 2- carboxylic acid f1- acetvl- 5, 7- dimethoxysv- 4-( 4- methoxysv- phenyl)- 2, 2, 4-trimethylvl- 1, 2, 3, 4- tetrahydro- quinoline- 6 - vn-amide
I henhold til generell prosedyre B, ble forbindelsen beskrevet i eksempel 1e (800 mg), acylert med 5-bromtiofen-2-karboksylsyre (456 mg), DMA (768 ul) og HATU (1,1 g) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/volum) som elueringsmidlet. According to General Procedure B, the compound described in Example 1e (800 mg) was acylated with 5-bromothiophene-2-carboxylic acid (456 mg), DMA (768 µl) and HATU (1.1 g) in CH 2 Cl 2 (10 mL ). The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.
Utbytte: 1,0 g. MS-ESI: [M+H]<+>= 589,2; HPLC: Rt = 18,90 min (metode 2). Yield: 1.0 g. MS-ESI: [M+H]<+>= 589.2; HPLC: Rt = 18.90 min (method 2).
Eksempel 4 Example 4
Bifenyl- 4- karboksvlsyre ri- acetvl- 5, 7- dimetoksv- 4-( 4- metoksv- fenyl)- 2, 2, 4- trimetvl-1. 2, 3, 4- tetrahvdro- kinolin- 6- vn- amid Biphenyl- 4- carboxylic acid ri-acetyl- 5, 7- dimethoxy- 4-( 4- methoxy- phenyl)- 2, 2, 4- trimethyl-1. 2, 3, 4-tetrahydroquinoline-6-vn-amide
Generell prosedyre C: Til en løsning av forbindelsen beskrevet i eksempel 1e (800 mg) og 4-bifenylkarbonylklorid (475 mg) i CH2CI2(10 ml) ble det tilsatt DMA (768 ul) ved romtemperatur. Reaksjonsblandingen ble omrørt inntil intet utgangsmateriale var tilbake ved hvilket punkt vann ble tilsatt. Det organiske laget ble se parert, tørket (MgSCv) og konsentrert in vakuum. Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/ volum) som elueringsmidlet. General Procedure C: To a solution of the compound described in Example 1e (800 mg) and 4-biphenylcarbonyl chloride (475 mg) in CH 2 Cl 2 (10 mL) was added DMA (768 µl) at room temperature. The reaction mixture was stirred until no starting material remained at which point water was added. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.
Utbytte: 678 mg. MS-ESI: [M+H]<+>= 579,4; HPLC: Rt = 26,19 min (metode 2). Yield: 678 mg. MS-ESI: [M+H]<+>= 579.4; HPLC: Rt = 26.19 min (method 2).
Eksempel 5 Example 5
Furan- 2- karboksylsyre [ 1- acetvl- 5- hvdroksv- 7- metoksv- 4-( 4- metoksv- fenyl)- 2, 2, 4-trimetvl- 1, 2, 3, 4- tetrahydro- kinolin- 6- vn- amid Furan- 2- carboxylic acid [ 1- acetvl- 5- hydroxy- 7- methoxy- 4-( 4- methoxy- phenyl)- 2, 2, 4-trimethyl- 1, 2, 3, 4- tetrahydro- quinoline- 6- vn-amide
(a) . Furan- 2- karboksvlsvre [ 1- acetvl- 5, 7- dimetoksv- 4-( 4- metoksvfenvl)- 2, 2, 4- trimetvl- 1, 2, 3, 4- tetrahvdrokinolin- 6- vn- amid (a) . Furan- 2- carboxylic acid [ 1- acetyl- 5, 7- dimethoxy- 4-( 4- methoxyphenyl)- 2, 2, 4- trimethyl- 1, 2, 3, 4- tetrahydroquinoline- 6- vana- amide
I henhold til generell prosedyre C, ble forbindelsen beskrevet i eksempel 1e (800 mg) acylert med 2-furoylklorid (217 ul) og DMA (768 pl) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/volum) som elueringsmidlet. According to General Procedure C, the compound described in Example 1e (800 mg) was acylated with 2-furoyl chloride (217 µl) and DMA (768 µl) in CH 2 Cl 2 (10 mL). The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.
Utbytte: 896 mg Yield: 896 mg
(b) . Furan- 2- karboksvlsvre H- acetvl- 5- hvdroksv- 7- metoksv- 4-( 4- metoksv- fenvl)-2, 2, 4- trimetvl- 1. 2, 3, 4- tetrahvdro- kinolin- 6- vn- amid (b) . Furan- 2- carboxylic acid H- acetvl- 5- hydroxy- 7- methoxy- 4-( 4- methoxy- phenyl)-2, 2, 4- trimethyl- 1. 2, 3, 4- tetrahydro- quinolin- 6- vn - amide
Generell prosedyre D: en løsning av forbindelsen beskrevet i eksempel 5a (50 mg) i CH2CI2(4 ml) ble avkjølt til -78°C, under en atmosfære av N2. Bortribromid (28 ul) ble tilsatt dråpevis og etter fullstendig tilsetning, fikk reaksjonsblandingen langsomt varmes til romtemperatur. Reaksjonen ble stanset med vann og CH2CI2ble tilsatt. Det organiske laget ble separert, tørket (MgSCv) og konsentrert in vakuum. Tittelforbindelsen ble renset ved preparativ HPLC (metode A). Under betingelsene beskrevet over, blir det generelt dannet blandinger av forbindelser med en varierende grad av demetylering, som kan separeres ved preparative HPLC metoder. General procedure D: a solution of the compound described in Example 5a (50 mg) in CH 2 Cl 2 (4 mL) was cooled to -78°C, under an atmosphere of N 2 . Boron tribromide (28 µl) was added dropwise and after complete addition, the reaction mixture was allowed to slowly warm to room temperature. The reaction was quenched with water and CH 2 Cl 2 was added. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The title compound was purified by preparative HPLC (Method A). Under the conditions described above, mixtures of compounds with a varying degree of demethylation are generally formed, which can be separated by preparative HPLC methods.
Utbytte: 9,1 mg; MS-ESI: [M+H]<+>= 479,4; HPLC: Rt = 23,40 min (metode 2). Yield: 9.1 mg; MS-ESI: [M+H]<+>= 479.4; HPLC: Rt = 23.40 min (method 2).
Eksempel 6 Example 6
A/- ri- acetvl- 5- hvdroksv- 7- metoksv- 4-( 4- metoksv- fenvl)- 2. 2. 4- trimetvl- 1. 2. 3. 4- tetrahydro- kinolin- 6- vn- 3, 5- diklor- benzamid A/- ri- acetvl- 5- hydroxy- 7- methoxy- 4-( 4- methoxy- phenyl)- 2. 2. 4- trimethyl- 1. 2. 3. 4- tetrahydro- quinoline- 6- vn- 3 , 5-dichlorobenzamide
(a) . A/- ri- acetvl- 57- dimetoksv- 4-( 4- metoksvfenvl)- 2, 2, 4- trimetvl- 1, 2, 3, 4- tetrahydro^ kinolin- 6- yll- 3, 5- diklorbenzamid (a) . A/- riacetyl- 57- dimethoxy- 4-( 4- methoxyphenyl)- 2, 2, 4- trimethyl- 1, 2, 3, 4- tetrahydro^ quinolin- 6- yl- 3, 5- dichlorobenzamide
I henhold til generell prosedyre C, ble forbindelsen beskrevet i eksempel 1e (800 mg) acylert med 3,5-diklorbenzoylklorid (460 mg) og DMA (768 ul) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/volum) som elueringsmidlet. According to General Procedure C, the compound described in Example 1e (800 mg) was acylated with 3,5-dichlorobenzoyl chloride (460 mg) and DMA (768 µl) in CH 2 Cl 2 (10 mL). The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.
Utbytte: 1,03g Yield: 1.03g
(b) . A/- ri- acetvl- 5- hvdroksv- 7- metoksv- 4-( 4- metoksv- fenvl)- 2. 2. 4- trimetvl- 1. 2. 3. 4-tetrahvdro- kinolin- 6- vn- 3, 5- diklor- benzamid (b) . A/- ri- acetvl- 5- hydroxy- 7- methoxy- 4-( 4- methoxy- phenyl)- 2. 2. 4- trimethyl- 1. 2. 3. 4- tetrahydro- quinolin- 6- vn- 3 , 5-dichlorobenzamide
I henhold til generell prosedyre D, ble forbindelsen beskrevet i eksempel 6a (50 mg) behandlet med bortribromid (24 ul) i CH2CI2(4 ml). Tittelforbindelsen ble renset ved preparativ HPLC. (metode A). According to general procedure D, the compound described in Example 6a (50 mg) was treated with boron tribromide (24 µl) in CH 2 Cl 2 (4 mL). The title compound was purified by preparative HPLC. (method A).
Utbytte: 9,6 mg; MS-ESI: [M+H]<+>= 557,2; HPLC: Rt = 23,40 min (metode 2). Yield: 9.6 mg; MS-ESI: [M+H]<+>= 557.2; HPLC: Rt = 23.40 min (method 2).
Eksempel 7 Example 7
5- klor- tiofen- 2- karboksvlsvre H- acetvl- 5- hvdroksv- 7- metoksv- 4-( 4- metoksv- fenvl)-2, 2, 4- trimetvl- 1. 2, 3, 4- tetrahvdro- kinolin- 6- vn- amid 5- chloro- thiophene- 2- carboxylic acid H- acetyl- 5- hydroxy- 7- methoxy- 4-( 4- methoxy- phenyl)-2, 2, 4- trimethyl- 1. 2, 3, 4- tetrahydroquinoline - 6-vn-amide
(a) . 5- klortiofen- 2- karboksvlsyre f1- acetvl- 5, 7- dimetoksv- 4-( 4- metoksvfenyl)- 2, 2, 4-trimetvl- 1, 2, 3, 4- tetrahydrokinolin- 6- vn- amid (a) . 5- chlorothiophene- 2- carboxylic acid f1- acetvl- 5, 7- dimethoxysv- 4-( 4- methoxysvphenyl)- 2, 2, 4- trimethylvl- 1, 2, 3, 4- tetrahydroquinoline- 6- vn- amide
I henhold til generell prosedyre B, ble forbindelsen beskrevet i eksempel 1e (800 mg) acylert med 5-klortiofen-2-karboksylsyre (456 mg), DMA (768 ul) og HATU (1,1 g) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/volum) som elueringsmidlet. According to General Procedure B, the compound described in Example 1e (800 mg) was acylated with 5-chlorothiophene-2-carboxylic acid (456 mg), DMA (768 µl) and HATU (1.1 g) in CH 2 Cl 2 (10 mL) . The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.
Utbytte: 1,0 g Yield: 1.0 g
(b) . 5- klor- tiofen- 2- karboksvlsyre ri- acetvl- 5- hvdroksv- 7- metoksv- 4-( 4- metoksv-fenvl)- 2, 2, 4- trimetvl- 1, 2, 3, 4- tetrahydro- kinolin- 6- vn- amid (b) . 5- chloro- thiophene- 2- carboxylic acid ria- acetyl- 5- hydroxy- 7- methoxy- 4-( 4- methoxy- phenyl)- 2, 2, 4- trimethyl- 1, 2, 3, 4- tetrahydro- quinoline - 6-vn-amide
I henhold til generell prosedyre D, ble forbindelsen beskrevet i eksempel 7a (200 mg) behandlet med bortribromid (350 pl) i CH2CI2(25 ml) men i dette tilfellet temperaturen ble ikke tillatt å overstige -30°C. Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/ volum) som elueringsmidlet, fulgt av preparativ HPLC (metode A). According to general procedure D, the compound described in Example 7a (200 mg) was treated with boron tribromide (350 µl) in CH 2 Cl 2 (25 ml) but in this case the temperature was not allowed to exceed -30°C. The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent, followed by preparative HPLC (method A).
Utbytte: 35 mg; MS-ESI: [M+H]<+>= 529,2; HPLC: Rt = 28,24 min (metode 2). Yield: 35 mg; MS-ESI: [M+H]<+>= 529.2; HPLC: Rt = 28.24 min (method 2).
Eksempel 8 Example 8
Bifenvl- 4- karboksvlsvre ri- acetvl- 5- hvdroksv- 7- metoksv- 4-( 4- metoksv- fenvl)- 2, 2, 4-trimetvl- 1, 2, 3, 4- tetrahydro- kinolin- 6- vn- amid Biphenyl- 4- carboxylic acid ria- acetyl- 5- hydroxy- 7- methoxy- 4-( 4- methoxy- phenyl)- 2, 2, 4-trimethyl- 1, 2, 3, 4- tetrahydro- quinoline- 6- ven - amide
I henhold til generell prosedyre D, ble forbindelsen beskrevet i eksempel 4 (50 mg) behandlet med bortribromid (100 ul) i CH2CI2(4 ml) men i dette tilfellet ble temperaturen ikke tillatt å overstige 0°C. Reaksjonsblandingen inneholder også produktet beskrevet i eksempel 10. Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/volum) som elueringsmidlet. According to general procedure D, the compound described in Example 4 (50 mg) was treated with boron tribromide (100 µl) in CH 2 Cl 2 (4 mL) but in this case the temperature was not allowed to exceed 0°C. The reaction mixture also contains the product described in Example 10. The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.
Utbytte: 43 mg; MS-ESI: [M+H]<+>= 565,4; HPLC: Rt = 32,53 min (metode 2). Yield: 43 mg; MS-ESI: [M+H]<+>= 565.4; HPLC: Rt = 32.53 min (method 2).
Eksempel 9 Example 9
Bifenyl- 4- karboksvlsyre H- acetvl- 5, 7- dihvdroksv- 4-( 4- hvdroksv- fenvl)- 2, 2, 4- trimetvl- 1, 2, 3, 4- tetrahydro- kinolin- 6- vn- amid Biphenyl- 4- carboxylic acid H- acetvl- 5, 7- dihydroxv- 4-( 4- hydroxy- phenyl)- 2, 2, 4- trimethyl- 1, 2, 3, 4- tetrahydro- quinolin- 6- vn- amide
I henhold til generell prosedyre D, ble forbindelsen beskrevet i eksempel 4 (50 mg) behandlet med bortribromid (100 pl) i CH2CI2(4 ml) men i dette tilfellet fikk temperaturen nå 15°C. Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/volum) som elueringsmidlet. Utbytte: 33 mg; MS-ESI: [M+H]<+>= 537,4; HPLC: Rt = 24,16 min (metode 2). According to general procedure D, the compound described in Example 4 (50 mg) was treated with boron tribromide (100 µl) in CH 2 Cl 2 (4 ml) but in this case the temperature reached 15°C. The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent. Yield: 33 mg; MS-ESI: [M+H]<+>= 537.4; HPLC: Rt = 24.16 min (method 2).
Eksempel 10 Example 10
Bifenvl- 4- karboksvlsvre H- acetvl- 5- hvdroksv- 4-( 4- hvdroksv- fenvl)- 7- metoksv-2, 2, 4- trimetvl- 1, 2, 3, 4- tetrahydro- kinolin- 6- vn- amid Biphenyl- 4- carboxylic acid H- acetyl- 5- hydroxy- 4-( 4- hydroxy- phenyl)- 7- methoxy- 2, 2, 4- trimethyl- 1, 2, 3, 4- tetrahydro- quinoline- 6- vn - amide
I henhold til generell prosedyre D, ble forbindelsen beskrevet i eksempel 4 (400 mg) behandlet med bortribromid (800 ul) i CH2CI2(25 ml) men i dette tilfellet temperaturen ble ikke tillatt å overstige 0°C. Tittelforbindelsen (= et biprodukt som beskrevet i eksempel 8) ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/volum) som elueringsmidlet. According to general procedure D, the compound described in Example 4 (400 mg) was treated with boron tribromide (800 µl) in CH 2 Cl 2 (25 ml) but in this case the temperature was not allowed to exceed 0°C. The title compound (= a by-product as described in Example 8) was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.
Utbytte: 50 mg; MS-ESI: [M+H]<+>= 551,4; HPLC: Rt = 27,58 min (metode 2). Yield: 50 mg; MS-ESI: [M+H]<+>= 551.4; HPLC: Rt = 27.58 min (method 2).
Eksempel 11 Example 11
4, 5- dimetyl- furan- 2- karboksvlsvre f1- acetvl- 5- hvdroksv- 7- metoksv- 4-( 4- metoksv-fenvl)- 2, 2, 4- trimetvl- 1, 2, 3, 4- tetrahvdro- kinolin- 6- vl1- amid 4, 5- dimethyl- furan- 2- carboxylic acid f1- acetyl- 5- hydroxy- 7- methoxy- 4-( 4- methoxy- phenyl)- 2, 2, 4- trimethyl- 1, 2, 3, 4- tetrahydro - quinoline-6-vl1-amide
I henhold til generell prosedyre D, ble forbindelsen beskrevet i eksempel 2 (200 mg) behandlet med bortribromid (336 ul) i CH2CI2(25 ml) men i dette tilfellet temperaturen ble holdt ved -78°C. Tittelforbindelsen ble renset ved preparativ HPLC (metode A). According to general procedure D, the compound described in Example 2 (200 mg) was treated with boron tribromide (336 µl) in CH 2 Cl 2 (25 mL) but in this case the temperature was maintained at -78°C. The title compound was purified by preparative HPLC (Method A).
Utbytte: 51 mg; MS-ESI: [M+H]<+>= 507,4; HPLC: Rt = 24,32 min (metode 1). Yield: 51 mg; MS-ESI: [M+H]<+>= 507.4; HPLC: Rt = 24.32 min (method 1).
Eksempel 12 Example 12
A/- ri- acetyl- 5- hvdroksy- 4-( 4- hvdroksy- fenyl)- 7- metoksy- 2, 2, 4- trimetyl- 1, 2, 3, 4-tetrahydro- kinolin- 6- vn- 3, 5- diklor- benzamid A/- ri- acetyl- 5- hydroxy- 4-( 4- hydroxy- phenyl)- 7- methoxy- 2, 2, 4- trimethyl- 1, 2, 3, 4-tetrahydro- quinoline- 6- vn- 3 , 5-dichlorobenzamide
I henhold til generell prosedyre D, ble forbindelsen beskrevet i eksempel 6a (75 mg) behandlet med bortribromid (38 ul) i CH2CI2(5 ml). Tittelforbindelsen ble renset ved preparativ HPLC (metode A). According to general procedure D, the compound described in Example 6a (75 mg) was treated with boron tribromide (38 µl) in CH 2 Cl 2 (5 mL). The title compound was purified by preparative HPLC (Method A).
Utbytte: 11 mg; MS-ESI: [M+H]<+>= 543,4; HPLC: Rt = 25,66 min (metode 2). Yield: 11 mg; MS-ESI: [M+H]<+>= 543.4; HPLC: Rt = 25.66 min (method 2).
Eksempel 13 Example 13
A/- ri- acetvl- 5- hvdroksv- 7- metoksv- 4-( 4- metoksv- fenyl)- 2, 2, 4- trimetvl- 1, 2, 3, 4- tetrahydro- kinolin- 6- vn- 3, 5- dimetyl- benzamid A/- ri- acetvl- 5- hydroxy- 7- methoxy- 4-( 4- methoxy- phenyl)- 2, 2, 4- trimethyl- 1, 2, 3, 4- tetrahydro- quinoline- 6- vn- 3 , 5-dimethylbenzamide
(a) . A/- ri- acetvl- 5, 7- dimetoksv- 4-( 4- metoksvfenyl)- 2, 2, 4- trimetvl- 1, 2, 3, 4- tetrahvdrokinolin- 6- vn- 3, 5- dimetvl- benzamid (a) . A/- ri- acetvl- 5, 7- dimethoxysv- 4-( 4- methoxysvphenyl)- 2, 2, 4- trimethvl- 1, 2, 3, 4- tetrahydroquinoline- 6- vn- 3, 5- dimethylbenzamide
I henhold til generell prosedyre B, ble forbindelsen beskrevet i eksempel 1e (800 mg), acylert med 3,5-dimetylbenzosyre (330 mg), DMA (768 ul) og HATU (1,1 g) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/volum) som elueringsmidlet. Utbytte: 1,18 g According to General Procedure B, the compound described in Example 1e (800 mg) was acylated with 3,5-dimethylbenzoic acid (330 mg), DMA (768 µl) and HATU (1.1 g) in CH 2 Cl 2 (10 mL). The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent. Yield: 1.18 g
(b) . A/- ri- acetvl- 5- hvdroksv- 7- metoksv- 4-( 4- metoksv- fenyl)- 2, 2, 4- trimetvl- 1, 2, 3, 4-tetrahvdro- kinolin- 6- vn- 3, 5- dimetvl- benzamid (b) . A/- ri- acetvl- 5- hydroxy- 7- methoxy- 4-( 4- methoxy- phenyl)- 2, 2, 4- trimethyl- 1, 2, 3, 4-tetrahydro- quinoline- 6- vn- 3 , 5-dimethylbenzamide
I henhold til generell prosedyre D, ble forbindelsen beskrevet i eksempel 13a (300 mg) behandlet med bortribromid (513 pl) i CH2CI2(25 ml), men i dette tilfellet ble temperaturen ikke tillatt å overstige -40°C. Tittelforbindelsen ble renset ved preparativ HPLC (metode A). According to general procedure D, the compound described in Example 13a (300 mg) was treated with boron tribromide (513 µl) in CH 2 Cl 2 (25 mL), but in this case the temperature was not allowed to exceed -40°C. The title compound was purified by preparative HPLC (Method A).
Utbytte: 41 mg; MS-ESI: [M+H]<+>= 517,4; HPLC: Rt = 13,89 min (metode 3). Yield: 41 mg; MS-ESI: [M+H]<+>= 517.4; HPLC: Rt = 13.89 min (method 3).
Eksempel 14 Example 14
A/- ri- acetvl- 5- hvdroksv- 7- metoksv- 4-( 4- metoksv- fenvl)- 2. 2. 4- trimetvl- 1. 2. 3. 4- tetrahydro- kinolin- 6- vn- 3, 5- dibrom- benzamid A/- ri- acetvl- 5- hydroxy- 7- methoxy- 4-( 4- methoxy- phenyl)- 2. 2. 4- trimethyl- 1. 2. 3. 4- tetrahydro- quinoline- 6- vn- 3 , 5-dibromobenzamide
(a) . A/- ri- acetvl- 5, 7- dimetoksv- 4-( 4- metoksvfenvl)- 2, 2, 4- trimetvl- 1. 2, 3, 4- tetrahydrokinolin- 6- vn- 3, 5- dibrombenzamid (a) . A/- Riacetvl- 5, 7- dimethoxysv- 4-( 4- methoxysvphenyl)- 2, 2, 4- trimethyl- 1, 2, 3, 4- tetrahydroquinoline- 6- vn- 3, 5- dibromobenzamide
I henhold til generell prosedyre B, ble forbindelsen beskrevet i eksempel 1e (800 mg), acylert med 3,5-dibrombenzosyre (616 mg), DMA (768 ul) og HATU (1,1 g) i DMF (10 ml). Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/volum) som elueringsmidlet. Utbytte: 900 mg According to General Procedure B, the compound described in Example 1e (800 mg) was acylated with 3,5-dibromobenzoic acid (616 mg), DMA (768 µl) and HATU (1.1 g) in DMF (10 mL). The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent. Yield: 900 mg
(b) . A/- ri- acetvl- 5- hvdroksv- 7- metoksv- 4-( 4- metoksv- fenvl)- 2, 2, 4- trimetvl- 1, 2, 3, 4-tetrahydro- kinolin- 6- vn- 3, 5- dibrom- benzamid (b) . A/- riacetyl- 5- hydroxy- 7- methoxy- 4-( 4- methoxy- phenyl)- 2, 2, 4- trimethyl- 1, 2, 3, 4-tetrahydro- quinoline- 6- vn- 3 , 5-dibromobenzamide
I henhold til generell prosedyre D, ble forbindelsen beskrevet i eksempel 14a (300 mg) behandlet med bortribromid (639 pl) i CH2CI2(25 ml), men i dette tilfellet ble ikke temperaturen tillatt å overstige -60°C. Tittelforbindelsen ble renset ved preparativ HPLC (metode B). According to general procedure D, the compound described in Example 14a (300 mg) was treated with boron tribromide (639 µl) in CH 2 Cl 2 (25 mL), but in this case the temperature was not allowed to exceed -60°C. The title compound was purified by preparative HPLC (Method B).
Utbytte: 28 mg; MS-ESI: [M+H]<+>= 647,2; HPLC: Rt = 16,29 min (metode 3). Yield: 28 mg; MS-ESI: [M+H]<+>= 647.2; HPLC: Rt = 16.29 min (method 3).
Eksempel 15 Example 15
Bifenvl- 4- karboksvlsvre ri- acetvl- 2, 2, 4- trimetvl- 7-( 2- morfolin- 4- vl- etoksv)- 4- fenvl-1, 2, 3, 4- tetrahydro- kinolin- 6- yn- amid Biphenyl- 4- carboxylic acid triacetyl- 2, 2, 4- trimethyl- 7-( 2- morpholine- 4- ethoxy)- 4- phenyl- 1, 2, 3, 4- tetrahydro- quinolin- 6- yne - amide
(a). 1 - Fmoc- 2- metoksv- 4- nitroanilin (a). 1 - Fmoc- 2- methoxy- 4- nitroaniline
En løsning av 2-metoksy-4-nitroanilin (3,0 g) og pyridin (1,6 ml) i THF (30 ml) ble avkjølt til 0°C. FmocCI (5,07 g) ble tilsatt i porsjoner og etter fullstendig tilsetning ble is-badet fjernet og blandingen ble omrørt i 5 timer. THF ble fjernet in vakuum og residuet oppløst i CH2CI2(175 ml). Metanol (ca 100 ml) ble tilsatt og CH2CI2-en ble delvis fjernet in vakuum inntil et presipitat ble dannet. Blandingen fikk stå i 1 time, etter denne tiden ble krystallene samlet opp ved filtrering og tørket in vakuum, for å gi tittelforbindelsen. A solution of 2-methoxy-4-nitroaniline (3.0 g) and pyridine (1.6 mL) in THF (30 mL) was cooled to 0 °C. FmocCl (5.07 g) was added in portions and after complete addition the ice bath was removed and the mixture was stirred for 5 hours. The THF was removed in vacuo and the residue dissolved in CH 2 Cl 2 (175 ml). Methanol (ca. 100 mL) was added and the CH 2 Cl 2 was partially removed in vacuo until a precipitate formed. The mixture was allowed to stand for 1 hour, after which time the crystals were collected by filtration and dried in vacuo to give the title compound.
Utbytte: 6,32 g; MS-ESI: [M+H]<+>= 391,2 Yield: 6.32 g; MS-ESI: [M+H]<+>= 391.2
(b) . 9- fluorenvlmetvl A/-( 2- metoksv- 4- aminofenyl) karbamat (b) . 9- Fluorenylmethyl A/-(2-Methox-4-aminophenyl) Carbamate
Generell prosedyre E: En blanding av forbindelsen beskrevet i eksempel 15a (6,07 g), eddiksyre (8,9 ml) og THF (150 ml) ble avkjølt til 0°C. Sinkstøv (20,4 g) ble tilsatt i porsjoner og isbadet ble fjernet. Etter at temperaturen langsomt nådde 10°C steg den raskt til 45°C. Etter at reaksjonsblandingen fikk avkjøles ned til romtemperatur, ble overskuddet av sink fjernet ved filtrering og en stor mengde CH2CI2(ca 500 ml) ble tilsatt. Blandingen ble vasket med mettet vandig NaHC03(3*200ml) og saltvann (1 *200 ml). Det organiske laget ble separert, tørket (MgS04), filtrert og konsentrert in vakuum inntil et presipitat dannet. Blandingen fikk stå natten over ved 0°C, etter hvilken tid krystallene ble samlet opp ved filtrering og tørket in vakuum, for å gi tittelforbindelsen. General Procedure E: A mixture of the compound described in Example 15a (6.07 g), acetic acid (8.9 mL) and THF (150 mL) was cooled to 0°C. Zinc dust (20.4 g) was added in portions and the ice bath was removed. After the temperature slowly reached 10°C, it quickly rose to 45°C. After the reaction mixture was allowed to cool to room temperature, the excess zinc was removed by filtration and a large amount of CH 2 Cl 2 (about 500 ml) was added. The mixture was washed with saturated aqueous NaHCO 3 (3*200ml) and brine (1*200ml). The organic layer was separated, dried (MgSO 4 ), filtered and concentrated in vacuo until a precipitate formed. The mixture was allowed to stand overnight at 0°C, after which time the crystals were collected by filtration and dried in vacuo to give the title compound.
Utbytte: 4,45 g. Yield: 4.45 g.
(c) . ( 7- metoksv- 2, 2, 4- trimetvl- 1, 2- dihvdrokinolin- 6- vl)- karbaminsvre 9/-/- fluoren- 9-ylmetylester (c) . (7-Methox-2,2,4-trimethyl-1,2-dihydroquinolin-6-yl)-carbamic acid 9/-/-fluoren-9-yl methyl ester
En blanding av forbindelsen beskrevet i eksempel 15b (4,45 g), l2(157 mg), MgS04(7,4 g), 4-ferf-butylkatekol (61 mg) og aceton (ca 350 ml) ble varmet opp ved tilbakeløp i 5 timer. MgSCvble fjernet ved filtrering og filtratet ble konsentrert in vakuum. Tittelforbindelsen ble oppnådd ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 9/1 => 7/3 (volum/volum) som elueringsmidlet. Utbytte: 4,24 g. A mixture of the compound described in Example 15b (4.45 g), 12 (157 mg), MgSO 4 (7.4 g), 4- tert -butylcatechol (61 mg) and acetone (ca. 350 ml) was heated at reflux for 5 hours. MgSCv was removed by filtration and the filtrate was concentrated in vacuo. The title compound was obtained by chromatography on silica gel using heptane/ethyl acetate = 9/1 => 7/3 (v/v) as the eluent. Yield: 4.24 g.
(d) . ( 1- acetvl- 7- metoksv- 2, 2, 4- trimetvl- 1, 2- dihvdrokinolin- 6- vl)- karbaminsvre 9H-fluoren- 9- ylmetylester (d) . (1- acetvl- 7- methoxyvl- 2, 2, 4- trimethylvl- 1, 2- dihydroquinoline- 6- vl)- carbamic acid 9H-fluoren- 9- yl methyl ester
Til en løsning av forbindelsen beskrevet i eksempel 15c (4,24 g) i pyridin (25 ml) og CH2CI2(25 ml) ble det tilsatt en liten mengde DMAP (ca 20 mg). Acetylklorid (2,0 ml) i CH2CI2(20 ml) ble langsomt tilsatt. Etter fullstendig tilsetning ble blandingen fortynnet med CH2CI2(ca 100 ml) og vasket med vann (3*100 ml), 0,1 M vandig HCI (3*100 ml), 0,5 M vandig HCI (1*100 ml) og saltvann (1*100 ml). Det organiske laget ble tørket (MgSCv) og konsentrert in vakuum. Tittelforbindelsen ble oppnådd ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 9/1 => 7/3 (volum/volum) som elueringsmidlet. To a solution of the compound described in Example 15c (4.24 g) in pyridine (25 ml) and CH 2 Cl 2 (25 ml) was added a small amount of DMAP (about 20 mg). Acetyl chloride (2.0 mL) in CH 2 Cl 2 (20 mL) was slowly added. After complete addition, the mixture was diluted with CH2Cl2 (ca. 100 mL) and washed with water (3*100 mL), 0.1 M aqueous HCl (3*100 mL), 0.5 M aqueous HCl (1*100 mL) and saline (1*100 ml). The organic layer was dried (MgSO4) and concentrated in vacuo. The title compound was obtained by chromatography on silica gel using heptane/ethyl acetate = 9/1 => 7/3 (v/v) as the eluent.
Utbytte: 3,91 g. Yield: 3.91 g.
(e) . 1- acetvl- 6- amino- 7- metoksv- 2, 2, 4- trimetvl- 1, 2- dihvdrokinolin Piperidin (8,0 ml) ble satt til en løsning av forbindelsen beskrevet i eksempel 15d (3,91 g) i CH2CI2(80 ml). Etter 1,5 timer, ble reaksjonsblandingen konsentrert in vakuum og tittelforbindelsen ble oppnådd ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 9/1 => 7/3 (volum/volum) som elueringsmidlet. Utbytte: 2,2 g (f) . Bifenyl- 4- karboksvlsyre ( 1- acetvl- 7- metoksv- 2, 2, 4- trimetvl- 1, 2- dihydrokinolin- 6-vl)- amid Generell prosedyre F: Til en blanding av forbindelsen beskrevet i eksempel 15e (2,2 g), toluen (45 ml) og pyridin (5 ml) ble det tilsatt 4-bifenylkarbonylklorid (2,21 g). Hvis reaksjonen ikke nådde fullførelse etter 3 timer ved romtemperatur, ble en ytterligere porsjon av 4-bifenylkarbonylklorid (2,0 g) tilsatt. Omrøring ble fortsatt i 30 min, etter som reaksjonsblandingen ble konsentrert in vakuum. Residuet ble tatt opp i etylacetat (ca 100 ml) og vasket med mettet vandig NaHC03(100 ml), 1 M vandig HCI (3*100 ml) og saltvann (100 ml). Det organiske laget ble tørket (MgS04) og konsentrert in vakuum. Til residuet ble det tilsatt CH2CI2(ca 50 ml) og faststoffene ble fjernet ved filtrering og kastet. Filtratet ble konsentrert in vakuum og tittelforbindelsen ble oppnådd ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 1/1 (volum/volum) som elueringsmidlet. (e) . 1-acetyl-6-amino-7-methoxy-2,2,4-trimethyl-1,2-dihydroquinoline Piperidine (8.0 ml) was added to a solution of the compound described in Example 15d (3.91 g) in CH 2 Cl 2 (80 mL). After 1.5 hours, the reaction mixture was concentrated in vacuo and the title compound was obtained by chromatography on silica gel using heptane/ethyl acetate = 9/1 => 7/3 (v/v) as the eluent. Yield: 2.2 g (f) . Biphenyl-4-carboxylic acid (1-acetyl-7-methoxy-2,2,4-trimethyl-1,2-dihydroquinolin-6-yl)-amide General procedure F: To a mixture of the compound described in Example 15e (2, 2 g), toluene (45 ml) and pyridine (5 ml) was added 4-biphenylcarbonyl chloride (2.21 g). If the reaction did not reach completion after 3 hours at room temperature, an additional portion of 4-biphenylcarbonyl chloride (2.0 g) was added. Stirring was continued for 30 min, after which the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (ca. 100 ml) and washed with saturated aqueous NaHCO 3 (100 ml), 1 M aqueous HCl (3*100 ml) and brine (100 ml). The organic layer was dried (MgSO 4 ) and concentrated in vacuo. CH2Cl2 (about 50 ml) was added to the residue and the solids were removed by filtration and discarded. The filtrate was concentrated in vacuo and the title compound was obtained by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 1/1 (vol/vol) as the eluent.
Utbytte: 3,1 g. Yield: 3.1 g.
(g) . Bifenvl- 4- karboksvlsvre ( 1- acetvl- 7- hvdroksv- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3, 4-tetrahydrokinolin- 6- yl)- amid (g) . Biphenyl-4-carboxylic acid (1-acetyl-7-hydroxy-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-amide
Generell prosedyre G: Til en løsning av forbindelsen beskrevet i eksempel 15f (3,1 g) i benzen (100 ml) ble det tilsatt aluminiumtriklorid (5,6 g) og reaksjonsblandingen ble omrørt i 20 timer ved romtemperatur. Reaksjonen ble stanset med H20 (ca 100 ml) og pH i blandingen ble regulert til pH 8 med 2 M vandig NaOH under kraftig omrøring. Etylacetat (ca 300 ml) ble tilsatt og det organiske laget ble vasket med H20 (2*150 ml) og saltvann (1*150 ml), tørket (MgS04) og konsentrert in vakuum, for å gi produktet som ble anvendt uten ytterligere rensning. General Procedure G: To a solution of the compound described in Example 15f (3.1 g) in benzene (100 ml) was added aluminum trichloride (5.6 g) and the reaction mixture was stirred for 20 hours at room temperature. The reaction was quenched with H 2 O (about 100 ml) and the pH of the mixture was adjusted to pH 8 with 2 M aqueous NaOH under vigorous stirring. Ethyl acetate (ca. 300 mL) was added and the organic layer was washed with H 2 O (2 x 150 mL) and brine (1 x 150 mL), dried (MgSO 4 ) and concentrated in vacuo to give the product which was used without further purification .
Utbytte: 3,5 g. Yield: 3.5 g.
(h). Bifenyl- 4- karboksvlsyre [ 1- acetvl- 2, 2, 4- trimetvl- 7-( 2- morfolin- 4- vl- etoksv)- 4-fenvl- 1, 2, 3, 4- tetrahydro- kinolin- 6- vn- amid (h). Biphenyl- 4- carboxylic acid [ 1- acetyl- 2, 2, 4- trimethyl- 7-( 2- morpholine- 4- v- ethoxy)- 4- phenyl- 1, 2, 3, 4- tetrahydro- quinoline- 6- vn-amide
Generell prosedyre H: En blanding av forbindelsen beskrevet i eksempel 15 g (70 mg), A/-(2-kloretyl)-morfolin hydroklorid (31 mg), Cs2C03og DMF (3 ml) ble omrørt ved 50°C, inntil intet utgangsmateriale var tilbake. Reaksjonsblandingen ble fortynnet med etylacetat (15 ml) og vann ble tilsatt (ca 15 ml). Det organiske laget ble vasket med vann (3*15 ml), separert, tørket (MgSCu), filtrert og konsentrert in vakuum. Tittelforbindelsen ble oppnådd som det tilsvarende HCI saltet ved lyofilisering fra en blanding av 1,4-dioksan og H20 inneholdende HCI. General Procedure H: A mixture of the compound described in Example 15 g (70 mg), N-(2-chloroethyl)-morpholine hydrochloride (31 mg), Cs 2 CO 3 and DMF (3 ml) was stirred at 50°C, until no starting material was back. The reaction mixture was diluted with ethyl acetate (15 mL) and water was added (about 15 mL). The organic layer was washed with water (3*15 ml), separated, dried (MgScu), filtered and concentrated in vacuo. The title compound was obtained as the corresponding HCl salt by lyophilization from a mixture of 1,4-dioxane and H 2 O containing HCl.
Utbytte: 63 mg (HCI salt); MS-ESI: [M+H]<+>= 618,6; HPLC: Rt = 19,49 min (metode 4) . Yield: 63 mg (HCl salt); MS-ESI: [M+H]<+>= 618.6; HPLC: Rt = 19.49 min (method 4).
Eksempel 16 Example 16
Bifenvl- 4- karboksvlsvre ( 1- acetvl- 7- dimetvlkarbamovlmetoksv- 2, 2, 4- trimetvl- 4-fenyl- 1, 2, 3, 4- tetrahvdro- kinolin- 6- yl)- amid Biphenyl-4-carboxylic acid (1-acetyl-7-dimethylcarbamoylmethoxy-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-amide
I henhold til generell prosedyre H, ble forbindelsen beskrevet i eksempel 15g (79 mg) alkylert med 2-klor-/V,A/-dimetylacetamid (23 mg) og Cs2C03(255 mg) i DMF (2 ml). Tittelforbindelsen ble renset ved krystallisering fra CH3CN. According to General Procedure H, the compound described in Example 15g (79 mg) was alkylated with 2-chloro-[V,N]-dimethylacetamide (23 mg) and Cs 2 CO 3 (255 mg) in DMF (2 mL). The title compound was purified by crystallization from CH 3 CN.
Utbytte: 15 mg; MS-ESI: [M+H]<+>= 590,6; HPLC: Rt = 23,58 min (metode 5). Yield: 15 mg; MS-ESI: [M+H]<+>= 590.6; HPLC: Rt = 23.58 min (method 5).
Eksempel 17 Example 17
Bifenvl- 4- karboksvlsvre H - acetvl- 2, 2, 4- trimetvl- 4- fenvl- 7-( 3- piperidin- 1 - vl- pro-poksv)- 1. 2. 3. 4- tetrahvdro- kinolin- 6- vll- amid Biphenyl- 4- carboxylic acid H - acetyl- 2, 2, 4- trimethyl- 4- phenyl- 7-( 3- piperidine- 1 - yl- propoxy)- 1. 2. 3. 4- tetrahydroquinoline- 6 - vll-amide
I henhold til generell prosedyre H, ble forbindelsen beskrevet i eksempel 15g (79 mg) alkylert med A/-(3-klorpropyl)piperidin hydroklorid (37,4 mg) og Cs2C03(255 mg) i DMF (2 ml). Tittelforbindelsen ble renset ved krystallisering fra CH3CN. Utbytte: 83 mg (HCI salt); MS-ESI: [M+H]<+>= 630,8; HPLC: Rt = 15,49 min (metode 5) . According to General Procedure H, the compound described in Example 15g (79 mg) was alkylated with N-(3-chloropropyl)piperidine hydrochloride (37.4 mg) and Cs 2 CO 3 (255 mg) in DMF (2 mL). The title compound was purified by crystallization from CH 3 CN. Yield: 83 mg (HCl salt); MS-ESI: [M+H]<+>= 630.8; HPLC: Rt = 15.49 min (method 5).
Eksempel 18 Example 18
Bifenyl- 4- karboksvlsyre H- acetvl- 2, 2, 4- trimetvl- 4- fenvl- 7-( pyridin- 2- vlmetoksv)-1, 2, 3, 4- tetrahydro- kinolin- 6- yn- amid Biphenyl- 4- carboxylic acid H- acetvl- 2, 2, 4- trimethyl- 4- phenyl- 7-( pyridine- 2- vylmethoxy)-1, 2, 3, 4- tetrahydro- quinolin- 6- yn- amide
I henhold til generell prosedyre H, ble forbindelsen beskrevet i eksempel 15g (79 mg) alkylert med 2-pikolylklorid hydroklorid (31 mg) og Cs2C03(255 mg) i DMF (2 ml). Tittelforbindelsen ble renset ved krystallisering fra CH3CN. According to General Procedure H, the compound described in Example 15g (79 mg) was alkylated with 2-picolyl chloride hydrochloride (31 mg) and Cs 2 CO 3 (255 mg) in DMF (2 mL). The title compound was purified by crystallization from CH 3 CN.
Utbytte: 32 mg (HCI salt); MS-ESI: [M+H]<+>= 596,6; HPLC: Rt = 22,41 min (metode 6). Yield: 32 mg (HCl salt); MS-ESI: [M+H]<+>= 596.6; HPLC: Rt = 22.41 min (method 6).
Eksempel 19 Example 19
Bifenyl- 4- karboksylsyre H- acetyl- 2, 2, 4- trimetyl- 4- fenvl- 7-( pvridin- 3- ylmetoksy)-1, 2, 3, 4- tetrahydro- kinolin- 6- vn- amid Biphenyl- 4- carboxylic acid H- acetyl- 2, 2, 4- trimethyl- 4- phenyl- 7-( pvridin- 3-ylmethoxy)-1, 2, 3, 4- tetrahydro- quinolin- 6- vn- amide
I henhold til generell prosedyre H, ble forbindelsen beskrevet i eksempel 15g (79 mg) alkylert med 3-pikolylklorid hydroklorid (31 mg) og Cs2C03(255 mg) i DMF (2 ml). Tittelforbindelsen ble renset ved krystallisering fra CH3CN. According to General Procedure H, the compound described in Example 15g (79 mg) was alkylated with 3-picolyl chloride hydrochloride (31 mg) and Cs 2 CO 3 (255 mg) in DMF (2 mL). The title compound was purified by crystallization from CH 3 CN.
Utbytte: 36 mg (HCI salt); MS-ESI: [M+H]<+>= 596,6; HPLC: Rt = 19,70 min (metode 6). Yield: 36 mg (HCl salt); MS-ESI: [M+H]<+>= 596.6; HPLC: Rt = 19.70 min (method 6).
Eksempel 20 Example 20
Bifenyl- 4- karboksvlsyre H- acetvl- 2, 2, 4- trimetvl- 4- fenvl- 7-( pvridin- 4- vlmetoksv)-1, 2, 3, 4- tetrahydro- kinolin- 6- vn- amid Biphenyl- 4- carboxylic acid H- acetvl- 2, 2, 4- trimethyl- 4- phenyl- 7-( pvridin- 4- vylmethoxy)-1, 2, 3, 4- tetrahydro- quinolin- 6- vn- amide
I henhold til generell prosedyre H, ble forbindelsen beskrevet i eksempel 15g (79 mg) alkylert med 4-pikolylklorid hydroklorid (31 mg) og Cs2C03(255 mg) i DMF (2 ml). Tittelforbindelsen ble renset ved krystallisering fra CH3CN According to General Procedure H, the compound described in Example 15g (79 mg) was alkylated with 4-picolyl chloride hydrochloride (31 mg) and Cs 2 CO 3 (255 mg) in DMF (2 mL). The title compound was purified by crystallization from CH 3 CN
Utbytte: 31 mg (HCI salt); MS-ESI: [M+H]<+>= 596,4; HPLC: Rt = 17,09 min (metode 6). Yield: 31 mg (HCl salt); MS-ESI: [M+H]<+>= 596.4; HPLC: Rt = 17.09 min (method 6).
Eksempel 21 Example 21
Bifenyl- 4- karboksvlsvre ri- acetvl- 7-( 2- dimetvlamino- etoksv)- 2, 2, 4- trimetvl- 4- fenyl-1. 2, 3, 4- tetrahvdro- kinolin- 6- vn- amid Biphenyl- 4- carboxylic acid ria- acetyl- 7-(2- dimethylamino- ethoxy)- 2, 2, 4- trimethyl- 4- phenyl-1. 2, 3, 4-tetrahydroquinoline-6-vn-amide
I henhold til generell prosedyre H, ble forbindelsen beskrevet i eksempel 15g (79 mg) alkylert med 2-dimetylaminoetylklorid hydroklorid (27 mg) og Cs2C03(255 mg) i DMF (2 ml). Tittelforbindelsen ble renset ved krystallisering fra CH3CN. Utbytte: 55 mg (HCI salt); MS-ESI: [M+H]<+>= 576,6; HPLC: Rt = 14,94 min (metode 5). According to General Procedure H, the compound described in Example 15g (79 mg) was alkylated with 2-dimethylaminoethyl chloride hydrochloride (27 mg) and Cs 2 CO 3 (255 mg) in DMF (2 mL). The title compound was purified by crystallization from CH 3 CN. Yield: 55 mg (HCl salt); MS-ESI: [M+H]<+>= 576.6; HPLC: Rt = 14.94 min (method 5).
Eksempel 22 Example 22
Bifenyl- 4- karboksvlsyre ( 1- acetvl- 7- karbamovlmetoksv- 2, 2, 4- trimetvl- 4- fenyl-1. 2, 3, 4- tetrahvdro- kinolin- 6- vl)- amid Biphenyl- 4- carboxylic acid (1- acetvl- 7- carbamovlmethoxv- 2, 2, 4- trimethyl- 4- phenyl-1. 2, 3, 4- tetrahydroquinolin- 6- vl)- amide
I henhold til generell prosedyre H, ble forbindelsen beskrevet i eksempel 15g (79 mg) alkylert med 2-kloracetamid (18 mg) og Cs2C03(255 mg) i DMF (2 ml). Tittelforbindelsen ble renset ved preparativ HPLC (metode A). According to General Procedure H, the compound described in Example 15g (79 mg) was alkylated with 2-chloroacetamide (18 mg) and Cs 2 CO 3 (255 mg) in DMF (2 mL). The title compound was purified by preparative HPLC (Method A).
Utbytte: 60,2 mg; MS-ESI: [M+H]<+>= 562,4; HPLC: Rt = 20,47 min (metode 5). Yield: 60.2 mg; MS-ESI: [M+H]<+>= 562.4; HPLC: Rt = 20.47 min (method 5).
Eksempel 23 Example 23
Morfolin- 4- karboksvlsyre ( 3-{ 1- acetvl- 6-[( bifenvl- 4- karbonyl)- aminol- 2, 2, 4- trimetvl-4- fenvl- 1, 2, 3, 4- tetrahvdro- kinolin- 7- vloksv)- propvl)- amid Morpholine- 4- carboxylic acid ( 3-{ 1- acetyl- 6-[(biphenyl- 4- carbonyl)- aminol- 2, 2, 4- trimethyl-4- phenyl- 1, 2, 3, 4- tetrahydroquinoline- 7-cyclohexyl)-propyl)-amide
I henhold til generell prosedyre H, ble forbindelsen beskrevet i eksempel 15g (79 mg) alkylert med morfolin-4-karboksylsyre (3-klorpropyl)amid (40 mg) og Cs2C03(255 mg) i DMF (2 ml). Tittelforbindelsen ble renset ved preparativ HPLC (metode According to General Procedure H, the compound described in Example 15g (79 mg) was alkylated with morpholine-4-carboxylic acid (3-chloropropyl)amide (40 mg) and Cs 2 CO 3 (255 mg) in DMF (2 mL). The title compound was purified by preparative HPLC (method
A). A).
Utbytte: 52,4 mg; MS-ESI: [M+H]<+>= 675,6; HPLC: Rt = 22,31 min (metode 5). Yield: 52.4 mg; MS-ESI: [M+H]<+>= 675.6; HPLC: Rt = 22.31 min (method 5).
Eksempel 24 Example 24
Furan- 2- karboksvlsvre 1- acetvl- 6-( 3, 5- dibrom- benzovlamino)- 2, 2, 4- trimetvl- 4-fenvl- 1, 2, 3. 4- tetrahvdro- kinolin- 7- vlester Furan- 2- carboxylic acid 1- acetyl- 6-( 3, 5- dibromo- benzoylamino)- 2, 2, 4- trimethyl- 4- phenyl- 1, 2, 3. 4- tetrahydroquinoline- 7- ester
(a). A/-( 1- acetyl- 7- metoksy- 2, 2, 4- trimetyl- 1, 2- dihydrokinolin- 6- yl)- 3, 5- dibrom-benzamid (a). A/-(1- acetyl- 7- methoxy- 2, 2, 4- trimethyl- 1, 2- dihydroquinolin- 6- yl)- 3, 5- dibromo-benzamide
I henhold til generell prosedyre F, ble forbindelsen beskrevet i eksempel 15e (1,0 According to General Procedure F, the compound described in Example 15e (1.0
g) acylert med 3,5-dibrombenzoylklorid (1,72 g) i toluen (9 ml) og pyridin (1 ml). Tittelforbindelsen ble oppnådd ved kromatografi på silikagel ved anvendelse av g) acylated with 3,5-dibromobenzoyl chloride (1.72 g) in toluene (9 ml) and pyridine (1 ml). The title compound was obtained by chromatography on silica gel using
heptan/etylacetat = 8/2 (volum/volum) som elueringsmidlet. heptane/ethyl acetate = 8/2 (v/v) as the eluent.
Utbytte: 1,3g Yield: 1.3g
(b) . / V-( 1- acetvl- 7- hvdroksv- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3, 4- tetrahvdrokinolin- 6- vl)-3. 5- dibrom- benzamid (b) . /V-(1-acetvl-7-hydroxyl-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline-6-vl)-3. 5-dibromobenzamide
I henhold til generell prosedyre G, ble forbindelsen beskrevet i eksempel 24a (1,3 g) omrørt med AICI3(1,0 g) i benzen (50 ml). Det oppnådde produktet ble anvendt uten ytterligere rensning. According to General Procedure G, the compound described in Example 24a (1.3 g) was stirred with AlCl 3 (1.0 g) in benzene (50 mL). The product obtained was used without further purification.
Utbytte: 1,39 g Yield: 1.39 g
(c) . Furan- 2- karboksvlsvre 1- acetvl- 6-( 3, 5- dibrom- benzovlamino)- 2, 2, 4- trimetvl- 4-fenyl- 1, 2, 3, 4- tetrahvdro- kinolin- 7- ylester (c) . Furan- 2- carboxylic acid 1- acetyl- 6-(3, 5- dibromo- benzoylamino)- 2, 2, 4- trimethyl- 4-phenyl- 1, 2, 3, 4- tetrahydroquinolin- 7- yl ester
En blanding av forbindelsen beskrevet i eksempel 24b (100 mg), furoylklorid (16 ul) og DIPEA (60 ul) og CH2CI2(5 ml) ble omrørt ved romtemperatur inntil intet utgangsmateriale var tilbake. Vann ble tilsatt og det organiske laget ble separert, vasket med saltvann, tørket (MgSCu) og konsentrert in vakuum. Tittelforbindelsen ble renset ved preparativ HPLC (metode A). A mixture of the compound described in Example 24b (100 mg), furoyl chloride (16 µl) and DIPEA (60 µl) and CH 2 Cl 2 (5 mL) was stirred at room temperature until no starting material remained. Water was added and the organic layer was separated, washed with brine, dried (MgScu) and concentrated in vacuo. The title compound was purified by preparative HPLC (Method A).
Utbytte: 47 mg; MS-ESI: [M+H]<+>= 681,2; HPLC: Rt = 31,6 min (metode 2). Yield: 47 mg; MS-ESI: [M+H]<+>= 681.2; HPLC: Rt = 31.6 min (method 2).
Eksempel 25 Example 25
A/-[ 1- acetvl- 7-( 2- amino- etoksv)- 2, 2, 4- trimetvl- 4- fenyl- 1, 2, 3, 4- tetrahvdro- kinolin- 6-vn- 3, 5- dibrom- benzamid A/-[ 1- acetvl- 7-( 2- amino- ethoxy)- 2, 2, 4- trimethvl- 4- phenyl- 1, 2, 3, 4- tetrahydroquinoline- 6-vn- 3, 5- dibromobenzamide
Generell prosedyre I: En blanding av forbindelsen beskrevet i eksempel 24b (100 mg), fert-butyl /V-(2-hydroksyetyl)karbamat (29 mg), DtBAD (79 mg), DIPEA (60 ul) og et overskudd av polymerbundet trifenylfosfin i CH2CI2(5 ml) ble omrørt ved romtemperatur inntil intet utgangsmateriale var tilbake. Reaksjonsblandingen ble filtrert og vasket med vann og saltvann. Det organiske laget ble separert, tørket (MgSCvi) og konsentrert in vakuum. Råproduktet ble tatt opp i CH3CN (ca 1 ml) og noen få dråper TFA ble tilsatt for å forenkle spalting av fert-butylkarbamatet. Tittelforbindelsen ble renset ved preparativ HPLC (metode A). General Procedure I: A mixture of the compound described in Example 24b (100 mg), tert-butyl N-(2-hydroxyethyl)carbamate (29 mg), DtBAD (79 mg), DIPEA (60 µl) and an excess of polymer bound triphenylphosphine in CH 2 Cl 2 (5 mL) was stirred at room temperature until no starting material remained. The reaction mixture was filtered and washed with water and brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The crude product was taken up in CH 3 CN (ca. 1 mL) and a few drops of TFA were added to facilitate cleavage of the tert-butyl carbamate. The title compound was purified by preparative HPLC (Method A).
Utbytte: 17 mg (TFA salt); MS-ESI: [M+H]<+>= 630,2; HPLC: Rt = 15,6 min (metode 2). Yield: 17 mg (TFA salt); MS-ESI: [M+H]<+>= 630.2; HPLC: Rt = 15.6 min (method 2).
Eksempel 26 Example 26
{ 2- ri- acetvl- 6-( 3, 5- dimetvl- benzovlamino)- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3, 4- tetrahvdro^ kinolin- 7- vloksvl- etyl)- karbaminsyre- tert- butylester { 2- triacetyl- 6-( 3, 5- dimethyl- benzoylamino)- 2, 2, 4- trimethyl- 4- phenyl- 1, 2, 3, 4- tetrahydro^ quinoline- 7- chloro- ethyl)- carbamic acid tert-butyl ester
(a) . A/-( 1- acetvl- 7- metoksv- 2, 2, 4- trimetvl- 1, 2- dihvdrokinolin- 6- vl)- 3, 5- dimetvl-benzamid (a) . A/-( 1- Acetyl- 7- methoxy- 2, 2, 4- trimethyl- 1, 2- dihydroquinoline- 6- yl)- 3, 5- dimethylbenzamide
I henhold til generell prosedyre F, ble forbindelsen beskrevet i eksempel 15e (1,0 According to General Procedure F, the compound described in Example 15e (1.0
g) acylert med 3,5-dimetylbenzoylklorid (0,97 g) i toluen (9 ml) og pyridin (1 ml). Tittelforbindelsen ble oppnådd ved kromatografi på silikagel ved anvendelse av g) acylated with 3,5-dimethylbenzoyl chloride (0.97 g) in toluene (9 ml) and pyridine (1 ml). The title compound was obtained by chromatography on silica gel using
heptan/etylacetat = 8/2 (volum/volum) som elueringsmidlet. heptane/ethyl acetate = 8/2 (v/v) as the eluent.
Utbytte: 1,1 g Yield: 1.1 g
(b) . A/-( 1- acetvl- 7- hvdroksv- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3, 4- tetrahvdrokinolin- 6- vl)-3, 5- dimetylbenzamid (b) . A/-( 1- Acetyl- 7- Hydroxyl- 2, 2, 4- Trimethyl- 4- Phenyl- 1, 2, 3, 4- Tetrahydroquinoline- 6-yl)-3, 5- Dimethylbenzamide
I henhold til generell prosedyre G, ble forbindelsen beskrevet i eksempel 26a (1,1 g) omrørt med AICI3(1,0 g) i benzen (50 ml). Det oppnådde produktet ble anvendt uten ytterligere rensning. According to General Procedure G, the compound described in Example 26a (1.1 g) was stirred with AlCl 3 (1.0 g) in benzene (50 mL). The product obtained was used without further purification.
Utbytte: 1,3 g Yield: 1.3 g
(c) . { 2- ri- acetvl- 6-( 3, 5- dimetvl- benzovlamino)- 2, 2, 4- trimetvl- 4- fenyl- 1, 2, 3, 4- tetrahvdro- kinolin- 7- vloksv1- etvl)- karbaminsvre- tert- butylester (c) . { 2- ri- acetvl- 6-( 3, 5- dimethyl- benzovlamino)- 2, 2, 4- trimethyl- 4- phenyl- 1, 2, 3, 4- tetrahdro- quinolin- 7- loxivl- ethvl)- carbamine tert-butyl ester
I henhold til generell prosedyre I, ble forbindelsen beskrevet i eksempel 26b (100 mg) alkylert med ferf-butyl A/-(2-hydroksyetyl)karbamat (37 mg), DtBAD (101 mg), DIPEA (77 ul) og et overskudd av polymerbundet trifenylfosfin i CH2CI2(5 ml). I dette tilfellet ble tert-butylkarbamatet ikke spaltet, hvilket gir tittelproduktet etter preparativ HPLC (metode A) og lyofilisering. According to general procedure I, the compound described in Example 26b (100 mg) was alkylated with tert-butyl N -(2-hydroxyethyl)carbamate (37 mg), DtBAD (101 mg), DIPEA (77 µl) and an excess of polymer-bound triphenylphosphine in CH2Cl2 (5 ml). In this case, the tert-butyl carbamate was not cleaved, giving the title product after preparative HPLC (Method A) and lyophilization.
Utbytte: 38 mg; MS-ESI: [M+H]<+>= 600,4; HPLC: Rt = 33,1 min (metode 2). Yield: 38 mg; MS-ESI: [M+H]<+>= 600.4; HPLC: Rt = 33.1 min (method 2).
Eksempel 27 Example 27
/ V-[ 1- acetvl- 7-( furan- 2- vlmetoksv)- 2, 2, 4- trimetvl- 4- fenyl- 1, 2, 3, 4- tetrahvdrokinolin- 6-vl1- 3. 5- dimetvl- benzamid / V-[ 1- acetvl- 7-(furan- 2- vlmethoxy)- 2, 2, 4- trimethylvl- 4- phenyl- 1, 2, 3, 4- tetrahydroquinoline- 6-vl1- 3. 5- dimethylvl- benzamide
I henhold til generell prosedyre I, ble forbindelsen beskrevet i eksempel 26b (100 mg) alkylert med 2-(hydroksymetyl)furan (21 pl), DtBAD (101 mg), DIPEA (77 pl) og et overskudd av polymer bundet trifenylfosfin i CH2CI2(5 ml). Tittelproduktet ble renset ved preparativ HPLC (metode A), fulgt av lyofilisering. According to general procedure I, the compound described in Example 26b (100 mg) was alkylated with 2-(hydroxymethyl)furan (21 µl), DtBAD (101 mg), DIPEA (77 µl) and an excess of polymer bound triphenylphosphine in CH 2 Cl 2 (5 ml). The title product was purified by preparative HPLC (Method A), followed by lyophilization.
Utbytte: 16 mg; MS-ESI: [M+H]<+>= 537,4; HPLC: Rt = 32,8 min (metode 2). Yield: 16 mg; MS-ESI: [M+H]<+>= 537.4; HPLC: Rt = 32.8 min (method 2).
Eksempel 28 Example 28
A/- ri- acetvl- 2, 2, 4- trimetvl- 4- fenvl- 7-( pvridin- 4- vlmetoksv)- 1, 2, 3, 4- tetrahvdrokinolin-6- vn- 3, 5- diklor- benzamid A/- riacetyl- 2, 2, 4- trimethyl- 4- phenyl- 7-( pvridin- 4- vylmethoxy)- 1, 2, 3, 4- tetrahydroquinoline-6- n- 3, 5- dichloro- benzamide
(a) . A/-( 1- acetvl- 7- metoksv- 2. 2. 4- trimetvl- 1. 2- dihvdrokinolin- 6- vl)- 3. 5- diklorbenzamid (a) . A/-( 1- acetvl- 7- methoxysv- 2. 2. 4- trimethylvl- 1. 2- dihydroquinoline- 6- vl)- 3. 5- dichlorobenzamide
I henhold til generell prosedyre F, ble forbindelsen beskrevet i eksempel 15e (1,0 According to General Procedure F, the compound described in Example 15e (1.0
g) acylert med 3,5-diklorbenzoylklorid (1,2 g) i toluen (9 ml) og pyridin (1 ml). Tittelforbindelsen ble oppnådd ved kromatografi på silikagel ved anvendelse av g) acylated with 3,5-dichlorobenzoyl chloride (1.2 g) in toluene (9 ml) and pyridine (1 ml). The title compound was obtained by chromatography on silica gel using
heptan/etylacetat = 8/2 (volum/volum) som elueringsmidlet. heptane/ethyl acetate = 8/2 (v/v) as the eluent.
Utbytte: 1,47 g Yield: 1.47 g
(b) . A/-( 1- acetvl- 7- hvdroksv- 2. 2. 4- trimetvl- 4- fenvl- 1. 2. 3. 4- tetrahvdrokinolin- 6- vl)-3, 5- diklorbenzamid (b) . A/-( 1- Acetyl- 7- Hydroxyl- 2. 2. 4- Trimethyl- 4- Phenyl- 1. 2. 3. 4- Tetrahydroquinoline- 6-yl)-3, 5- Dichlorobenzamide
I henhold til generell prosedyre G, ble forbindelsen beskrevet i eksempel 28a (1,47 g) omrørt med AICI3(1,5 g) i benzen (75 ml). Det oppnådde produktet ble anvendt uten ytterligere rensning. According to General Procedure G, the compound described in Example 28a (1.47 g) was stirred with AlCl 3 (1.5 g) in benzene (75 mL). The product obtained was used without further purification.
Utbytte: 1,51 g Yield: 1.51 g
(c) . A/- ri- acetvl- 2, 2, 4- trimetvl- 4- fenvl- 7-( pvridin- 4- vlmetoksv)- 1, 2, 3, 4- tetrahydrokinolin- 6- vn- 3, 5- diklor- benzamid (c) . A/- triacetyl- 2, 2, 4- trimethyl- 4- phenyl- 7-( pvridin- 4- vylmethoxy)- 1, 2, 3, 4- tetrahydroquinoline- 6- n- 3, 5- dichloro- benzamide
I henhold til generell prosedyre H, ble forbindelsen beskrevet i eksempel 28b (100 mg) alkylert med 4-pikolylklorid hydroklorid (36 mg) og Cs2C03(255 mg) i en blanding av DMF (1 ml) og CH2CI2(4 ml). Tittelforbindelse ble oppnådd som det tilsvarende TFA salt etter preparativ HPLC (metode A), fulgt av lyofilisering. Utbytte: 35 mg (TFA salt); MS-ESI: [M+H]<+>= 588,4; HPLC: Rt = 18,0 min (metode 2). According to General Procedure H, the compound described in Example 28b (100 mg) was alkylated with 4-picolyl chloride hydrochloride (36 mg) and Cs 2 CO 3 (255 mg) in a mixture of DMF (1 mL) and CH 2 Cl 2 (4 mL). Title compound was obtained as the corresponding TFA salt by preparative HPLC (method A), followed by lyophilization. Yield: 35 mg (TFA salt); MS-ESI: [M+H]<+>= 588.4; HPLC: Rt = 18.0 min (method 2).
Eksempel 29 Example 29
/ V- H - acetvl- 2, 2, 4- trimetvl- 4- fenvl- 7-( 2- pyrrolidin- 1 - vl- etoksv)- 1, 2, 3. 4- tetrahvdrokinolin- 6- yll- 3, 5- dimetyl- benzamid / V- H - acetvl- 2, 2, 4- trimethyl- 4- phenyl- 7-( 2- pyrrolidine- 1 - v- ethoxy)- 1, 2, 3. 4- tetrahydroquinoline- 6- yl- 3, 5 - dimethylbenzamide
Generell prosedyre J: En blanding av forbindelsen beskrevet i eksempel 26b (100 mg), 2-kloretylpyrrolidin hydroklorid (41 mg) og DIPEA (77 ul) i CH2CI2(5 ml) ble omrørt ved romtemperatur inntil intet mer utgangsmateriale var tilbake. Vann ble tilsatt og det organiske laget ble separert, vasket med saltvann, tørket (MgSCv) og konsentrert in vakuum. Rensning ved hjelp av preparativ HPLC, fulgt av lyofilisering ga tittelforbindelsen som det tilsvarende TFA salt. General Procedure J: A mixture of the compound described in Example 26b (100 mg), 2-chloroethylpyrrolidine hydrochloride (41 mg) and DIPEA (77 µl) in CH 2 Cl 2 (5 mL) was stirred at room temperature until no more starting material remained. Water was added and the organic layer was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by preparative HPLC, followed by lyophilization gave the title compound as the corresponding TFA salt.
Utbytte: 104 mg (TFA salt); MS-ESI: [M+H]<+>= 554,4; HPLC: Rt = 15,2 min (metode 2). Yield: 104 mg (TFA salt); MS-ESI: [M+H]<+>= 554.4; HPLC: Rt = 15.2 min (method 2).
Eksempel 30 Example 30
A/- ri- acetvl- 2. 2. 4- trimetvl- 7-( 5- metvl- isoksazol- 3- vlmetoksv)- 4- fenvl- 1. 2. 3. 4- tetrahvdro- kinolin- 6- vn- 3, 5- dimetvl- benzamid A/- ri- acetvl- 2. 2. 4- trimethyl- 7-( 5- methyl- isoxazol- 3- vlmethoxy)- 4- phenvl- 1. 2. 3. 4- tetrahydro- quinolin- 6- vn- 3 , 5-dimethylbenzamide
I henhold til generell prosedyre J, ble forbindelsen beskrevet i eksempel 26b (100 mg) alkylert med (klormetyl)-5-metylisooksazol (32 mg) og DIPEA (77 ul) i CH2CI2(5 ml). Rensning ved hjelp av preparativ HPLC (metode A), fulgt av lyofilisering ga tittelforbindelsen. According to General Procedure J, the compound described in Example 26b (100 mg) was alkylated with (chloromethyl)-5-methylisoxazole (32 mg) and DIPEA (77 µl) in CH 2 Cl 2 (5 mL). Purification by preparative HPLC (Method A), followed by lyophilization gave the title compound.
Utbytte: 41 mg; MS-ESI: [M+H]<+>= 552,4; HPLC: Rt = 31,3 min (metode 2). Yield: 41 mg; MS-ESI: [M+H]<+>= 552.4; HPLC: Rt = 31.3 min (method 2).
Eksempel 31 Example 31
A/- ri- acetvl- 7-( 2- dietvlamino- etoksv)- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3, 4- tetrahvdro- kinolin- 6- vl1- 3, 5- dimetvl- benzamid; forbindelse med trifluor- eddiksyre I henhold til generell prosedyre J, ble forbindelsen beskrevet i eksempel 26b (100 mg) alkylert med A/,/V-dietylaminoetylklorid hydroklorid (42 mg) og DIPEA (77 ul) i CH2CI2(5 ml). Rensning ved hjelp av preparativ HPLC (metode A), fulgt av lyofilisering ga tittelforbindelsen som dens tilsvarende TFA salt. A/-riacetyl-7-(2- diethylamino- ethoxy)- 2, 2, 4- trimethyl- 4- phenyl- 1, 2, 3, 4- tetrahydroquinoline- 6- yl1- 3, 5- dimethyl - benzamide; compound with trifluoroacetic acid According to general procedure J, the compound described in Example 26b (100 mg) was alkylated with A/,/V-diethylaminoethyl chloride hydrochloride (42 mg) and DIPEA (77 µl) in CH 2 Cl 2 (5 mL). Purification by preparative HPLC (Method A), followed by lyophilization gave the title compound as its corresponding TFA salt.
Utbytte: 43 mg (TFA salt); MS-ESI: [M+H]<+>= 556,4; HPLC: Rt = 15,2 min (metode 2). Yield: 43 mg (TFA salt); MS-ESI: [M+H]<+>= 556.4; HPLC: Rt = 15.2 min (method 2).
Eksempel 32 Example 32
A/-[ 1- acetvl- 2, 2, 4- trimetvl- 4- fenvl- 7-( pvridin- 4- vlmetoksv)- 1, 2, 3, 4- tetrahydro- kinolin-6- vn- 5- brom- 2- metylamino- benzamid A/-[ 1- acetvl- 2, 2, 4- trimethyl- 4- phenyl- 7-( pvridin- 4- vylmethoxy)- 1, 2, 3, 4- tetrahydro- quinoline-6- vn- 5- bromo- 2-methylaminobenzamide
(a). A/-( 1- acetvl- 7- metoksv- 2, 2, 4- trimetvl- 1, 2- dihvdrokinolin- 6- vl)- 5- brom- 2- metvl-amino- benzamid (a). A/-(1-acetyl-7-methoxy-2,2,4-trimethyl-1,2-dihydroquinoline-6-yl)-5-bromo-2- methylaminobenzamide
I henhold til generell prosedyre F, ble forbindelsen beskrevet i eksempel 15e (1,0 According to General Procedure F, the compound described in Example 15e (1.0
g) acylert med 5-brom-2-metylamino-benzoylklorid (1,43 g) i toluen (9 ml) og pyri din (1 ml). Tittelforbindelsen ble oppnådd ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 8/2 (volum/volum) som elueringsmidlet. g) acylated with 5-bromo-2-methylamino-benzoyl chloride (1.43 g) in toluene (9 ml) and pyridine (1 ml). The title compound was obtained by chromatography on silica gel using heptane/ethyl acetate = 8/2 (v/v) as the eluent.
Utbytte: 595 mg Yield: 595 mg
(b) . A/-( 1- acetvl- 7- hvdroksv- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3, 4- tetrahvdrokinolin- 6- vl)- 5-brom- 2- metvlamino- benzamid (b) . A/-( 1- Acetyl- 7- Hydroxyl- 2, 2, 4- Trimethyl- 4- Phenyl- 1, 2, 3, 4- Tetrahydroquinoline- 6-yl)- 5- Bromo- 2- Methylamino- benzamide
I henhold til generell prosedyre G, ble forbindelsen beskrevet i eksempel 32a (595 mg) omrørt med AICI3(0,75 g) i benzen (50 ml). Det oppnådde produktet ble anvendt uten ytterligere rensning. According to General Procedure G, the compound described in Example 32a (595 mg) was stirred with AlCl 3 (0.75 g) in benzene (50 mL). The product obtained was used without further purification.
Utbytte: 437 mg Yield: 437 mg
(c) . A/- ri- acetvl- 2, 2, 4- trimetvl- 4- fenvl- 7-( pvridin- 4- vlmetoksv)- 1, 2, 3, 4- tetrahydrokinolin- 6- vn- 5- brom- 2- metylamino- benzamid (c) . A/- triacetyl- 2, 2, 4- trimethyl- 4- phenyl- 7-( pvridin- 4- vylmethoxy)- 1, 2, 3, 4- tetrahydroquinoline- 6- n- 5- bromo- 2- methylamino - benzamide
I henhold til generell prosedyre H, ble forbindelsen beskrevet i eksempel 32b (44 mg) alkylert med 4-pikolylklorid hydroklorid (15 mg) og CS2CO3(ca 100 mg) i en blanding av DMF (1 ml) og CH2CI2(4 ml). Tittelforbindelsen ble oppnådd som det tilsvarende TFA salt etter preparativ HPLC (metode B). According to General Procedure H, the compound described in Example 32b (44 mg) was alkylated with 4-picolyl chloride hydrochloride (15 mg) and CS 2 CO 3 (ca. 100 mg) in a mixture of DMF (1 mL) and CH 2 Cl 2 (4 mL). The title compound was obtained as the corresponding TFA salt by preparative HPLC (method B).
Utbytte: 18 mg (TFA salt); MS-ESI: [M+H]<+>= 629,4; HPLC: Rt = 18,1 min (metode 2). Yield: 18 mg (TFA salt); MS-ESI: [M+H]<+>= 629.4; HPLC: Rt = 18.1 min (method 2).
Eksempel 33 Example 33
Furan- 2- karboksylsyre ( 1- acetyl- 7- dimetylamino- 2, 2, 4- trimetyl- 4- fenyl- 1, 2, 3, 4-tetrahvdro- kinolin- 6- vl)- amid (a). ( 2, 2, 4- trimetvl- 1, 2- dihvdrokinolin- 6- vl)- karbaminsvre- tert- butylester En blanding av A/-Boc-1,4-fenylendiamin (75 g), MgSCv(216 g), 4-ferf-butylkatekol (1,8 g) og jod (4,7 g) i vannfritt aceton (600 ml) ble tilbakeløpskokt i 20 timer. MgS04ble fjernet ved filtrering og filtratet ble konsentrert in vakuum. Residuet ble kromatografert på en kort plugg av silikagel ved anvendelse av heptan/etylacetat = 8/2 (volum/volum) som elueringsmidlet, for å gi produktet som en brun olje. Utbytte: 41 g. (b) . ( 1- acetvl- 2, 2, 4- trimetvl- 1, 2- dihvdro^ En løsning av forbindelsen beskrevet i eksempel 33a (41 g) i pyridin (200 ml) og CH2CI2(200 ml) ble avkjølt til 0°C. Acetylklorid (21 ml) i CH2CI2(50 ml) ble tilsatt dråpevis. Etter fullstendig tilsetning ble blandingen omrørt i 3 timer ved romtemperatur. Etylacetat (2 I) og H20 (2 I) ble tilsatt og det organiske laget ble separert, tørket (MgSCv) og konsentrert in vakuum. Tittelforbindelsen ble oppnådd ved krystallisering fra etylacetat. Furan-2-carboxylic acid (1-acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-vl)-amide (a). ( 2, 2, 4- trimethvl- 1, 2- dihydroquinoline- 6- vl)- carbamine re- tert-butyl ester A mixture of A/-Boc-1,4-phenylenediamine (75 g), MgSCv (216 g), 4 -terf-butylcatechol (1.8 g) and iodine (4.7 g) in anhydrous acetone (600 ml) were refluxed for 20 hours. MgSO 4 was removed by filtration and the filtrate was concentrated in vacuo. The residue was chromatographed on a short plug of silica gel using heptane/ethyl acetate = 8/2 (v/v) as the eluent to give the product as a brown oil. Yield: 41 g. (b) . (1-acetvl-2,2,4-trimethyl-1,2-dihydro^) A solution of the compound described in Example 33a (41 g) in pyridine (200 ml) and CH 2 Cl 2 (200 ml) was cooled to 0°C. Acetyl chloride (21 mL) in CH 2 Cl 2 (50 mL) was added dropwise. After complete addition, the mixture was stirred for 3 h at room temperature. Ethyl acetate (2 L) and H 2 O (2 L) were added and the organic layer was separated, dried (MgSCv ) and concentrated in vacuo The title compound was obtained by crystallization from ethyl acetate.
Utbytte: 23 g. Yield: 23 g.
(c) . 1- acetvl- 6- amino- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3, 4- tetrahvdrokinolin I henhold til generell prosedyre G, ble forbindelsen beskrevet i eksempel 33b (33,3 g) omrørt med AICI3(40,4 g) i benzen (700 ml). Produktet ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 8/2 (volum/volum) som (c) . 1-acetvl-6-amino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline According to general procedure G, the compound described in Example 33b (33.3 g) was stirred with AlCl 3 (40.4 g) in benzene (700 mL). The product was purified by chromatography on silica gel using heptane/ethyl acetate = 8/2 (v/v) as
elueringsmidlet. the eluent.
Utbytte: 22,4 g Yield: 22.4 g
(d) . ( 1- acetvl- 2, 2, 4- trimetvl- 4- fenvl- 1, 2. 3, 4- tetrahvdrokinolin- 6- vl)- karbaminsvre 9-fluorenvlmetvlester (d) . ( 1- Acetyl- 2, 2, 4- Trimethyl- 4- Phenyl- 1, 2. 3, 4- Tetrahydroquinoline- 6- yl)- Carbamic acid 9-Fluorenylmethyl ester
Pyridin (6,4 ml) ble satt til en løsning av forbindelsen beskrevet i eksempel 33c (22,4 g) i THF (300 ml) og den resulterende blandingen ble avkjølt til 0°C. en løs-ning av FmocCI (20,7 g) i THF (100 ml) ble tilsatt dråpevis og etter at tilsetningen var fullstendig ble blandingen omrørt i 1 time ved romtemperatur. Reaksjonsblandingen ble konsentrert in vakuum og etylacetat (800 ml) og 0,3 M vandig HCI (500 ml) ble tilsatt. Det organiske laget ble separert og vasket med 0,3 M HCI (2*500ml), H20 (500 ml) og saltvann (500 ml), fulgt av tørking (MgSCvt) og konsentrasjon in vakuum. Produktet ble anvendt uten ytterligere rensning i det neste trinnet. Utbytte: 43 g Pyridine (6.4 mL) was added to a solution of the compound described in Example 33c (22.4 g) in THF (300 mL) and the resulting mixture was cooled to 0°C. a solution of FmocCl (20.7 g) in THF (100 ml) was added dropwise and after the addition was complete the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and ethyl acetate (800 mL) and 0.3 M aqueous HCl (500 mL) were added. The organic layer was separated and washed with 0.3 M HCl (2*500 mL), H 2 O (500 mL) and brine (500 mL), followed by drying (MgSO4) and concentration in vacuo. The product was used without further purification in the next step. Yield: 43 g
(e) ( 1- acetvl- 2, 2, 4- trimetvl- 7- nitro- 4- fenyl- 1, 2, 3, 4- tetrahvdrokinolin- 6- vl)- karbaminsvre 9- fluorenvlmetvlester (e) ( 1- Acetyl- 2, 2, 4- Trimethyl- 7- Nitro- 4- Phenyl- 1, 2, 3, 4- Tetrahydroquinoline- 6- yl)- Carbamic acid 9- Fluorenylmethyl ester
Rykende salpetersyre (3,07 ml) ble tilsatt dråpevis over en periode på 10 min til en blanding av forbindelsen beskrevet i eksempel 33d (43 g) og eddiksyre (230 ml) i CH2CI2(230 ml). Reaksjonsblandingen ble omrørt inntil fullstendig omsetning av utgangsmateriale etter hvilken H20 (150 ml) ble tilsatt. Det vandige laget ble sepa rert og ekstrahert med CH2CI2(150 ml). De kombinerte organiske lagene ble vasket med mettet vandig NaHC03(3*200 ml) og saltvann (200 ml), fulgt av tørking over MgS04og filtrering. Metanol (ca 200 ml) ble tilsatt og CH2CI2ble forsiktig fjernet in vakuum, etter dette fikk blandingen stå ved romtemperatur natten over. De klare gule krystallene ble samlet opp ved filtrering og tørket (MgS04) in vakuum. Fuming nitric acid (3.07 mL) was added dropwise over a period of 10 min to a mixture of the compound described in Example 33d (43 g) and acetic acid (230 mL) in CH 2 Cl 2 (230 mL). The reaction mixture was stirred until complete reaction of starting material after which H 2 O (150 mL) was added. The aqueous layer was separated and extracted with CH 2 Cl 2 (150 mL). The combined organic layers were washed with saturated aqueous NaHCO 3 (3*200 mL) and brine (200 mL), followed by drying over MgSO 4 and filtration. Methanol (about 200 ml) was added and the CH 2 Cl 2 was carefully removed in vacuo, after which the mixture was allowed to stand at room temperature overnight. The clear yellow crystals were collected by filtration and dried (MgSO 4 ) in vacuo.
Utbytte: 29,3 g. Yield: 29.3 g.
(f) . ( 1- acetvl- 7- amino- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3, 4- tetrahvdrokinolin- 6- vl)- karbaminsvre 9- fluorenvlmetvlester (f) . ( 1- Acetyl- 7- amino- 2, 2, 4- trimethyl- 4- phenyl- 1, 2, 3, 4- tetrahydroquinoline- 6- yl)- carbamic acid 9- fluoroenyl methyl ester
I henhold til generell prosedyre E, ble forbindelsen beskrevet i eksempel 33e (20 g) redusert ved anvendelse av sinkstøv (45 g) og eddiksyre (20 ml) i THF (ca 600 ml), for å gi produktet som ble anvendt ubearbeidet i det neste trinnet. According to General Procedure E, the compound described in Example 33e (20 g) was reduced using zinc dust (45 g) and acetic acid (20 mL) in THF (ca. 600 mL), to give the product used crudely in the the next step.
Utbytte: 21 g Yield: 21 g
(g) ( 1- acetvl- 7- dimetvlamino- 2, 2, 4- trimetvl- 4- fenyl- 1, 2, 3, 4- tetrahvdrokinolin- 6- vl)-karbaminsvre 9- fluorenvlmetvlester (g) (1-acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)-carbamic acid 9-fluoroenylmethyl ester
En vandig løsning av formaldehyd (37%, 3,8 ml) ble satt til en løsning av forbindelsen beskrevet i eksempel 33f (12 g), eddiksyre (15,7 ml) og natriumcyanoborhydrid (2,9 g) i metanol (200 ml), som ga opphav til en eksoterm reaksjon og dannelsen av et hvitt presipitat. En ytterligere mengde MeOH ble tilsatt for å lette om-røring. Etter omrøring i 15 min, ble utfellingen oppsamlet ved filtrering og vasket med MeOH/H20 = 1/1 (volum/volum). Filtratet ble delvis konsentrert, for å gi mer fast materiale som ble også oppsamlet. De kombinerte faststoffene ble omkrystal-lisert fra C^Cfe/MeOH, for å gi den dimetylerte forbindelse. An aqueous solution of formaldehyde (37%, 3.8 mL) was added to a solution of the compound described in Example 33f (12 g), acetic acid (15.7 mL) and sodium cyanoborohydride (2.9 g) in methanol (200 mL ), which gave rise to an exothermic reaction and the formation of a white precipitate. An additional amount of MeOH was added to facilitate stirring. After stirring for 15 min, the precipitate was collected by filtration and washed with MeOH/H 2 O = 1/1 (v/v). The filtrate was partially concentrated to give more solid material which was also collected. The combined solids were recrystallized from C 2 C 2 Fe/MeOH to give the dimethylated compound.
Utbytte: 9,7 g Yield: 9.7 g
(h) . 1- acetvl- 6- amino- 7- dimetvlamino- 2, 2, 4- trimetvl- 4- fenyl- 1, 2, 3, 4- tetrahvdrokinolin (h) . 1- acetvl- 6- amino- 7- dimethylamino- 2, 2, 4- trimethyl- 4- phenyl- 1, 2, 3, 4- tetrahydroquinoline
Piperidin (7,7 ml) ble satt til en løsning av forbindelsen beskrevet i eksempel 33 g (4,5 g) i CH2CI2(70 ml). Etter 24 timer, ble reaksjonsblandingen fortynnet med CH2CI2(100 ml) og vasket med 0,5 M vandig HCI (2*150 ml), vann (100 ml) og saltvann (1 ml). Det organiske laget ble tørket (MgS04) og fortynnet til et totalt vo lum på 200 ml. Denne stamløsningen av tittelforbindelsen (ca 13,8 mg/ml) ble anvendt for videre reaksjoner. Piperidine (7.7 ml) was added to a solution of the compound described in Example 33 g (4.5 g) in CH 2 Cl 2 (70 ml). After 24 hours, the reaction mixture was diluted with CH 2 Cl 2 (100 mL) and washed with 0.5 M aqueous HCl (2*150 mL), water (100 mL) and brine (1 mL). The organic layer was dried (MgSO 4 ) and diluted to a total volume of 200 ml. This stock solution of the title compound (about 13.8 mg/ml) was used for further reactions.
(i). Furan- 2- karboksvlsvre ( 1 - acetvl- 7- dimetvlamino- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3, 4-tetrahvdro- kinolin- 6- yl)- amid (in). Furan-2-carboxylic acid (1-acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-amide
Trietylamin (38 ul) og 2-furoylklorid (27 ul) ble satt til en løsning av forbindelsen beskrevet i eksempel 33 timer (96,6 mg) i CH2CI2(10 ml) og den resulterende blandingen ble omrørt inntil fullstendig omsetning av utgangsmateriale ble oppnådd. Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/volum) som elueringsmidlet. Triethylamine (38 µl) and 2-furoyl chloride (27 µl) were added to a solution of the compound described in Example 33h (96.6 mg) in CH 2 Cl 2 (10 mL) and the resulting mixture was stirred until complete reaction of starting material was achieved . The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.
Utbytte: 5,5 mg. MS-ESI: [M+H]<+>= 446,2; HPLC: Rt = 19,02 min (metode 2). Yield: 5.5 mg. MS-ESI: [M+H]<+>= 446.2; HPLC: Rt = 19.02 min (method 2).
Eksempel 34 Example 34
5- metvl- tiofen- 2- karboksvlsvre ( 1- acetvl- 7- dimetvlamino- 2, 2, 4- trimetvl- 4- fenvl-1, 2, 3, 4- tetrahydro- kinolin- 6- vl)- amid 5-methyl-thiophene-2-carboxylic acid (1-acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 33h (96,6 mg) acylert med 5-metyltiofen-2-karboksylsyre (39,1 mg), HATU (157 mg) og DIPEA (239 ul) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved preparativ HPLC (metode B). According to General Procedure A, the compound described in Example 33h (96.6 mg) was acylated with 5-methylthiophene-2-carboxylic acid (39.1 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 ml). The title compound was purified by preparative HPLC (Method B).
Utbytte: 35,5 mg; MS-ESI: [M+H]<+>= 476,2; HPLC: Rt = 21,26 min (metode 2). Yield: 35.5 mg; MS-ESI: [M+H]<+>= 476.2; HPLC: Rt = 21.26 min (method 2).
Eksempel 35 Example 35
Bifenvl- 4- karboksvlsvre ( 1- acetvl- 7- dimetvlamino- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3, 4-tetrahydro- kinolin- 6- yl)- amid Biphenyl-4-carboxylic acid (1-acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 33h (96,6 mg) acylert med 4-bifenylkarboksylsyre (54,4 mg), HATU (157 mg) og DIPEA (239 ul) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved preparativ HPLC (metode B). Utbytte: 31,5 mg; MS-ESI: [M+H]<+>= 532,4; HPLC: Rt = 24,92 min (metode 2). According to General Procedure A, the compound described in Example 33h (96.6 mg) was acylated with 4-biphenylcarboxylic acid (54.4 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 mL). The title compound was purified by preparative HPLC (Method B). Yield: 31.5 mg; MS-ESI: [M+H]<+>= 532.4; HPLC: Rt = 24.92 min (method 2).
Eksempel 36 Example 36
A/-( 1- acetvl- 7- dimetvlamino- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3, 4- tetrahvdro- kinolin- 6- vl)-3, 5- dibrom- benzamid A/-(1-acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)-3,5- dibromobenzamide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 33h (96,6 mg) acylert med 3,5-dibrombenzosyre (77 mg), HATU (157 mg) og DIPEA (239 ul) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved krystallisering fra CH2CI2/CH3CN. According to General Procedure A, the compound described in Example 33h (96.6 mg) was acylated with 3,5-dibromobenzoic acid (77 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 mL). The title compound was purified by crystallization from CH 2 Cl 2 /CH 3 CN.
Utbytte: 24,3 mg; MS-ESI: [M+H]<+>= 614,2; HPLC: Rt = 27,71 min (metode 2). Yield: 24.3 mg; MS-ESI: [M+H]<+>= 614.2; HPLC: Rt = 27.71 min (method 2).
Eksempel 37 Example 37
Cvklopentankarboksvlsvre ( 1 - acetvl- 7- dimetvlamino- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3. 4-tetrahydro- kinolin- 6- yl)- amid Cyclopentanecarboxylic acid (1-acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3.4-tetrahydro-quinolin-6-yl)-amide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 33h (137 mg) acylert med cyklopentankarboksylsyre (128 ul), HATU (224 mg) og DIPEA (400 pl) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/volum) som elueringsmidlet. According to General Procedure A, the compound described in Example 33h (137 mg) was acylated with cyclopentanecarboxylic acid (128 µl), HATU (224 mg) and DIPEA (400 µl) in CH 2 Cl 2 (10 mL). The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.
Utbytte: 148 mg; MS-ESI: [M+H]<+>= 448,4; HPLC: Rt = 12,93 min (metode 1). Yield: 148 mg; MS-ESI: [M+H]<+>= 448.4; HPLC: Rt = 12.93 min (method 1).
Eksempel 38 Example 38
A/-( 1- acetyl- 7- dimetvlamino- 2, 2, 4- trimetvl- 4- fenyl- 1, 2, 3, 4- tetrahvdro- kinolin- 6- vl)-isobutvramid A/-(1-acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline-6-vl)-isobutyramide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 33h (137 mg) acylert med isosmørsyre (110 ul), HATU (224 mg) og DIPEA (400 ul) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/volum) som elueringsmidlet. According to General Procedure A, the compound described in Example 33h (137 mg) was acylated with isobutyric acid (110 µl), HATU (224 mg) and DIPEA (400 µl) in CH 2 Cl 2 (10 mL). The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.
Utbytte: 43 mg; MS-ESI: [M+H]<+>= 422,4; HPLC: Rt = 9,99 min (metode 1). Yield: 43 mg; MS-ESI: [M+H]<+>= 422.4; HPLC: Rt = 9.99 min (method 1).
Eksempel 39 Example 39
Furan- 2- karboksvlsvre ( 1- acetvl- 7- furan- 2- vlkarbonvlamino- 2, 2, 4- trimetvl- 4- fenvl-1, 2, 3, 4- tetrahydrokinolin- 6- vl)- amid Furan-2-carboxylic acid (1-acetyl-7- furan-2-ylcarbonylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)-amide
Til løsning av forbindelsen beskrevet i eksempel 33f (150 mg) og trietylamin (43 ul) i CH2CI2(1 ml) ble det tilsatt 2-furoylklorid (30 ul). Etter fullstendig forbruk av utgangsmateriale, ble 1 M vandig HCI tilsatt, det organiske laget ble separert fulgt av tilsetning av piperidin (1 ml) og den resulterende blandingen ble omrørt natten over. Reaksjonsblandingen ble vasket med 1 M vandig HCI, det organiske laget separert, tørket (MgS04) og konsentrert in vakuum. Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 1/0 => 0/1 (volum/volum) som elueringsmidlet, fulgt av preparativ HPLC (metode A). To a solution of the compound described in example 33f (150 mg) and triethylamine (43 ul) in CH 2 Cl 2 (1 ml) 2-furoyl chloride (30 ul) was added. After complete consumption of starting material, 1 M aqueous HCl was added, the organic layer was separated followed by the addition of piperidine (1 mL) and the resulting mixture was stirred overnight. The reaction mixture was washed with 1 M aqueous HCl, the organic layer separated, dried (MgSO 4 ) and concentrated in vacuo. The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent, followed by preparative HPLC (Method A).
Utbytte: 18 mg; MS-ESI: [M+H]<+>= 512,4; HPLC: Rt = 19,92 min (metode 2). Yield: 18 mg; MS-ESI: [M+H]<+>= 512.4; HPLC: Rt = 19.92 min (method 2).
Eksempel 40 Example 40
5- metvl- tiofen- 2- karboksvlsvre ( 1- acetvl- 2, 2, 4- trimetvl- 4- fenvl- 7- propylamino-1, 2, 3, 4- tetrahydro- kinolin- 6- vl)- amid (a) . 1- acetvl- 6- amino- 2, 2, 4- trimetvl- 4- fenvl- 7- propylamino- 1, 2, 3, 4- tetrahvdrokinolin Generell prosedyre K: Til en blanding av forbindelsen beskrevet i eksempel 33f (750 mg), eddiksyre (953 ul), natriumcyanoborhydrid (135 mg) og MeOH (10 ml) ble det tilsatt propionaldehyd (94,2 ul). Blandingen ble omrørt i 18 timer, vann ble tilsatt og utfellingen ble samlet opp ved filtrering. Utfellingen ble tatt opp i CH2CI2(10 ml), piperidin (1 ml) ble tilsatt og den resulterende blandingen ble omrørt i 18 timer. Reaksjonsblandingen ble vasket med 1 M vandig HCI, det organiske laget ble separert og fortynnet til et totalt volum på 50 ml. Denne løsningen ble anvendt for følgende reaksjoner. (b) . 5- metyl- tiofen- 2- karboksvlsyre ( 1- acetyl- 2, 2, 4- trimetvl- 4- fenvl- 7- propylamino-1. 2, 3, 4- tetrahvdro- kinolin- 6- vl)- amid 5-methyl-thiophene-2-carboxylic acid (1-acetyl-2,2,4-trimethyl-4-phenyl-7-propylamino-1,2,3,4-tetrahydro-quinolin-6-yl)-amide (a ). 1- acetvl- 6- amino- 2, 2, 4- trimethyl- 4- phenyl- 7- propylamino- 1, 2, 3, 4- tetrahydroquinoline General procedure K: To a mixture of the compound described in example 33f (750 mg) , acetic acid (953 µl), sodium cyanoborohydride (135 mg) and MeOH (10 mL) was added propionaldehyde (94.2 µl). The mixture was stirred for 18 hours, water was added and the precipitate was collected by filtration. The precipitate was taken up in CH 2 Cl 2 (10 mL), piperidine (1 mL) was added and the resulting mixture was stirred for 18 h. The reaction mixture was washed with 1 M aqueous HCl, the organic layer was separated and diluted to a total volume of 50 mL. This solution was used for the following reactions. (b) . 5- methyl- thiophene- 2- carboxylic acid (1- acetyl- 2, 2, 4- trimethyl- 4- phenyl- 7- propylamino-1. 2, 3, 4- tetrahydroquinolin- 6- yl)- amide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 40a (100 mg) acylert med 5-metyltiofen-2-karboksylsyre (39,1 mg), HATU (157 mg) og DIPEA (239 pl) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved preparativ HPLC og lyofilisert. According to General Procedure A, the compound described in Example 40a (100 mg) was acylated with 5-methylthiophene-2-carboxylic acid (39.1 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 mL) . The title compound was purified by preparative HPLC and lyophilized.
Utbytte: 18,3 mg; MS-ESI: [M+H]<+>= 490,4; HPLC: Rt = 23,96 min (metode 2). Yield: 18.3 mg; MS-ESI: [M+H]<+>= 490.4; HPLC: Rt = 23.96 min (method 2).
Eksempel 41 Example 41
Bifenvl- 4- karboksvlsvre ( 1- acetvl- 7- etvlamino- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3, 4- tetrahydro- kinolin- 6- yl)- amid (a) . 1- acetvl- 6- amino- 7- etvlamino- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3, 4- tetrahvdrokinolin I henhold til generell prosedyre K, ble forbindelsen beskrevet i eksempel 33f (750 mg) alkylert ved anvendelse av acetaldehyd (73,3 ul) og avbeskyttet med piperidin (1 ml), for å gi, etter opparbeiding og fortynning, en løsning av tittelforbindelsen i CH2CI2. (b) . Bifenyl- 4- karboksvlsvre ( 1- acetyl- 7- etvlamino- 2, 2, 4- trimetvl- 4- fenyl- 1, 2, 3, 4-tetrahydro- kinolin- 6- yl)- amid Biphenyl-4-carboxylic acid (1-acetyl-7-ethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide (a). 1- acetvl- 6- amino- 7- ethylamino- 2, 2, 4- trimethyl- 4- phenyl- 1, 2, 3, 4- tetrahydroquinoline According to General Procedure K, the compound described in Example 33f (750 mg) alkylated using acetaldehyde (73.3 µl) and deprotected with piperidine (1 mL), to give, after workup and dilution, a solution of the title compound in CH 2 Cl 2 . (b) . Biphenyl-4-carboxylic acid (1-acetyl-7-ethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 41a (100 mg) acylert med 4-bifenylkarboksylsyre (54,4 mg), HATU (157 mg) og DIPEA (239 ul) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved preparativ HPLC og lyofilisert. According to General Procedure A, the compound described in Example 41a (100 mg) was acylated with 4-biphenylcarboxylic acid (54.4 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 mL). The title compound was purified by preparative HPLC and lyophilized.
Utbytte: 9,8 mg; MS-ESI: [M+H]<+>= 532,4; HPLC: Rt = 25,55 min (metode 2). Yield: 9.8 mg; MS-ESI: [M+H]<+>= 532.4; HPLC: Rt = 25.55 min (method 2).
Eksempel 42 Example 42
5- metyl- tiofen- 2- karboksvlsyre { 1- acetvl- 2, 2, 4- trimetvl- 4- fenvl- 7-[( pyridin- 4-vlmetvl)- amino1- 1, 2, 3, 4- tetrahvdro- kinolin- 6- vl)- amid 5- methyl- thiophene- 2- carboxylic acid { 1- acetvl- 2, 2, 4- trimethyl- 4- phenyl- 7-[( pyridine- 4- vylmethyl)- amino1- 1, 2, 3, 4- tetrahydroquinoline - 6-vl)-amide
(a) . 1- acetvl- 6- amino- 2, 2, 4- trimetvl- 4- fenvl- 7- r( pvridin- 4- vlmetvl)- amino1- 1, 2, 3, 4-tetrahydrokinolin (a) . 1- acetvl- 6- amino- 2, 2, 4- trimethyl- 4- phenyl- 7- r( pvridin- 4- vylmethyl)- amino1- 1, 2, 3, 4-tetrahydroquinoline
I henhold til generell prosedyre K, ble forbindelsen beskrevet i eksempel 33f (750 mg) alkylert ved anvendelse av 4-pyridinkarboksaldehyd (125 ul) og avbeskyttet med piperidin (1 ml), for å gi, etter opparbeiding og fortynning, en løsning av tittelforbindelsen i CH2CI2. According to General Procedure K, the compound described in Example 33f (750 mg) was alkylated using 4-pyridinecarboxaldehyde (125 µl) and deprotected with piperidine (1 mL), to give, after workup and dilution, a solution of the title compound in CH2Cl2.
(b) . 5- metvl- tiofen- 2- karboksvlsvre { 1- acetvl- 2, 2, 4- trimetvl- 4- fenvl- 7- r( pyridin- 4-vlmetvl)- amino1- 1, 2, 3, 4- tetrahvdro- kinolin- 6- vl)- amid (b) . 5- methylthiophene- 2- carboxylic acid { 1- acetyl- 2, 2, 4- trimethyl- 4- phenyl- 7- r( pyridine- 4-ylmethyl)- amino1- 1, 2, 3, 4- tetrahydroquinoline - 6-vl)-amide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 42a (114 mg) acylert med 5-metyltiofen-2-karboksylsyre (39,1 mg), HATU (157 mg) og DIPEA (239 pl) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved preparativ HPLC og lyofilisert. According to General Procedure A, the compound described in Example 42a (114 mg) was acylated with 5-methylthiophene-2-carboxylic acid (39.1 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 mL) . The title compound was purified by preparative HPLC and lyophilized.
Utbytte: 51 mg; MS-ESI: [M+H]<+>= 539,4; HPLC: Rt = 13,19 min (metode 2). Yield: 51 mg; MS-ESI: [M+H]<+>= 539.4; HPLC: Rt = 13.19 min (method 2).
Eksempel 43 Example 43
5- metyl- tiofen- 2- karboksvlsyre { 1- acetvl- 2, 2, 4- trimetvl- 4- fenvl- 7-[( pyridin- 3-vlmetvl)- aminol- 1, 2, 3, 4- tetrahvdro- kinolin- 6- vl)- amid 5- methyl- thiophene- 2- carboxylic acid { 1- acetvl- 2, 2, 4- trimethyl- 4- phenyl- 7-[( pyridine- 3- vylmethyl)- aminol- 1, 2, 3, 4- tetrahydroquinoline - 6-vl)-amide
(a). 1- acetvl- 6- amino- 2, 2, 4- trimetvl- 4- fenvl- 7- r( pyridin- 3- vlmetvl)- amino1- 1, 2, 3, 4-tetrahydrokinolin (a). 1- acetvl- 6- amino- 2, 2, 4- trimethyl- 4- phenyl- 7- r( pyridine- 3- vylmethyl)- amino1- 1, 2, 3, 4-tetrahydroquinoline
I henhold til generell prosedyre K, ble forbindelsen beskrevet i eksempel 33f (750 mg) alkylert ved anvendelse av 3-pyridinkarboksaldehyd (125 og avbeskyttet med piperidin (1 ml), for å gi, etter opparbeiding og fortynning, en løsning av tittelforbindelsen i CH2CI2. According to General Procedure K, the compound described in Example 33f (750 mg) was alkylated using 3-pyridinecarboxaldehyde (125 and deprotected with piperidine (1 mL), to give, after workup and dilution, a solution of the title compound in CH 2 Cl 2 .
(b). 5- metyl- tiofen- 2- karboksvlsvre { 1- acetvl- 2, 2, 4- trimetvl- 4- fenvl- 7-[( pyridin- 3-vlmetyl)- aminol- 1, 2, 3, 4- tetrahydro- kinolin- 6- vl)- amid (b). 5- methyl- thiophene- 2- carboxylic acid { 1- acetyl- 2, 2, 4- trimethyl- 4- phenyl- 7-[( pyridine- 3-ylmethyl)- aminol- 1, 2, 3, 4- tetrahydro- quinoline - 6-vl)-amide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 43a (114 mg) acylert med 5-metyltiofen-2-karboksylsyre (39,1 mg), HATU (157 mg) og DIPEA (239 ul) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved preparativ HPLC og lyofilisert. According to General Procedure A, the compound described in Example 43a (114 mg) was acylated with 5-methylthiophene-2-carboxylic acid (39.1 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 mL) . The title compound was purified by preparative HPLC and lyophilized.
Utbytte: 44 mg; MS-ESI: [M+H]<+>= 539,4; HPLC: Rt = 13,45 min (metode 2). Yield: 44 mg; MS-ESI: [M+H]<+>= 539.4; HPLC: Rt = 13.45 min (method 2).
Eksempel 44 Example 44
A/-( 1- acetvl- 7- isobutvlamino- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3, 4- tetrahvdro- kinolin- 6- vl)-3, 5- dibrom- benzamid A/-(1-acetyl-7-isobutylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)-3,5- dibromobenzamide
(a) . 1- acetvl- 6- amino- 7- isobutvlamino- 2, 2, 4- trimetvl- 4- fenyl- 1, 2, 3, 4- tetrahvdrokinolin (a) . 1- acetvl- 6- amino- 7- isobutylamino- 2, 2, 4- trimethyl- 4- phenyl- 1, 2, 3, 4- tetrahydroquinoline
I henhold til generell prosedyre K, ble forbindelsen beskrevet i eksempel 33f (750 mg) alkylert [med] isobutyraldehyd (119 ul) og avbeskyttet med piperidin (1 ml), for å gi, etter opparbeiding og fortynning, en løsning av tittelforbindelsen i CH2CI2. According to General Procedure K, the compound described in Example 33f (750 mg) was alkylated [with] isobutyraldehyde (119 µl) and deprotected with piperidine (1 mL), to give, after workup and dilution, a solution of the title compound in CH 2 Cl 2 .
(b) . A/-( 1- acetvl- 7- isobutvlamino- 2, 2, 4- trimetvl- 4- fenyl- 1, 2, 3, 4- tetrahvdro- kinolin- 6-yl)- 3, 5- dibrom- benzamid (b) . A/-(1- Acetyl- 7- isobutylamino- 2, 2, 4- trimethyl- 4- phenyl- 1, 2, 3, 4- tetrahydroquinolin- 6-yl)- 3, 5- dibromobenzamide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 44a (114 mg) acylert med 3,5-dibrombenzosyre (77 mg), HATU (157 mg) og DIPEA (239 ul) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved preparativ HPLC og lyofilisert. Utbytte: 54 mg; MS-ESI: [M+H]<+>= 642,4; HPLC: Rt = 29,47 min (metode 2). According to General Procedure A, the compound described in Example 44a (114 mg) was acylated with 3,5-dibromobenzoic acid (77 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 mL). The title compound was purified by preparative HPLC and lyophilized. Yield: 54 mg; MS-ESI: [M+H]<+>= 642.4; HPLC: Rt = 29.47 min (method 2).
Eksempel 45 Example 45
Bifenyl- 4- karboksvlsyre ( 1 - acetvl- 7- benzvlamino- 2, 2, 4- trimetvl- 4- fenyl- 1, 2, 3, 4-tetrahydro- kinolin- 6- yl)- amid Biphenyl-4-carboxylic acid (1-acetyl-7-benzvlamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide
(a) . 1- acetvl- 6- amino- 7- benzvlamino- 2, 2, 4- trimetvl- 4- fenvl- 1, 2, 3, 4- tetrahvdrokinolin I henhold til generell prosedyre K, ble forbindelsen beskrevet i eksempel 33f (750 mg) alkylert ved anvendelse av benzaldehyd (133 ul) og avbeskyttet med piperidin (1 ml), for å gi, etter opparbeiding og fortynning, en løsning av tittelforbindelsen i CH2CI2-(b) . Bifenvl- 4- karboksvlsvre ( 1- acetvl- 7- benzvlamino- 2, 2. 4- trimetvl- 4- fenvl- 1, 2, 3, 4-tetrahydro- kinolin- 6- yl)- amid (a) . 1- acetvl- 6- amino- 7- benzylamino- 2, 2, 4- trimethyl- 4- phenyl- 1, 2, 3, 4- tetrahydroquinoline According to general procedure K, the compound described in Example 33f (750 mg) alkylated using benzaldehyde (133 µl) and deprotected with piperidine (1 mL), to give, after workup and dilution, a solution of the title compound in CH 2 Cl 2 -(b) . Biphenyl-4-carboxylic acid (1-acetyl-7-benzylamino-2,2.4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 45a (113 mg) acylert med 4-bifenylkarboksylsyre (54,4 mg), HATU (157 mg) og DIPEA (239 ul) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved preparativ HPLC og lyofilisert. According to General Procedure A, the compound described in Example 45a (113 mg) was acylated with 4-biphenylcarboxylic acid (54.4 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 mL). The title compound was purified by preparative HPLC and lyophilized.
Utbytte: 114 mg; MS-ESI: [M+H]<+>= 594,4; HPLC: Rt = 26,46 min (metode 2). Yield: 114 mg; MS-ESI: [M+H]<+>= 594.4; HPLC: Rt = 26.46 min (method 2).
Eksempel 46 Example 46
5- metyl- tiofen- 2- karboksvlsyre ( 1- acetyl- 7- benzvlamino- 2, 2, 4- trimetvl- 4- fenyl-1, 2, 3, 4- tetrahydro- kinolin- 6- vl)- amid 5- methyl- thiophene- 2- carboxylic acid (1- acetyl- 7- benzvlamino- 2, 2, 4- trimethyl- 4- phenyl-1, 2, 3, 4- tetrahydro- quinolin- 6- vl)- amide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 45a (113 mg) acylert med 5-metyltiofen-2-karboksylsyre (39,1 mg), HATU (157 mg) og DIPEA (239 pl) i CH2CI2(10 ml). Tittelforbindelsen ble renset ved preparativ HPLC og lyofilisert. According to General Procedure A, the compound described in Example 45a (113 mg) was acylated with 5-methylthiophene-2-carboxylic acid (39.1 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 mL) . The title compound was purified by preparative HPLC and lyophilized.
Utbytte: 107 mg; MS-ESI: [M+H]<+>= 538,4; HPLC: Rt = 18,59 min (metode 2). Yield: 107 mg; MS-ESI: [M+H]<+>= 538.4; HPLC: Rt = 18.59 min (method 2).
Eksempel 47 Example 47
A/-{ 1- acetvl- 2, 2, 4- trimetvl- 4- fenvl- 7- r( pyridin- 3- vlmetvl)- amino1- 1, 2, 3, 4- tetrahvdrokinolin- 6- yl)- 3, 5- dibrom- benzamid A/-{ 1- acetvl- 2, 2, 4- trimethyl- 4- phenyl- 7- r( pyridine- 3- vylmethyl)- amino1- 1, 2, 3, 4- tetrahydroquinolin- 6- yl)- 3, 5-dibromobenzamide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 43a (114 mg) acylert med 3,5-dibrombenzosyre (77 mg), HATU (157 mg) og DIPEA (239 i CH2CI2(10 ml). Tittelforbindelsen ble renset ved preparativ HPLC og lyofilisert. According to General Procedure A, the compound described in Example 43a (114 mg) was acylated with 3,5-dibromobenzoic acid (77 mg), HATU (157 mg) and DIPEA (239 in CH 2 Cl 2 (10 mL). The title compound was purified by preparative HPLC and lyophilized.
Utbytte: 41 mg; MS-ESI: [M+H]<+>= 677,2; HPLC: Rt = 14,88 min (metode 2). Yield: 41 mg; MS-ESI: [M+H]<+>= 677.2; HPLC: Rt = 14.88 min (method 2).
Eksempel 48 Example 48
A/-( 1- acetvl- 7- dimetvlamino- 4- metvl- 4- fenvl- 1, 2, 3, 4- tetrahvdro- kinolin- 6- vl)- 3, 5-dibrom- benzamid A/-(1- Acetyl- 7- Dimethylamino- 4- Methyl- 4- Phenyl- 1, 2, 3, 4- Tetrahydroquinoline- 6-yl)- 3, 5- Dibromobenzamide
(a) . 4- metvl- 1, 2- dihvdrokinolin (a) . 4- methyl-1, 2- dihydroquinoline
En løsning av lepidin (10,0 g) i THF ble avkjølt til -78°C, etter hvilket en løsning av BH3 THF i THF (1 M, 70 ml) ble tilsatt. Etter 2 timer, ble en løsning av natrium bis(2-metoksy-etoksy)aluminium dihydrid i toluen (3,5 M, 40 ml) tilsatt og reaksjonsblandingen ble omrørt i ytterligere 2 timer. Vann ble tilsatt og blandingen fortynnet med etylacetat. Det organiske laget ble separert, tørket (MgS04) og delvis konsentrert in vakuum som forårsaker krystallisering av tittelforbindelsen. Krystallene ble samlet opp ved filtrering, for å gi 3,5 g etter tørking in vakuum. Den gjenværende moderluten ble konsentrert in vakuum og residuet ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 0/1 => 1/0 (volum/volum) som elueringsmidlet, for å gi ytterligere 4,4 g av tittelforbindelsen. A solution of lepidin (10.0 g) in THF was cooled to -78°C, after which a solution of BH 3 THF in THF (1 M, 70 mL) was added. After 2 h, a solution of sodium bis(2-methoxy-ethoxy)aluminum dihydride in toluene (3.5 M, 40 mL) was added and the reaction mixture was stirred for an additional 2 h. Water was added and the mixture diluted with ethyl acetate. The organic layer was separated, dried (MgSO 4 ) and partially concentrated in vacuo causing crystallization of the title compound. The crystals were collected by filtration to give 3.5 g after drying in vacuo. The remaining mother liquor was concentrated in vacuo and the residue was purified by chromatography on silica gel using heptane/ethyl acetate = 0/1 => 1/0 (v/v) as the eluent to give an additional 4.4 g of the title compound.
Utbytte: 7,9 g. Yield: 7.9 g.
(b) ,1- a cetyl- 4- metyl- 1, 2- dihvdrokinolin (b) ,1- a cetyl- 4- methyl- 1, 2- dihydroquinoline
I henhold til generell prosedyre C, ble forbindelsen beskrevet i eksempel 48a (7,9 According to General Procedure C, the compound described in Example 48a (7.9
g) acylert med acetylklorid (11,8 ml) og DMA (34 ml) i CH2CI2(50 ml) ved 0°C. Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av g) acylated with acetyl chloride (11.8 mL) and DMA (34 mL) in CH 2 Cl 2 (50 mL) at 0 °C. The title compound was purified by chromatography on silica gel using
heptan/etylacetat = 6/4 som elueringsmidlet. heptane/ethyl acetate = 6/4 as the eluent.
Utbytte: 8,8 g Yield: 8.8 g
(c) . 1 - acetyl- 4- metyl- 4- fenyl- 1, 2, 3, 4- tetrahydrokinolin (c) . 1 - acetyl- 4- methyl- 4- phenyl- 1, 2, 3, 4- tetrahydroquinoline
I henhold til generell prosedyre G, ble forbindelsen beskrevet i eksempel 48b (8,8 g) omrørt med AICI3(18,8 g) i benzen (250 ml). Det oppnådde produktet ble anvendt uten ytterligere rensning. According to General Procedure G, the compound described in Example 48b (8.8 g) was stirred with AlCl 3 (18.8 g) in benzene (250 mL). The product obtained was used without further purification.
Utbytte: 12,0 g Yield: 12.0 g
(d) . 1 - acetyl- 4- metyl- 6- nitro- 4- fenyl- 1, 2, 3, 4- tetrahydrokinolin (d) . 1 - acetyl- 4- methyl- 6- nitro- 4- phenyl- 1, 2, 3, 4- tetrahydroquinoline
Til en løsning av forbindelsen beskrevet i eksempel 48c (5,0 g) og eddiksyreanhydrid (189 ul) i CH2CI2(50 ml) ble det dråpevis tilsatt rykende HN03(9,4 ml). Etter at reaksjonen var fullstendig, ble vann tilsatt og det organiske laget ble vasket med saltvann, separert og konsentrert in vakuum. Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 6/4 (volum/volum) som elueringsmidlet. To a solution of the compound described in Example 48c (5.0 g) and acetic anhydride (189 µl) in CH 2 Cl 2 (50 mL) fuming HN0 3 (9.4 mL) was added dropwise. After the reaction was complete, water was added and the organic layer was washed with brine, separated and concentrated in vacuo. The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 6/4 (v/v) as the eluent.
Utbytte: 3,86 g Yield: 3.86 g
(e) . 1 - acetyl- 6- amino- 4- metvl- 4- fenyl- 1, 2, 3, 4- tetrahydrokinolin I henhold til generell prosedyre E, ble forbindelsen beskrevet i eksempel 48d (3,86 g) redusert ved anvendelse av sinkstøv (16 g) og eddiksyre (7 ml) i THF (ca 250 ml), for å gi produktet som ble anvendt ubearbeidet i det neste trinnet. (e) . 1-acetyl-6-amino-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinoline According to general procedure E, the compound described in Example 48d (3.86 g) was reduced using zinc dust ( 16 g) and acetic acid (7 ml) in THF (ca. 250 ml), to give the product which was used crudely in the next step.
Utbytte: 2,2 g Yield: 2.2 g
(f) . ( 1- acetvl- 4- metvl- 4- fenvl- 1, 2, 3, 4- tetrahvdrokinolin- 6- vl)- karbaminsvre 9- fluor-enylmetylester (f) . ( 1- acetvl- 4- methyl- 4- phenyl- 1, 2, 3, 4- tetrahydroquinoline- 6- vl)- carbamic acid 9- fluoro-enyl methyl ester
Pyridin (314 ul) ble satt til en løsning av forbindelsen beskrevet i eksempel 48e (1,0 g) i THF (10 ml) og den resulterende blandingen ble avkjølt til 0°C. FmocCI (1,01 g) ble tilsatt og blandingen ble omrørt i 18 timer ved romtemperatur, etter denne tiden ble reaksjonsblandingen konsentrert in vakuum. Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 6/4 (volum/volum) som elueringsmidlet. Pyridine (314 µl) was added to a solution of the compound described in Example 48e (1.0 g) in THF (10 mL) and the resulting mixture was cooled to 0 °C. FmocCl (1.01 g) was added and the mixture was stirred for 18 hours at room temperature, after which time the reaction mixture was concentrated in vacuo. The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 6/4 (v/v) as the eluent.
Utbytte: 950 mg Yield: 950 mg
(g) . ( 1- acetvl- 4- metvl- 7- nitro- 4- fenyl- 1, 2, 3, 4- tetrahvdrokinolin- 6- vl)- karbaminsvre 9-fluorenylmetvlester (g) . ( 1- acetvl- 4- methyl- 7- nitro- 4- phenyl- 1, 2, 3, 4- tetrahydroquinoline- 6- vl)- carbamic acid 9-fluorenyl methyl ester
Til en løsning av forbindelsen beskrevet i eksempel 48f (850 mg) og eddiksyreanhydrid (17 ul) i CH2CI2(5 ml) ble det dråpevis tilsatt rykende HN03(842 ul). Etter at reaksjonen var fullstendig, ble vann tilsatt og det organiske laget ble vasket med saltvann, separert og konsentrert in vakuum. Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 9/1 => 0/1 (volum/ volum) som elueringsmidlet. To a solution of the compound described in Example 48f (850 mg) and acetic anhydride (17 µl) in CH 2 Cl 2 (5 mL) fuming HN0 3 (842 µl) was added dropwise. After the reaction was complete, water was added and the organic layer was washed with brine, separated and concentrated in vacuo. The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 9/1 => 0/1 (v/v) as the eluent.
Utbytte: 714 mg Yield: 714 mg
(h) . ( 1- acetvl- 7- amino- 4- metvl- 4- fenyl- 1, 2, 3, 4- tetrahvdrokinolin- 6- vl)- karbaminsvre 9- fluorenvlmetvlester (h) . ( 1- acetvl- 7- amino- 4- methyl- 4- phenyl- 1, 2, 3, 4- tetrahydroquinoline- 6- vl)- carbamic acid 9- fluoroenvlmethyl ester
I henhold til generell prosedyre E, ble forbindelsen beskrevet i eksempel 48 g (2,37 g) redusert ved anvendelse av sinkstøv (5,6 g) og eddiksyre (2,4 ml) i THF (ca 50 ml), for å gi produktet som ble anvendt ubearbeidet i det neste trinnet. Utbytte: 2,66 g According to General Procedure E, the compound described in Example 48 g (2.37 g) was reduced using zinc dust (5.6 g) and acetic acid (2.4 mL) in THF (ca. 50 mL), to give the product used unprocessed in the next step. Yield: 2.66 g
(i) . ( 1- acetvl- 7- dimetvlamino- 4- metvl- 4- fenyl- 1, 2, 3, 4- tetrahvdrokinolin- 6- vl)-karbamins<y>re 9- fluorenvlmetvlester (i) . ( 1- Acetyl- 7- dimethylamino- 4- methyl- 4- phenyl- 1, 2, 3, 4- tetrahydroquinoline- 6- yl)- carbamine 9- fluoroenylmethyl ester
En vandig løsning av formaldehyd (37 %, 650 ul) ble satt til en løsning av forbindelsen beskrevet i eksempel 48h (2,66 g), eddiksyre (3,1 ml) og natriumcyanoborhydrid (232 mg) i metanol (50 ml) og den resulterende blandingen ble omrørt i 18 timer. Reaksjonsblandingen ble konsentrert in vakuum og residuet ble tatt opp i etylacetat og vasket med vann og saltvann. Det organiske laget ble separert, tør-ket (MgS04) og konsentrert in vakuum. Tittelforbindelsen ble renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 9/1 => 0/1 (volum/volum) som elueringsmidlet. An aqueous solution of formaldehyde (37%, 650 µl) was added to a solution of the compound described in Example 48h (2.66 g), acetic acid (3.1 mL) and sodium cyanoborohydride (232 mg) in methanol (50 mL) and the resulting mixture was stirred for 18 h. The reaction mixture was concentrated in vacuo and the residue was taken up in ethyl acetate and washed with water and brine. The organic layer was separated, dried (MgSO 4 ) and concentrated in vacuo. The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 9/1 => 0/1 (v/v) as the eluent.
Utbytte: 1,0 g Yield: 1.0 g
(j). 1- acetyl- 6- amino- 7- dimetylamino- 4- metyl- 4- fenyl- 1, 2, 3, 4- tetrahydrokinolin Piperidin (1,8 ml) ble satt til en løsning av forbindelsen beskrevet i eksempel 48i (1 (j). 1-acetyl-6-amino-7-dimethylamino-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinoline Piperidine (1.8 ml) was added to a solution of the compound described in Example 48i (1
g) i CH2CI2(20 ml) og blandingen ble omrørt inntil ikke mer utgangsmateriale var tilbake. Reaksjonsblandingen ble konsentrert in vakuum og tittelforbindelsen ble g) in CH 2 Cl 2 (20 mL) and the mixture was stirred until no more starting material remained. The reaction mixture was concentrated in vacuo to give the title compound
renset ved kromatografi på silikagel ved anvendelse av heptan/etylacetat = 9/1 => 0/1 (volum/volum) som elueringsmidlet. purified by chromatography on silica gel using heptane/ethyl acetate = 9/1 => 0/1 (v/v) as the eluent.
Utbytte: 370 mg. Yield: 370 mg.
(k). A/-( 1- acetyl- 7- dimetylamino- 4- metyl- 4- fenyl- 1, 2, 3, 4- tetrahvdro- kinolin- 6- yl)- 3, 5-dibrom- benzamid (k). A/-(1- acetyl- 7- dimethylamino- 4- methyl- 4- phenyl- 1, 2, 3, 4- tetrahydro- quinolin- 6- yl)- 3, 5-dibromobenzamide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 48j (74 mg) acylert med 3,5-dibrombenzosyre (70 mg), HATU (131 mg) og DIPEA (120 ul) i CH2CI2(3 ml). Tittelforbindelsen ble renset ved preparativ HPLC og lyofilisert. Utbytte: 82 mg; MS-ESI: [M+H]<+>= 586,2; HPLC: Rt = 22,40 min (metode 2). According to General Procedure A, the compound described in Example 48j (74 mg) was acylated with 3,5-dibromobenzoic acid (70 mg), HATU (131 mg) and DIPEA (120 µl) in CH 2 Cl 2 (3 mL). The title compound was purified by preparative HPLC and lyophilized. Yield: 82 mg; MS-ESI: [M+H]<+>= 586.2; HPLC: Rt = 22.40 min (method 2).
Eksempel 49 Example 49
5- brom- tiofen- 2- karboksvlsyre ( 1- acetyl- 7- dimetvlamino- 4- metvl- 4- fenyl- 1, 2, 3, 4-tetrahydro- kinolin- 6- yl)- amid 5-bromo-thiophene-2-carboxylic acid (1-acetyl-7-dimethylamino-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 48j (74 mg) acylert [med] 5-bromtiofen-2-karboksylsyre (52 mg), HATU (131 mg) og DIPEA (120 ul) i CH2CI2(3 ml). Tittelforbindelsen ble renset ved preparativ HPLC og lyofilisert. According to General Procedure A, the compound described in Example 48j (74 mg) was acylated [with] 5-bromothiophene-2-carboxylic acid (52 mg), HATU (131 mg) and DIPEA (120 µl) in CH 2 Cl 2 (3 mL) . The title compound was purified by preparative HPLC and lyophilized.
Utbytte: 69 mg; MS-ESI: [M+H]<+>= 514,2; HPLC: Rt = 17,01 min (metode 2). Yield: 69 mg; MS-ESI: [M+H]<+>= 514.2; HPLC: Rt = 17.01 min (method 2).
Eksempel 50 Example 50
5- klor- tiofen- 2- karboksvlsyre ( 1- acetyl- 7- dimetvlamino- 4- metvl- 4- fenyl- 1, 2, 3, 4-tetrahvdro- kinolin- 6- vl)- amid 5-chloro-thiophene-2-carboxylic acid (1-acetyl-7-dimethylamino-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-amide
I henhold til generell prosedyre A, ble forbindelsen beskrevet i eksempel 48j (74 mg) acylert [med] 5-klortiofen-2-karboksylsyre (52 mg), HATU (131 mg) og DIPEA (120 pl) i CH2CI2(3 ml). Tittelforbindelsen ble renset ved preparativ HPLC og lyofilisert. According to General Procedure A, the compound described in Example 48j (74 mg) was acylated [with] 5-chlorothiophene-2-carboxylic acid (52 mg), HATU (131 mg) and DIPEA (120 µl) in CH 2 Cl 2 (3 mL) . The title compound was purified by preparative HPLC and lyophilized.
Utbytte: 81 mg; MS-ESI: [M+H]<+>= 468,2; HPLC: Rt = 17,49 min (metode 2). Yield: 81 mg; MS-ESI: [M+H]<+>= 468.2; HPLC: Rt = 17.49 min (method 2).
Eksempel 51 Example 51
CHO- FSH in vitro bioaktivitet CHO-FSH in vitro bioactivity
FSH aktivitet av forbindelser ble testet i eggstokkceller fra kinesisk hamster (CHO) stabilt transfektert med den humane FSH reseptor og ko-transfektert med et cAMP mottagelig element (CRE) / promotor som styrer ekspresjonen av et ildflue luciferase rapportørgen. Binding av ligand til den Gs-koblede FSH reseptoren vil resultere i en økning av cAMP, som i sin tur vil fremkalle en øket transaktivering av luciferase rapportørkonstruktet. For å teste antagonistiske egenskaper ble rekombinant FSH i en konsentrasjon som induserer omtrent 80% av den maksimale stimulering av cAMP akkumulering i fravær av testforbindelse tilsatt (rec-hFSH, 10mU/ml). Luciferase signalet ble kvantifisert ved anvendelse av en luminescens- teller. For testforbindelser ble det beregnet EC50verdier (konsentrasjon av testforbindelse som forårsaker halv-maksimal (50 %) stimulering eller reduksjon). For det formål ble det anvendt dataprogrammet GraphPad PRISM, versjon 3.0 (GraphPad software Inc., San Diego). FSH activity of compounds was tested in Chinese hamster ovary (CHO) cells stably transfected with the human FSH receptor and co-transfected with a cAMP responsive element (CRE)/promoter driving the expression of a firefly luciferase reporter gene. Binding of ligand to the Gs-coupled FSH receptor will result in an increase in cAMP, which in turn will induce an increased transactivation of the luciferase reporter construct. To test antagonistic properties, recombinant FSH at a concentration that induces approximately 80% of the maximal stimulation of cAMP accumulation in the absence of test compound was added (rec-hFSH, 10 mU/ml). The luciferase signal was quantified using a luminescence counter. For test compounds, EC50 values (concentration of test compound causing half-maximal (50%) stimulation or reduction) were calculated. For that purpose, the computer program GraphPad PRISM, version 3.0 (GraphPad software Inc., San Diego) was used.
Forbindelser ifølge alle eksemplene viste en EC50(IC50) verdi på mindre enn 10"<5>M i enten et agonistisk eller antagonistisk forsøksoppsett eller begge. Forbindelsene ifølge eksemplene 5-8, 10-14, 16, 18-20, 33-35, 37, 38,41 og 45-50 viste en EC50 på mindre enn 10"<7>M i minst ett av forsøkene. Compounds of all examples showed an EC50 (IC50) value of less than 10"<5>M in either an agonistic or antagonistic assay setup or both. The compounds of Examples 5-8, 10-14, 16, 18-20, 33-35 , 37, 38,41 and 45-50 showed an EC50 of less than 10"<7>M in at least one of the experiments.
Claims (5)
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ECSP055871A (en) | 2005-09-20 |
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