CN100404508C - Tetrahydroquinoline derivatives - Google Patents
Tetrahydroquinoline derivatives Download PDFInfo
- Publication number
- CN100404508C CN100404508C CNB2003801066985A CN200380106698A CN100404508C CN 100404508 C CN100404508 C CN 100404508C CN B2003801066985 A CNB2003801066985 A CN B2003801066985A CN 200380106698 A CN200380106698 A CN 200380106698A CN 100404508 C CN100404508 C CN 100404508C
- Authority
- CN
- China
- Prior art keywords
- compound
- amino
- ethanoyl
- phenyl
- trimethylammonium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 title claims abstract description 20
- -1 hydroxy, amino Chemical group 0.000 claims abstract description 48
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 230000035558 fertility Effects 0.000 claims abstract description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 11
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 7
- 230000001105 regulatory effect Effects 0.000 claims description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
- 125000003368 amide group Chemical group 0.000 claims 1
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 abstract description 48
- 125000003282 alkyl amino group Chemical group 0.000 abstract description 30
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 19
- 125000000217 alkyl group Chemical group 0.000 abstract description 18
- 125000003118 aryl group Chemical group 0.000 abstract description 16
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 6
- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 abstract description 5
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 abstract description 4
- 125000004949 alkyl amino carbonyl amino group Chemical group 0.000 abstract description 3
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 abstract description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 abstract 2
- 125000004658 aryl carbonyl amino group Chemical group 0.000 abstract 1
- 125000005199 aryl carbonyloxy group Chemical group 0.000 abstract 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 1
- 125000005204 heteroarylcarbonyloxy group Chemical group 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 302
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
- 238000000034 method Methods 0.000 description 115
- 239000000460 chlorine Substances 0.000 description 75
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 72
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 61
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 57
- 239000000203 mixture Substances 0.000 description 54
- 239000002585 base Substances 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 44
- 238000002360 preparation method Methods 0.000 description 36
- 239000003480 eluent Substances 0.000 description 35
- 238000010898 silica gel chromatography Methods 0.000 description 34
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 26
- 239000007821 HATU Substances 0.000 description 25
- 125000004432 carbon atom Chemical group C* 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- 229910052799 carbon Inorganic materials 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 20
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 20
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 229940028334 follicle stimulating hormone Drugs 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 238000005804 alkylation reaction Methods 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 16
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 108010060374 FSH Receptors Proteins 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000002425 crystallisation Methods 0.000 description 15
- 230000008025 crystallization Effects 0.000 description 15
- 102000008175 FSH Receptors Human genes 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 13
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- NHNAEZDWNCRWRW-UHFFFAOYSA-N 2-bromobenzamide Chemical compound NC(=O)C1=CC=CC=C1Br NHNAEZDWNCRWRW-UHFFFAOYSA-N 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 239000001301 oxygen Substances 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- 150000003053 piperidines Chemical class 0.000 description 11
- 239000002994 raw material Substances 0.000 description 11
- 238000006722 reduction reaction Methods 0.000 description 11
- 230000029936 alkylation Effects 0.000 description 10
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 10
- 229940088597 hormone Drugs 0.000 description 10
- 239000005556 hormone Substances 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 9
- 230000017858 demethylation Effects 0.000 description 9
- 238000010520 demethylation reaction Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- VCNGNQLPFHVODE-UHFFFAOYSA-N 5-methylthiophene-2-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)S1 VCNGNQLPFHVODE-UHFFFAOYSA-N 0.000 description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 8
- 239000012895 dilution Substances 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 239000007787 solid Substances 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
- 108700008625 Reporter Genes Proteins 0.000 description 7
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 238000006396 nitration reaction Methods 0.000 description 7
- 239000012266 salt solution Substances 0.000 description 7
- 230000000638 stimulation Effects 0.000 description 7
- RBGDLYUEXLWQBZ-UHFFFAOYSA-N 2-chlorobenzamide Chemical compound NC(=O)C1=CC=CC=C1Cl RBGDLYUEXLWQBZ-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- QZLSBOVWPHXCLT-UHFFFAOYSA-N 5-chlorothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)S1 QZLSBOVWPHXCLT-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000370 acceptor Substances 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
- 238000001035 drying Methods 0.000 description 6
- 150000003840 hydrochlorides Chemical class 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- 150000003530 tetrahydroquinolines Chemical class 0.000 description 6
- 238000001291 vacuum drying Methods 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
- 239000012043 crude product Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 5
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 description 5
- 208000000509 infertility Diseases 0.000 description 5
- 230000036512 infertility Effects 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 210000001672 ovary Anatomy 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- OFTKFKYVSBNYEC-UHFFFAOYSA-N 2-furoyl chloride Chemical compound ClC(=O)C1=CC=CO1 OFTKFKYVSBNYEC-UHFFFAOYSA-N 0.000 description 4
- COWZPSUDTMGBAT-UHFFFAOYSA-N 5-bromothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Br)S1 COWZPSUDTMGBAT-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 238000005614 Skraup synthesis reaction Methods 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
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- 150000001263 acyl chlorides Chemical class 0.000 description 4
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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- 238000004587 chromatography analysis Methods 0.000 description 4
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- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
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- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 2
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- 230000007017 scission Effects 0.000 description 1
- 108010048734 sclerotin Proteins 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002863 seminiferous tubule Anatomy 0.000 description 1
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- 230000001568 sexual effect Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000007892 solid unit dosage form Substances 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WIVYTYZCVWHWSH-UHFFFAOYSA-N tert-butyl n-(4-aminophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(N)C=C1 WIVYTYZCVWHWSH-UHFFFAOYSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to tetrahydroquinoline derivatives having general formula (I) or a pharmaceutically acceptable salt thereof, wherein R<1> and R<2> are H or Me; R<3> is H, hydroxy, (1-4C)alkoxy, (di)(1-4C)alkylamino(2-4C)alkoxy or (2-6)heterocycloakl(2-4C)alkoxy; R<4> is H, OH, (1-4C)alkoxy or R<7>; R<5> is H, OH, (1-4C)alkoxy or R<7>,with the proviso that if R<4> is H, R<5> is not H, OH or (1-4C)alkoxy and that if R<5> is H, R<4> is not H, OH or (1-4C)alkoxy; R<6> is (2-5C)heteroaryl, (6C)aryl, (3-8C)cycloalkyl, (2 6C)heterocycloalkyl or (1-6C)alkyl; R<7> is amino, (di)(1-4C) alkylamino, (6C)arylcarbonylamino, (6C)arylcarbonyloxy, (2-5C) heteroarylcarbonylamino, (2-5C)heteroarylcarbonyloxy, R<8>-(2-4C)alkylamino, R<8>-(2-4C)alkoxy, R<9>-methylamino or R<9>-methoxy; R<8> is hydroxy, amino, (1-4C)alkoxy, (di)(1-4C)alkylamino, (2-6C)heterocycloalkyl, (2-6C) heterocycloalkylcarbonylamino, (di)(1-4C)alkylaminocarbonylamino, (1-4C) alkoxycarbonylamino and R<9> is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl. The present invention also relates to pharmaceutical compositions comprising said derivatives and the use of these derivatives to regulate fertility.
Description
The present invention relates to a kind ofly have fsh receptor and regulate active compound, a kind of specifically tetrahydroquinoline derivative also relates to the pharmaceutical composition that contains described compound, and the application of described compound in therapeutic treatment.
Gonad-stimulating hormone has vital role in the various functions that comprise metabolism, temperature regulation and reproductive process of body.Gonad-stimulating hormone acts on the sexual gland cell of particular type, starts ovary and testis differentiation and steroid and forms.For example, the gonad-stimulating hormone FSH (follicle stimulating hormone) of hypophysis has keying action in growth that stimulates ovarian follicle and maturation, and LH (lutropin) can induced ovulation (Sharp, R.M.Clin Endocrinol.33:787-807,1990; Dorrington and Armstrong, Recent Prog.Horm.Res.35:301-342,1979).At present, FSH combines with LH or hCG clinically and is applied to ovarian stimulation, just highly stimulate ovary with (IVF) in vitro fertilization with induce the sterility women ovulation (Insler of not ovulating, V.Int.J.Fertility, 33:85-97,1988, Navot andRosenwaks, J.Vitro Fert.Embryo Transfer 5:3-13,1988), and also can be applicable to male gonad hypofunction and male infertility.
Gonad-stimulating hormone FSH discharges from adenohypophysis under the influence of gonadotropin releasing hormone, and is discharged by placenta at pregnancy duration.In the women, FSH acts on the ovary that promotes follicular development, thereby is the major hormone of regulating estrogen secretion.In the male sex, the integrity of FSH decision seminiferous tubule acts on sustenticular cell simultaneously and forms to support gamete.Purifying FSH is used to treat the spermatogenetic depletion of some type of women's the infertility and the male sex clinically.The gonad-stimulating hormone that is used for the treatment of purpose can be separated by people's urine source and obtain, but purity lower people such as (, Amer.J.Reproduct.Immunol.andMicrobiology 17:143,1988) Morse.Perhaps, also they can be prepared as recombinant gonadotropins.Recombinant human FSH is available commercially, and can be used for promoting reproduction (people .Mol.Hum.Reprod.2:371 such as Olijve, 1996; People .Lancet 339:1170 such as Devroey, 1992).The FSH functions of hormones is by the specific physique membrane receptor-mediated that belongs to a member in the g protein coupled receptor extended familys.These acceptors are made of single polypeptide and seven membrane spaning domains, can with the Gs protein-interacting, for example cause the activation of adenylate cyclase.
Fsh receptor is the target that has high degree of specificity in the ovarian follicular growth process, unique being expressed in the ovary.Normally after receptor activation, begin to induce this acceptor of blocking-up or suppress sending of this signal, will disturb the growth of ovarian follicle like this and then disturb ovulation and fertility by the FSH mediation.Thereby low-molecular-weight FSH antagonist may constitute the basis of novel contraceptive medicine.This class FSH antagonist can cause that ovarian follicle form to reduce (not ovulating), can also generate enough oestrogenic hormon simultaneously and for example sclerotin be had side effects avoiding.On the other hand, stimulate the compound of fsh receptor can also simulate the gonad-stimulating hormone effect of native ligand.
The invention describes optionally the fsh receptor activity is had the preparation of regulating active lower molecular weight hormone analogs.Compound of the present invention can be used as fsh receptor (part) agonist or (part) antagonist.
Therefore, have now found that, below the formula I 3,4-tetrahydroquinoline compounds of a class or its pharmacologically acceptable salt have FSH and regulate active:
Wherein
R
1And R
2Be H or Me;
R
3Be H, hydroxyl, (1-4C) alkoxyl group, (two) (1-4C) alkylamino (2-4C) alkoxyl group or (2-6) Heterocyclylalkyl (2-4C) alkoxyl group;
R
4Be H, OH, (1-4C) alkoxyl group or R
7
R
5Be H, OH, (1-4C) alkoxyl group or R
7
Its condition is: if R
4Be H, R so
5Not H, OH or (1-4C) alkoxyl group, and if R
5Be H, R so
4Not H, OH or (1-4C) alkoxyl group;
R
6Be (2-5C) heteroaryl, (6C) aryl, (3-8C) cycloalkyl, (2-6C) Heterocyclylalkyl or (1-6C) alkyl;
R
7Be amino, (two) (1-4C) alkylamino, (6C) aryl-amino-carbonyl, (6C) aryl-carbonyl oxygen, (2-5C) heteroaryl carbonylamino, (2-5C) heteroaryl carbonyl oxygen base, R8-(2-4C) alkylamino, R
8-(2-4C) alkoxyl group, R
9-methylamino or R
9-methoxyl group;
R
8Be (1-4C) (1-4C) alkyl amino-carbonyl amino, (1-4C) alkoxycarbonyl amido of alkylamino, (2-6C) Heterocyclylalkyl, (2-6C) Heterocyclylalkyl carbonylamino, (two) of hydroxyl, amino, (1-4C) alkoxyl group, (two); And
R
9Be aminocarboxyl, (two) (1-4C) alkyl amino-carbonyl, (2-5C) heteroaryl or (6C) aryl.
R
4And R
5Be independently selected from above-mentioned each group, not necessarily identical.
The compounds of this invention can be regulated the function of fsh receptor, if thereby they show to such an extent that be similar to agonist, can be used for the clinical purpose identical with natural FSH, it is advantageous that, they demonstrate change stability and can pass through the different approaches administration.If they block fsh receptor, they can be used as for example contraceptive bian.
Therefore, fsh receptor conditioning agent of the present invention can be used for treating infertility, is used for contraception and is used for the treatment of hormone-dependent diseases, for example mammary cancer, prostate cancer and endometriosis.
Following pointed specific meanings represented to have in employed following term in this specification sheets and claims.
Term used herein (1-4C) alkyl is meant side chain or the unbranched alkyl with 1-4 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl and the tertiary butyl.
Term used herein (1-6C) alkyl is meant side chain or the unbranched alkyl with 1-6 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl and hexyl.Preferably (1-5C) alkyl, most preferably (1-4C) alkyl.
Term used in the present invention (3-8C) cycloalkyl represents to have the cycloalkyl of 3-8 carbon atom, and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group are arranged.Preferred (3-6C) cycloalkyl.
Term (2-6C) Heterocyclylalkyl is meant and has 2-6 carbon atom (preferred 3-5 carbon atom), comprises that at least one is selected from the heteroatomic Heterocyclylalkyl of N, O and/or S simultaneously, and they can link to each other (if feasible) or continuous by carbon atom by heteroatoms.Preferred heteroatoms is N or O.Most preferably piperidyl, morpholinyl and pyrrolidyl.
Term (1-4C) alkoxyl group is meant the alkoxyl group with 1-4 carbon atom, and wherein moieties has and above defines identical implication.Preferred (1-2C) alkoxyl group.
Term (2-4C) alkoxyl group is meant the alkoxyl group with 2-4 carbon atom, and wherein moieties has and above defines identical implication.
Term used herein (two) (1-4C) alkylamino is meant by the alkyl list and replaces or dibasic amino that wherein said each alkyl contains 1-4 carbon atom, and has and above define identical implication.
Term used herein (6C) aryl is meant phenyl, it can be chosen wantonly by one or more and be selected from following substituting group and replace: hydroxyl, amino, iodine, bromine, chlorine, fluorine, nitro, trifluoromethyl, cyano group, phenyl, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) (two) alkylamino, alkyl, alkoxyl group and (two) alkylamino, they have and above define identical implication, phenyl for example, 3, the 5-dibromo phenyl, the 4-xenyl, 3, the 5-dichlorophenyl, 3-bromo-6-methylamino-phenyl, 3-chloro-2,6-Dimethoxyphenyl and 3, the 5-3,5-dimethylphenyl.
Term (2-5C) heteroaryl is meant and is substituted or the unsubstituted 2-5 of a having carbon atom, comprises the heteroatomic aromatic group that is selected from N, O and/or S, for example imidazolyl, pyridyl, pyrimidyl, thienyl and a furyl at least.Substituting group on the heteroaryl can be selected from for cited substituting group in (6C) aryl.Heteroaryl can link to each other by carbon atom or heteroatoms (if feasible).Preferred heteroaryl is thienyl, furyl and pyridyl.
Term two used herein (1-4C) alkylamino (2-4C) alkoxyl group is meant (two) alkylamino that links to each other with moieties in the alkoxyl group with 2-4 carbon atom by amino, wherein moieties or a plurality of moieties contain 1-4 carbon atom separately, and described (two) alkylamino has with alkoxyl group and above defines identical implication.
Term used herein (2-6C) Heterocyclylalkyl (2-4C) alkoxyl group is meant the Heterocyclylalkyl with 2-6 carbon atom that links to each other with moieties in the alkoxyl group with 2-4 carbon atom, and described alkoxyl group has with Heterocyclylalkyl and above defines identical implication.
Term used herein (6C) aryl-amino-carbonyl is meant the phenyl that links to each other with carbonyl moiety in the carbonylamino, wherein phenyl is optional is replaced by one or more being selected from for the substituting group in the substituting group of enumerating in (6C) aryl, and described (6C) aryl has and above defines identical implication.
Term used herein (6C) aryl-carbonyl oxygen is meant the phenyl that links to each other with carbonyl moiety in the carbonyl oxygen base, wherein phenyl is optional is replaced by one or more being selected from for the substituting group in the substituting group of enumerating in (6C) aryl, and described (6C) aryl has and above defines identical implication.
Term used herein (2-5C) heteroaryl carbonylamino is meant the heteroaryl that contains 2-5 carbon atom that links to each other with carbonyl moiety in the carbonylamino, and wherein heteroaryl is optional is replaced by one or more being selected from for the substituting group in the substituting group of enumerating in (6C) aryl.Heteroaryl moieties in the described heteroaryl carbonylamino has and above defines identical implication.
Term used herein (2-5C) heteroaryl carbonyl oxygen base is meant the heteroaryl that contains 2-5 carbon atom that links to each other with carbonyl moiety in the carbonyl oxygen base, and wherein heteroaryl is optional is replaced by one or more being selected from for the substituting group in the substituting group of enumerating in (6C) aryl.Heteroaryl moieties in the described heteroaryl carbonyl oxygen base has and above defines identical implication.
Term used herein (2-6C) Heterocyclylalkyl carbonylamino is meant the Heterocyclylalkyl with 2-6 carbon atom that links to each other with carbonyl moiety in the carbonylamino, and described Heterocyclylalkyl has and above defines identical implication.
Term used herein (two) (1-4C) alkyl amino-carbonyl is meant (two) alkylamino that links to each other with carbonyl by amino, and wherein alkyl has 1-4 carbon atom, and described (two) alkylamino has and above defines identical implication.
Term used herein (two) (1-4C) alkyl amino-carbonyl amino is meant (two) alkylamino (can provide urea functional group like this) that links to each other with carbonyl moiety in the carbonylamino by amino, wherein alkyl has 1-4 carbon atom, and described (two) alkylamino has and above defines identical implication.
Term used herein (1-4C) alkoxycarbonyl amino is meant the alkoxyl group with 1-4 carbon atom (can provide carbamate-functional like this) that links to each other with carbonyl moiety in the carbonylamino, and described alkoxyl group has and above defines identical implication.
Term R used herein
8-(2-4C) alkylamino is meant the R that links to each other with moieties in (2-4C) alkylamino
8Group, described (2-4C) alkylamino has and above defines identical implication.
Term R used herein
8-(2-4C) alkoxyl group is meant the R that links to each other with moieties in (2-4C) alkoxyl group
8Group, described (2-4C) alkoxyl group has and above defines identical implication.
Term R used herein
9-methylamino is meant the R that links to each other with methyl moiety in the methylamino
9Group.
Term R used herein
9-methoxyl group is meant the R that links to each other with methyl moiety in the methoxyl group
9Group.
The term pharmacologically acceptable salt is meant that those fall within doctor's determination range and is fit to be used for human body or rudimentary animal tissues and the salt of no abnormal toxicity, pungency, transformation reactions etc. by the way of contact, and they adapt with rational benefit/risk ratio.Pharmacologically acceptable salt is well-known in the art.They can obtain in the final separation of The compounds of this invention and purge process, if perhaps there is free alkali functional group, by with this free alkali functional group and hydrochloric acid, phosphoric acid or sulfuric acid or with organic acid for example reactions such as xitix, citric acid, tartrate, lactic acid, toxilic acid, propanedioic acid, fumaric acid, oxyacetic acid, succsinic acid, propionic acid, acetate, methylsulfonic acid obtain.If present, can also be with acid functional group and for example sodium hydroxide, potassium hydroxide or the lithium hydroxide reaction of organic or inorganic alkali.
Therefore, the present invention relates to define as above formula I compound.
In another embodiment of the present invention, relate to compound, wherein R according to formula I
3Be H, hydroxyl or (1-4C) alkoxyl group.
The invention still further relates to formula I compound, wherein R
4Be H, OH or (1-4C) alkoxyl group.
In another embodiment of the present invention, provide formula I compound, wherein R
5Be OH, (1-4C) alkoxyl group or R
7.
In another embodiment of the present invention, provide formula I compound, wherein R
6Be (2-5C) heteroaryl, (6C) aryl, (3-8C) cycloalkyl or (1-6C) alkyl.
In another embodiment of the present invention, relate to compound, wherein R according to formula I
6Be (2-5C) heteroaryl or (6C) aryl.
Aspect another, described R
6In heteroaryl form by 4 or 5 carbon atoms.
The invention still further relates to compound, wherein R according to formula I
7Be (two) (1-4C) alkylamino, (2-5C) heteroaryl carbonylamino, (2-5C) heteroaryl carbonyl oxygen base, R
8-(2-4C) alkoxyl group, R
9-methylamino or R
9-methoxyl group.
The present invention is the compound according to formula I, wherein R on the other hand
7Be (two) (1-4C) alkylamino, (2-5C) heteroaryl carbonyl oxygen base, R
8-(2-4C) alkoxyl group, R
9-methylamino or R
9-methoxyl group.
Another aspect of the invention relates to the compound according to formula I, wherein R
7Be (two) (1-4C) alkylamino, R
8-(2-4C) alkoxyl group, R
9-methylamino or R
9-methoxyl group.
The present invention relates to the compound according to I, wherein R on the other hand
7In R
8-(2-4C) alkoxyl group is R
8-oxyethyl group.
Another aspect of the invention relates to the compound according to formula I, wherein R
7In R
8-(2-4C) alkylamino is R
8-ethylamino.
In another embodiment of the present invention, provide formula I compound, wherein R
8Be amino, (two) (1-4C) alkylamino, (2-6C) Heterocyclylalkyl, (2-6C) Heterocyclylalkyl carbonylamino or (1-4C) alkoxycarbonyl amido.
In another embodiment of the present invention, provide formula I compound, wherein R
8Be amino, (two) (1-4C) alkylamino, (2-6C) Heterocyclylalkyl or (1-4C) alkoxycarbonyl amido.
Again in the embodiment, provide formula I compound, wherein R in the present invention
8Be amino, (two) (1-4C) alkylamino, (2-6C) Heterocyclylalkyl or (2-6C) Heterocyclylalkyl carbonylamino.
The invention still further relates to compound, wherein R according to formula I
8Be amino, (two) (1-4C) alkylamino or (2-6C) Heterocyclylalkyl.
In further aspect of the present invention, the R in the formula I compound
8Be (two) (1-4C) alkylamino or (2-6C) Heterocyclylalkyl.
The present invention relates to the compound according to formula I, wherein R on the other hand
8In Heterocyclylalkyl form by 4 or 5 carbon atoms.
According to another embodiment of the invention, according to the R of formula I
9Be aminocarboxyl, (2-5C) heteroaryl or (6C) aryl.
The embodiment again according to the present invention is according to the R of formula I
9In heteroaryl form by 3,4 or 5 carbon atoms.
Further aspect of the present invention relates to such compound, wherein incites somebody to action radicals R as defined above
1-R
9All concrete combinations of definitions in formula I compound.
The proper method of preparation The compounds of this invention is summarized as follows.
R wherein
4And R
5Be (1-4C) alkoxyl group, R
1And R
2Be methyl, R
6Ding Yi the The compounds of this invention aniline that can suitably be replaced by the quilt of general formula I I sets out as mentioned, and the Skraup prepared in reaction by existing document write up obtains, and described reaction obtains 2,2 of general formula III-a, 4-trimethylammonium-1,2-dihydroquindine derivates.
Relevant Skraup cyclic condensation method is referring to following document: A.Knoevenagel, Chem.Ber.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.
Above-mentioned reaction normally iodine or protonic acid for example hydrochloric acid, tosic acid or aqueous solution of hydrogen iodide in the presence of, under the temperature that improves in acetone or
Carry out in the base oxide.Perhaps, 1 of formula III-a, 2-dihydro-2,2,4-trimethylquinoline also can by with the corresponding aniline of formula II and acetone at MgSO
4, 4-tert-butyl catechol and iodine existence under prepared in reaction obtain (L.G.Hamann, R.I.Higuchi, L.Zhi, J.P.Edwards and X.-N.Wang, J.Med.Chem, 41:623,1998).In a method again, this reaction can also use lanthanon fluoroform sulphonate (for example trifluoromethanesulfonic acid scandium salts) to carry out as catalyzer in acetone.In this case, the operation (M.E.Theoclitou and L.A.Robinson, Tetrahedron Lett.43:3907,2002) under the temperature that improves of conventional heating or microwave irradiation can at room temperature or be used in described reaction.
Starting raw material can directly be commercially available, and also can be prepared easily by those skilled in the art.
Formula III-b compound can be by the aniline of general formula I I by obtaining with the methyl vinyl ketone prepared in reaction.Relevant cyclization method is described in United States Patent (USP) 2,686,182 (BadischeAnilin-﹠amp; Soda-Fabrik Aktiengesellschaft) in.
Next, R wherein
1And R
2The 1-N-acetylization reaction of Ding Yi formula III-a-b compound can adopt standard conditions to carry out as mentioned.In general experiment; with the formula III compound in diacetyl oxide reflux or in the solvent of for example methylene dichloride, tetrahydrofuran (THF), toluene or pyridine with Acetyl Chloride 98Min. at alkali N for example; the existence of N-diisopropylethylamine, triethylamine or sodium hydride is reaction down; obtain the acetylizad 4-methyl isophthalic acid of N-of formula IV-a-b, the 2-dihydroquindine derivates.
The relevant N-process for acylating of dihydroquinoline skeleton is referring to following document: G.Reddelien and A.Thurm, Chem.Ber.65:1511,1932; Zh.V.Shmyreva, Kh.S.Shikhaliev and E.B.Shpanig, Izv.Vyssh.Uchebn.Zaved.Khim.Khim.Tekhnol.31:45,1988; Zh.V.Shmyreva, Kh.S.Shikhaliev, L.P.Zalukaev, Y.A.Ivanov, Y.S.Ryabokobylko and I.E.Pokrovskaya, Zh.Obshch.Khim.59:1391,1989.
Introducing essential (being substituted) phenyl on 4 of described dihydroquinoline skeleton can be by finishing benzene or the benzene that is suitably replaced with formula IV-a-b generation Friedel-Crafts alkylated reaction.This reaction normally under the temperature that improves, at purified benzene or the benzene that is suitably replaced or in suitable inert solvent (for example heptane or hexane), with as the benzene of reagent or the benzene that suitably replaced at Lewis acid (AlCl for example
3, AlBr
3, FeCl
3Or SnCl
4) carry out under the catalysis.4-trimethylammonium-1, the Friedel-Craft s alkylated reaction of 2-dihydroquinoline: B.A.Lugovik, L.G.Yudin and A.N.Kost, Dokl.Akad.Nauk SSSR, 170:340,1966 have been described and 2,2 in the following document; B.A.Lugovik, L.G.Yudin, S.M.Vinogradova and A.N.Kost, Khim.Geterosikl.Soedin, 7:795,1971.
Perhaps, also can with the aniline of formula II and the 1-vinyl toluene derivative that is suitably replaced and formaldehyde in acetonitrile under room temperature or high temperature reaction obtain formula V-b compound.Relevant cyclization is described in the following document: J.M.Mellor and G.D.Merriman, Tetrahedron, 51:6115,1995.
Formula V-a-b compound can be carried out the nitrated formula VI-a-b compound that obtains of regioselectivity then on 6 of tetrahydroquinoline skeleton.Described reaction is normally carried out as nitrating agent at-10 ℃ of mixtures that use nitric acid and diacetyl oxide to the temperature range of room temperature, in methylene dichloride.Perhaps, also nitric acid can be added to formula V-a-b compound in the solution of Glacial acetic acid or in the mixture of acetate and methylene dichloride.Relevant tetrahydroquinoline regioselectivity nitration reaction is described in the following document: B.Golankiewicz, Pol.J.Chem.54:355,1980; Zh.V.Shmyreva, Kh.S.Shikhaliev, L.P.Zalukaev, Y.A.Ivanov, Y.S.Ryabokobylko and I.E.Pokrovskaya, Zh.Obshch.Khim.59:1391,1989.
The reduction of nitro can be finished by the various methods that are used for the reduction of aromatic nitro-compound well known in the art in the formula VI-a-b compound, for example transition metal-catalyzed hydrogenation, handles, handles under acidic conditions with iron or other metal and (gentleness) acid treatment, with dichloro compound with sulfide etc.More particularly, the reduction of nitro can be finished under 0 ℃ to 100 ℃ temperature range in the 4-diox by using zinc powder and acetate in THF or 1 in the general formula VI-a-b compound.
Next, formula VII-a-b compound can be utilized normal condition well-known in the art to carry out the 6-N-acylation reaction and obtain formula I-a-b compound.For example, with formula VII compound in the solvent of for example methylene dichloride, tetrahydrofuran (THF), toluene or pyridine with carboxylic acid halides (R
6-C (O)-Cl) or acid anhydrides (R
6-C (O)-O-C (O)-R
6) at for example N, the existence of the alkali of N-diisopropylethylamine, triethylamine, pyridine or sodium hydride is reaction down, obtains the 6-N-acetylize-1,2,3 of formula I-a-b, the 4-tetrahydroquinoline derivative.Perhaps, by general formula VII-a-b compound acylation obtain general formula I-a-b compound also can by with suitable carboxylic acid (R
6-CO
2H) at coupling agent O-(benzotriazole-1-yl)-N for example, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU), O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HATU) or bromine tripyrrole Wan Ji Phosphonium hexafluorophosphate (PyBrOP) and tertiary base be N for example, under the existence of N-diisopropylethylamine,, under room temperature or high temperature, react in dinethylformamide or the methylene dichloride and finish at solvent N for example.
R wherein
3=H, OH or (1-4C) alkoxyl group, R
4=OH, R
5=OH or (1-4C) alkoxyl group, R simultaneously
1, R
2And R
6Ding Yi The compounds of this invention can prepare by making general formula I-c-d compound generation demethylating reaction as mentioned.The demethylating reaction of aromatics methyl ether is well-known to those skilled in the art.In representativeness experiment, by being lower than under the temperature of envrionment temperature, with formula 1-c-d compound and BBr
3For example react the demethylation compound that obtains general formula I-e-i in the methylene dichloride at inert solvent, thereby realize demethylation.Perhaps, demethylation also can realize like this, promptly at ambient temperature, and through type 1-c-d compound and BF
3Me
2The S complex compound reacts.By the consumption of careful control reaction temperature and demethylation reagent, can be with the demethylation extent control to a certain degree.Usually obtain be general formula I-e-i single, two with the mixture of trihydroxy-(if relevant) compound, these compounds can separate by chromatography.The carrying out of demethylating reaction has moderate selectivity usually, and preferably carries out demethylation on 5 of tetrahydroquinoline skeleton.The speed of reaction of general formula I-c-d compound demethylation (dealkylation) is 5-OMe＞4-(right-the OAlk-phenyl)＞7-OMe.
R wherein
3Be H or (functionalized) alkoxyl group and R
4And/or R
5Be (functionalized) alkoxyl group or acyloxy The compounds of this invention can by with the hydroxyl of general formula I-e-i compound under standard conditions respectively with (functionalized) alkyl halide (for example chloroethyl pyrrolidine) or acyl chlorides (for example 2-furoyl chloride or methyl-chloroformate) carries out alkylation again or cyclization prepares.
R wherein
4=H and R
5Link to each other and R with the tetrahydroquinoline skeleton by nitrogen-atoms
1, R
2And R
6Ding Yi The compounds of this invention can be by N-Boc-1 as mentioned, and 4-phenylenediamine (VIII) prepares.According to previously described method, make benzene or substituted benzene carry out following reaction successively: (a) Skraup reaction, (b) acetylization reaction, (c) carries out the Friedel-Crafts alkylated reaction and obtains general formula X-a compound then.It should be noted that the Boc blocking group is to slough under the reaction conditions of Friedel-Crafts reaction.
Perhaps, also can be with N-Boc-1, the 4-phenylenediamine is handled with methyl vinyl ketone, and acetylize and carry out Friedel-Crafts reaction according to previously described method then obtains general formula X-b compound.
In a method again, general formula X-b compound can obtain like this: at first 4-toluquinoline (XI) is used BH
3THF complex compound and two (2-methoxyl group-oxyethyl group) aluminium dihydro sodium partial reduction obtain the 4-methyl isophthalic acid, and the 2-dihydroquinoline obtains compounds X II according to previously described method acetylize then.By relevant quinoline to 1, the reduction reaction of 2-dihydroquinoline is described in the relevant document: referring to 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.XII and benzene or the benzene that is suitably replaced carry out the Friedel-Crafts reaction and obtain general formula X III compound, the latter is by the 6-nitration reaction of regioselectivity, utilize previously described condition to be reduced into corresponding 6-aminoderivative then, can be converted into general formula X-b compound like this.The regioselectivity nitration reaction that takes place on similar skeleton has been reported in the relevant document, referring to people such as for example Zh.V.Shmyreva, J.Gen.Chem.USSR (Engl.Transl.) 59:1234,1989.
General formula X-a-b compound can be protected with 9-fluorenyl methoxy carbonyl known in the art (Fmoc group) then, referring to for example: T.W.Greene and P.M.Wuts, Protectivegroups in organic synthesis (the 3rd edition, John Wiley ﹠amp; Sons, Inc.1999 is particularly referring to the 506th page).Above-mentioned protective reaction normally utilize FmocCl THF solution, carry out as alkali with pyridine.
On 7 of the tetrahydroquinoline skeleton of general formula X IV-a-b compound, carry out the regioselectivity nitration reaction,, obtain the 7-amino-1,2,3 of general formula X V-a-b, the 4-tetrahydroquinoline derivative then with nitroreduction (on seeing).The regioselectivity nitration reaction that has on the relevant skeleton of similar replacement situation can be referring to relevant document, referring to for example S.H.Reich, M.A.M.Fuhry, D.Nguyen, people such as M.J.Pino, 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 condition of nitration reaction and conditional likelihood described above.
Aldehydes that amino on 7 of the tetrahydroquinoline derivatives of general formula X V-a-b is used suitably to be replaced and suitable reductive agent (for example sodium cyanoborohydride or sodium triacetoxy borohydride) are at for example methyl alcohol or N, carry out reductive alkylation reaction in the solvent of dinethylformamide, form general formula X VIa-b compound.Usually, formaldehyde causes 7-dimethylamino tetrahydroquinoline derivative (D=E=Me) to form with preponderating, and other aldehyde mainly forms the general formula X VIa-b compound (D=H, E=(functionalized) alkyl) of monoalkylation.The reductive alkylation reaction of aromatic amine is that those skilled in the art are well-known.
The standard cracking of the Fmoc blocking group of use piperidines obtains the amino tetrahydroquinoline derivative of 6-of general formula X VII-a-b in the dichloromethane solution, its selectively acylating on 6 is obtained the The compounds of this invention of general formula I-j-k according to previously described method.
In other method, can be with the amino on 7 of the tetrahydroquinoline derivatives of general formula X V-a-b with (mixing) aryl carboxylic acid (G-CO
2H) or acyl chlorides (G-C (O)-Cl) carries out acidylate according to previously described method.In following step, (the 6-N-Fmoc deprotection is then with resulting 6-NH to carry out identical deacylation step according to previously described method
2Acidylate), obtain the The compounds of this invention of general formula I-l-m then.
R wherein
4=H and R
5Link to each other and R with the tetrahydroquinoline skeleton by Sauerstoffatom
1, R
2And R
6Ding Yi The compounds of this invention can be prepared by 2-methoxyl group-4-N-methyl-p-nitroaniline (XVII) as mentioned.Carry out following reaction successively: (a) the Fmoc protection obtains XIX; (b) nitroreduction is obtained XX, (c) carries out regioselectivity Skraup reaction, (d) acetylization reaction then; (e) carries out the Fmoc deprotection reaction according to previously described method then, forms general formula X XI-a compound like this.
General formula X XI-b compound can form like this, utilizes the formula II that makes described above to handle to the condition that the III-b compound transforms with methyl vinyl ketone the XX compound, carries out 1-N acetylize and Fmoc deprotection reaction according to previously described method then.
Next, general formula X XI can realize like this to the XXIII conversion of compounds, uses for example acyl chlorides R of suitable acylating reagent
6-C (O)-Cl is the amino acidylate of 6-, utilizes condition described above to carry out the Friedel-Crafts reaction with benzene or the benzene derivative that suitably replaced then.Under the lewis acidity condition in the Friedel-Crafts reaction, the demethylation of 7-OMe functional group in the general formula X XII compound appears in simultaneous.The free 7-OH group that obtains in general formula X XIII compound can be used (functionalized) alkyl halide (as chloroethyl pyrrolidine) or acyl chlorides (for example 2-furoyl base muriate or methyl-chloroformate) respectively alkylation or acidylate obtain general formula I-n-o compound (alkyl, acyl group or carbamate that E=is functionalized) again under standard conditions like this.
R wherein
4And R
5The The compounds of this invention that links to each other with the tetrahydroquinoline skeleton by nitrogen-atoms can obtain (wherein PG is that nitrogen-protecting group is rolled into a ball for example Boc, ethanoyl, methyl carbamate or Fmoc) by previously described prepared in reaction by general formula general formula X XIV compound, for example carries out the Skraup reaction or scission reaction, N-alkylated reaction, Friedel-Crafts reaction, nitration reaction, nitro-reduction reaction and the acylation reaction (the same) of contract ring reaction, 1-N-acetylization reaction, blocking group with methyl vinyl ketone.
On general formula X XV compound with acetone or
Base oxide carries out the Skraup reaction, can form two kinds of different zones isomerized products of general formula X XVI-a and XXVII-a respectively.Use methyl vinyl ketone that general formula X XV compound is transformed subject to the foregoing, can obtain having the regional isomerism product of general formula X XVI-b or XXVII-b respectively.In general, the dihydroquinoline of these regional isomerisms can utilize chromatographic techniques (silica gel, HPLC) or crystallization process to separate, and is converted into compound of the present invention by method described above.
R wherein
5The The compounds of this invention of=H can be by carrying out 7 deoxidations of reductibility with general formula X XVIII or XXXI compound (L and/or M are (substituted) alkyl, acyl group carbalkoxy or the alkyl amino-carbonyls that suits) through the triflated reaction of selectivity 7-O-, reduces 7-OTf (Tf=trifluoromethyl sulfonyl) group then.Essential general formula X XXI compound can utilize condition described above to obtain by general formula X XVII derivative.Should (selecting property of zone) triflated reaction can use Tf under certain condition
2N-phenyl and N, the DMF solution of N-diisopropylethylamine carries out under room temperature.In general, preferably on the 7-OH group, carry out triflated reaction.Ensuing reduction reaction can use the mixture of triphenylphosphine, triethylamine, formic acid and acid chloride (II) to finish according to the method for describing in the relevant document.Referring to for example K.A.Parker, Q.Ding, Tetrahedron 56:10249,2000.Utilize condition described above to transform with general formula X XX or XXXII resulting compound, obtain general formula I-p-q compound, wherein R then
5=H.
Some compound of the present invention can be the form of free alkali, and these compounds can be separated from reaction mixture with the form of pharmacologically acceptable salt.Pharmacologically acceptable salt also can be by for example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, phosphoric acid, acetate, propionic acid, oxyacetic acid, toxilic acid, propanedioic acid, methylsulfonic acid, fumaric acid, succsinic acid, tartrate, citric acid, phenylformic acid and xitix are handled and obtained with organic or inorganic acid with the free alkali of formula I.
The compounds of this invention has at least one chiral carbon atom, thereby can obtain with the mixture of pure enantiomorph or enantiomer or the form of mixtures of diastereomer.The method that obtains pure enantiomorph is well-known in the art, for example will obtain salt by optical activity acid and racemic mixture and carry out crystallization, perhaps utilizes the chromatography of chiral column.For diastereomer, can utilize positive or reversed-phase column.
The compounds of this invention can form hydrate or solvate.It is known to those skilled in the art that when feed compound and water-cooled freeze-drying were dry, it formed hydration material, formation solvate when perhaps in it is containing the solution of suitable organic solvent, concentrating.The compounds of this invention comprises the hydrate or the solvate of compound listed above.
For the selection of active compound, 10
-5The activity of the maximum activity high 20% that M is obtained when test must obtain ratio use FSH as reference down.Another kind of standard can be EC
50Value, its necessary＜10
-5M, preferred＜10
-7M.
It should be appreciated by those skilled in the art that ideal EC
50Value depends on tested compound.For example, it has been generally acknowledged that EC
50Value is less than 10
-5The compound of M is the candidate compound for medicament selection.Preferably should be worth less than 10
-7M.Yet, have higher EC
50If compound have selectivity for special receptor, may or even better candidate compound.
It all is well-known measuring the method for receptors bind and the interior measuring method of bioactive external and body of mensuration gonad-stimulating hormone.Usually, the acceptor that will be expressed contacts with testing compound, measures combination or stimulation or inhibition situation that function is replied then.
For measurement function is replied, the DNA (preferably being people's acceptor) of the coding fsh receptor gene that exsomatizes is expressed in suitable host cell.This cell can be a Chinese hamster ovary cell, but other cell also suits.Preferred this cell is cell people such as (, Mol.Endocrin.5:759-776,1991) Jia of mammalian source.
The method that makes up Recombinant FSH express cell system is (people such as Sambrook well-known in the art, Molecular Cloning:a Laboratory Manual, Cold SpringHarbor Laboratory Press, Cold Spring Harbor, latest edition).Receptor expression is that the expression by the DNA that expresses the coding desired protein realizes.The constructing technology of the connection of site-directed mutagenesis, appended sequence, PCR and appropriate expression system all is well-known in the art so far.Can utilize the synthetic part or all of DNA that makes up the coding desired protein of standard solid-phase technology, preferably include the restriction site that is used for easy connection.The suitable controlling elements (element) that can be provided for transcribing of the described encoding sequence that comprises and translate the dna encoding sequence.As well-known be, can obtain the expression system compatible with various hosts now, described host comprises: prokaryotic hosts is for example yeast, vegetable cell, insect cell, mammalian cell, birds cell etc. of bacterium and eucaryon host for example.
Then, the cell with expressed receptor contacts combination or the stimulation or the inhibition situation of replying with overview function with test compounds.
Perhaps, also can utilize the isolated cells film that comprises expressed acceptor measure compound in conjunction with situation.
As for mensuration, can utilize radiolabeled or fluorescently-labeled compound in conjunction with situation.In addition can also being at war with property in conjunction with mensuration.
Another kind of assay method relates to by the stimulation situation of measuring receptor-mediated cAMP accumulation screens the fsh receptor agonist compound.So this method comprises, expressed receptor on the host cell surface and with cellular exposure under test compounds.Measure the content of cAMP then.The level of cAMP can reduce or increase, inhibition when this depends on test compounds and receptors bind or hormesis.
Screening to the fsh receptor antagonist relates to, (promptly do not having under the situation of test compounds in FSH concentration fixing, inferior maximal effective dose (Submaximally effective), induce 80% FSH concentration of the maximal stimulation of about cAMP accumulation) under, with the test compounds incubation in fsh receptor express cell and the concentration range.According to concentration-effect curve, can measure and obtain the IC that each test compounds suppresses FSH inductive cAMP accumulation
50Value and percentage ratio.
Except directly being determined at for example cAMP level in the exposed cell, can also utilize such clone, these clones are except the DNA transfection with the coding acceptor, and also with second kind of DNA transfection of coding reporter gene, the expression of these reporter genes is replied the level of cAMP.Such reporter gene may be that cAMP is derivable, perhaps can make up by this way so that they can be connected with new cAMP response element.Usually, the expression of reporter gene can be by any response element control that change cAMP level is reacted.Suitable reporter gene for example is the gene of coding beta-galactosidase, alkaline phosphatase, Photinus pyralis LUC and green fluorescent protein.It is well-known in the art that this class trans-activation is measured ratio juris, is described in for example Stratowa, Ch.Himmler, and A. and Czernilofsky are among A.P. (1995) Curr.Opin.Biotechnol.6:574.Can utilize people's Recombinant FSH as reference compound.In alternative method, can also being at war with property in conjunction with mensuration.
The invention still further relates to a kind of pharmaceutical composition, it contains tetrahydroquinoline derivative or its pharmacologically acceptable salt that has general formula I with pharmaceutically acceptable assistant agent and other optional therapeutical agent blended.Described assistant agent with composition in the meaning of other component compatibility on, must be " acceptable " and harmless to its recipient.
Composition for example comprises that those forms with dosage unit are fit to the composition of oral, hypogloeeis, subcutaneous, intravenously, intramuscular, part or rectal administration etc.
For oral administration, active ingredient can provide with unit independently, for example tablet, capsule, powder, granule, solution, suspensoid etc.
For parenterai administration, pharmaceutical composition of the present invention can provide with the form of single dose or multi-dose container, the injection liquid of predetermined amount for example, as be contained in airtight bottle or the ampoule, can also under the condition of freeze-drying (lyophilize), store, only need to add for example water of sterile liquid carrier before using.
According to for example being described in normative document Gennaro, people such as A.R., Remington:TheScience and Practice of Pharmacy (the 20th edition, Lippincott Williams﹠amp; Wilkins, 2000, especially referring to the 5th part: the method PharmaceuticalManufacturing), after the pharmaceutically acceptable assistant agent of this class mixes, promoting agent can be pressed into the solid unit dosage form, and for example ball, sheet perhaps are processed into capsule or suppository.By by means of pharmaceutically acceptable liquid, promoting agent can use with the form of liquid composition, for example is the injection formulations of solution, suspensoid, emulsion form, perhaps sprays nasal mist for example.
In order to prepare solid dosage unit, expection can utilize conventional additive, for example weighting agent, tinting material, polymer binder etc.Usually, can utilize not function to produce any pharmaceutically acceptable additive of interferential to described active compound.Can comprise the lactose that uses with proper content, starch, derivatived cellulose etc. or its mixture with the suitable carrier that promoting agent of the present invention is used as solids composition.For parenterai administration, can utilize aqueous suspensions, etc. ooze salts solution agent and aseptic injectable solution agent, they contain pharmaceutically acceptable dispersion agent and/or wetting agent, for example propylene glycol or butyleneglycol.
The present invention further comprises aforesaid pharmaceutical composition, and it combines with the wrapping material that are suitable for described composition, and described wrapping material comprise the explanation of using said composition to be used for aforementioned applications.
Tetrahydroquinoline derivative derivative of the present invention can also be used with implantable medication device form, and it is made up of the active substance core of being regulated the film coating by release rate.This implant is in subcutaneous or local use, and can be in considerable time (for example several weeks are to the several years) disengage activeconstituents with the speed of constant.The method for preparing this implantable medication device is known in the art, for example is described in European patent 0,303, among 306 (the AKZO Nobel N.V.).
Use the exact dosage desired and the dosage regimen of active ingredient or its pharmaceutical composition to depend on the desired result of treatment that reaches (treatment infertility; But also can with specific compound, route of administration and to take individual patient age of this medicine different with the patient's condition and different contraception).
In general, parenterai administration requires than the lower dosage of other medication that more depends on absorption.Yet human dose preferably contains the 0.0001-25mg/kg body weight.Required dosage can be single dose form or as a plurality of sub-dosage forms in one day with the appropriate intervals administration, perhaps with regard to female subject, required dosage can also be with a plurality of sub-dosage form of suitable day interval administration in the menstrual cycle.Dosage can be different with male sex curee and different with the women with dosage regimen.
Therefore, compound according to the present invention can be used for treatment.
The present invention advances also to relate on the one hand the tetrahydroquinoline derivative compound with general formula I and is used to prepare treatment has the medicine of the disease of replying to the approach of fsh receptor mediation purposes.Therefore, there is the patient of above-mentioned needs can take the The compounds of this invention of suitable consumption.
In the present invention on the other hand, also relate to the purposes that the tetrahydroquinoline derivative compound with general formula I is used to prepare the medicine of controlling fertility.
In another aspect of the invention, also relate to the purposes that the tetrahydroquinoline derivative compound with general formula I is used to prepare the medicine for the treatment of infertility.
In further aspect of the present invention, also relate to the purposes that the tetrahydroquinoline derivative compound with general formula I is used to prepare the medicine that prevents fertility.
Compound of the present invention also can be used for treating hormone-dependent diseases, for example mammary cancer, prostate cancer and endometriosis.
Present invention is described by the following examples.
Embodiment
General note:
Shortenings below having used in an embodiment: DMA=N, accelerine, DIPEA=N, the N-diisopropylethylamine, TFA=trifluoroacetic acid, DtBAD=azo-2-carboxylic acid di tert butyl carbonate, HATU=O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate, Fmoc=9-fluorenes methoxycarbonyl, Fmoc-Cl=9-fluorenes methoxycarbonyl muriate, DMF=N, dinethylformamide, DMAP=4-Dimethylamino pyridine, THF=tetrahydrofuran (THF).
Except as otherwise noted, all end products among the following embodiment are by water/1,4-diox mixture or water/acetonitrile mixture lyophilize.If compound prepares with the form of HCl or tfa salt, can in lyophilize forward direction solvent mixture, add the respective acids of sufficient quantity.
The end product title of describing among the embodiment adopts Beilstein Autonom program (version: 2.02.119) generate.
In order to measure retention time, the analysis HPLC method below adopting:
Method 1: post: 5 μ m Luna C-18 (2) 150 * 4.6mm; Flow velocity: 1ml/ minute; Check point: 210nm; Column temperature: 40 ℃; Solvent orange 2 A: CH
3CN/H
2O=1/9 (v/v); Solvent B:CH
3CN; Solvent C: 0.1M trifluoroacetic acid aqueous solution; Gradient: solvent orange 2 A/B/C=65/30/5 to 10/85/5 (v/v/v) continues 30.00 minutes, and A/B/C=10/85/5 (v/v/v) is constant other 10.00 minutes then.
Method 2: other is with method 1 except used gradient, and gradient: A/B/C=75/20/5 to 15/80/5 (v/v/v) continues 30.00 minutes, and A/B/C=15/80/5 (v/v/v) is constant other 10.00 minutes then.
Method 3: other is with method 1 except used gradient, and gradient: A/B/C=35/60/5 to 10/85/5 (v/v/v) continues 30.00 minutes, and A/B/C=15/80/5 (v/v/v) is constant other 10.00 minutes then.
Method 4: post: 3 μ m Luna C-18 (2) 100 * 2mm; Flow velocity: 0.25ml/ minute; Check point: 210nm; Column temperature: 40 ℃; Solvent orange 2 A: H
2O; Solvent B:CH
3CN; Gradient: solvent orange 2 A/B=75/25 to 0/100 (v/v) continues 20.00 minutes, and A/B=0/100 (v/v) is constant other 10.00 minutes then.
Method 5: post: 3 μ m Luna C-18 (2) 100 * 2mm; Flow velocity: 0.25ml/ minute; Check point: 210nm; Column temperature: 40 ℃; Solvent orange 2 A: H
2O; Solvent B:CH
3CN; Solvent C: 50mM phosphate buffer soln, pH2.1; Gradient: solvent orange 2 A/B/C=70/20/10 to 10/80/10 (v/v/v) continues 20.00 minutes, and A/B/C=10/80/10 (v/v/v) is constant other 10.00 minutes then.
Method 6: other is with method 5 except used gradient, and gradient: solvent orange 2 A/B/C=65/30/5 continues 20.00 minutes to 10/85/5 (v/v/v), then A/B/C=10/85/5 (v/v/v) constant other 10.00 minutes.
Make being prepared property HPLC purifying in the following method:
Method A: post=Luna C-18.Gradient: the H of 0.1% trifluoroacetic acid
2O/CH
3CN (9/1, v/v)/CH
3CN=80/20 to 0/100 (v/v) continues 30-45 minute, depends on isolating degree of difficulty.Check point: 210nm.
Method B: post=Luna C-18.Gradient: H
2O/CH
3CN (9/1, v/v)/CH
3CN=80/20 to 0/100 (v/v) continues 30-45 minute, depends on isolating degree of difficulty.Check point: 210nm.
Embodiment 1
N-[1-ethanoyl-5,7-dimethoxy-4 '-(4-methoxyl group-phenyl)-2,2,4-trimethylammonium
-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-3-chloro-2,6-dimethoxy-benzamide
(a).
5.7-dimethoxy-2,2,4-trimethylammonium-1,2-dihydroquinoline
At room temperature, with 3, acetone (800ml) solution of 5-dimethoxyaniline (50g) dropwise is added to MgSO
4(100g) and Sc (OTf)
3(8.0g) in the mixture in 1 liter of acetone.After 5 hours, add the Sc (OTf) of another part
3(3.2g), stirred reaction mixture is up to there not being the starting raw material residue.After overanxious, part acetone is removed in vacuum-evaporation, makes the title compound crystallization by filtering collection, to obtain 22g after the vacuum-drying.Residual mother liquor vacuum concentration by silica gel chromatography purifying resistates, uses heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent, the 19.4g title compound of getting back.
Yield: 42g.
(b).
1-ethanoyl-5,7-dimethoxy-2,2,4-trimethylammonium-1,2-dihydroquinoline
The compound (42g) described among the embodiment 1a mixture with diacetyl oxide (100ml) was stirred 20 hours down at 100 ℃.In the reaction mixture impouring 500ml frozen water, stir simultaneously.By filtering the solid that collecting precipitation is separated out, then 40 ℃ of following vacuum-dryings 2 days.Residual brown solid can use crude product for further synthetic conversion.
Yield: 45g.
(c).
1-ethanoyl-5,7-dimethoxy-4 '-(4-p-methoxy-phenyl)-2,2,4-trimethylammonium -1,2,3,4-tetrahydrochysene-quinoline
With compound (30g) and the AlCl that describes among the embodiment 1b
3(44g) mixture in methyl-phenoxide (500ml) stirred 18 hours down at 50 ℃.Make reaction mixture cooling (0 ℃), water quencher simultaneously adds ethyl acetate.Mixture stirs and spends the night.Separate organic layer, use MgSO
4Drying is filtered and vacuum concentration.Resistates is handled through silica gel chromatography, uses heptane/ethyl acetate=8/2 (v/v) as eluent.
Yield: 15g.
(d).
1-ethanoyl-5,7-dimethoxy-4 '-(4-p-methoxy-phenyl)-2,2,4-trimethylammonium -6-nitro-1,2,3, the 4-tetrahydroquinoline
Under 0 ℃, nitrosonitric acid (22.5ml) solution of diacetyl oxide (450 μ l) dropwise is added to the CH of the compound of describing among the embodiment 1c (15g)
2Cl
2(500ml) in the solution.After reinforced the finishing, reaction mixture at room temperature stirred 3 hours.Add entry, separate organic layer, use MgSO
4Drying is filtered and vacuum concentration.Resistates obtains title compound into crystalline solid by alcohol crystal.
Yield: 10g.
(e).
1-ethanoyl-6-amino-5,7-dimethoxy-4 '-(4-p-methoxy-phenyl)-2,2,4- Trimethylammonium-1,2,3, the 4-tetrahydroquinoline
The compound (11.75g) described among the embodiment 1d and THF (600ml) solution of acetate (15.5ml) are cooled to 0 ℃.Add zinc powder (36g) in batches, remove ice bath simultaneously.Temperature rises to 30 ℃ rapidly, then reaction is cooled to room temperature.By removing by filter excessive zinc powder, in filtrate, add CH
2Cl
2With saturated Na
2CO
3The aqueous solution.Separate organic layer, use MgSO
4Drying is filtered and vacuum concentration.This product directly uses its crude product in next step.
Yield: 10.9g.
(f).
N-[1-ethanoyl-5,7-dimethoxy-4 '-(4-methoxyl group-phenyl)-2,2,4-three Methyl isophthalic acid, 2,3,4-tetrahydrochysene-quinoline-6-yl]-3-chloro-2,6-dimethoxy-benzamide
General step A: at room temperature, the compound of in embodiment 1e, describing (100mg), 3-chloro-2, the CH of 6-dimethoxybenzoic acid (60mg) and DIPEA (132 μ l)
2Cl
2(2ml) add HATU (143mg) in the solution.If incomplete as yet after being reflected at 18 hours, add more HATU and DIPEA.After reaction is finished, add NaHCO
3Saturated aqueous solution separates organic layer, dry (MgSO
4) and vacuum concentration.By preparation property HPLC purifying title compound (method A).
Yield: 87mg.
MS-ESI：[M+H]
+＝597.4
HPLC:R
t=17.98 minutes (method 1).
Embodiment 2
4,5-dimethyl-furans-2-carboxylic acid [1-ethanoyl-5,7-dimethoxy-4 '-(4-methoxyl group
-phenyl)-2,2,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
General step B: at room temperature, the compound of describing in embodiment 1e (800mg), 4 adds HATU (1.1g) in DMF (10ml) solution of 5-dimethyl furan-2-carboxylic acid (308mg) and DMA (768 μ l).If incomplete as yet after being reflected at 18 hours, reaction mixture is heated to 50 ℃.After reaction is finished, add entry and ethyl acetate, separate organic layer, dry (MgSO
4) and vacuum concentration.By silica gel chromatography purifying title compound, use heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent.
Yield: 444mg.
MS-ESI：[M+H]
+＝521.4
HPLC:R
t=16.96 minutes (method 1).
Embodiment 3
5-bromo-thiophene-2-carboxylic acid [1-ethanoyl-57-dimethoxy-4 '-(4-methoxyl group-benzene
Base)-2,2,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
According to general step B, with the compound (800mg) described among the embodiment 1e with 5-bromo thiophene-2-carboxylic acid (456mg), DMA (768 μ l) and HATU (1.1g) at CH
2Cl
2Acidylate (10ml).By silica gel chromatography purifying title compound, use heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent.
Yield: 1.0g.
MS-ESI:[M+H]
+=589.2; HPLC:R
t=18.90 minutes (method 2).
Embodiment 4
Xenyl-4-carboxylic acid [1-ethanoyl-5,7-dimethoxy-4 '-(4-methoxyl group-benzene
Base)-2,2,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
General step C: at room temperature, compound of describing in embodiment 1e (800mg) and 4-xenyl carbonyl chloride (475mg) are at CH
2Cl
2Add DMA (7681) in the solution (10ml).Stirred reaction mixture remains up to no starting raw material, adds entry this moment.Separate organic layer, dry (MgSO
4) and vacuum concentration.By silica gel chromatography purifying title compound, use heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent.
Yield: 678mg.
MS-ESI:[M+H]
+=579.4; HPLC:R
t=26.19 minutes (method 2).
Embodiment 5
Furans-2-carboxylic acid [1-ethanoyl-5-hydroxyl-7-methoxyl group-4-(4-methoxyl group-benzene
Base)-2,2,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
(a).
Furans-2-carboxylic acid [1-ethanoyl-5,7-dimethoxy-4 '-(4-anisole Base)-2,2,4-trimethylammonium-1,2,3,4-tetrahydroquinoline-6-yl] acid amides
According to general step C, use 2-furoyl base muriate (217 μ l) and DMA (768 μ l) at CH the compound of describing among the embodiment 1e (800mg)
2Cl
2Acidylate (10ml).By silica gel chromatography purifying title compound, use heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent.
Yield: 896mg.
(b).
Furans-2-carboxylic acid [1-ethanoyl-5-hydroxyl-7-methoxyl group-4-(4-methoxyl group-benzene Base)-2,2,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
General step D: with the compound (50mg) described among the embodiment 5a at CH
2Cl
2Under nitrogen atmosphere, be cooled to-78 ℃ (4ml).Dropwise add boron tribromide (28 μ l), after reinforced the finishing, reaction mixture slowly is warmed to room temperature.To react the water quencher, add CH
2Cl
2Separate organic layer, dry (MgSO
4) and vacuum concentration.By preparation property HPLC purifying title compound (method A).Under these conditions, form the mixture of compound usually, it is passed through preparation property HPLC method purifying with variable demethylation degree.
Yield: 9.1mg; MS-ESI:[M+H]
+=479.4; HPLC:R
t=23.40 minutes (method 2).
Embodiment 6
N-[1-ethanoyl-5-hydroxyl-7-methoxyl group-4-(4-methoxyl group-phenyl)-2,2, the 4-front three
Base-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-3,5-two chloro-benzamide
(a).
N-[1-ethanoyl-5,7-dimethoxy-4 '-(4-p-methoxy-phenyl)-2,2,4-three Methyl isophthalic acid, 2,3,4-tetrahydroquinoline-6-yl]-3, the 5-dichloro-benzamide
According to general step C, with 3,5-dichlorobenzoyl chloride (460mg) and DMA (768 μ l) are at CH with the compound (800mg) described among the embodiment 1e
2Cl
2Acidylate (10ml).By silica gel chromatography purifying title compound, use heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent.
Yield: 1.03g.
(b).
N-[1-ethanoyl-5-hydroxyl-7-methoxyl group-4-(4-methoxyl group-benzene Base)-2,2,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-3,5-two chloro-benzamide
According to general step D, use boron tribromide (24 μ l) at CH the compound of describing among the embodiment 6a (50mg)
2Cl
2Handle (4ml).By preparation property HPLC method purifying title compound (method A).
Yield: 9.6mg; MS-ESI:[M+H]
+=557.2; HPLC:R
t=23.40 minutes (method 2).
Embodiment 7
5-chloro-thiophene-2-carboxylic acid [1-ethanoyl-5-hydroxyl-7-methoxyl group-4-(4-methoxyl group-benzene
Base)-2,2,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
(a).
5-chlorothiophene-2-carboxylic acid [1-ethanoyl-5, the 7-dimethoxy-4 '-(the 4-methoxyl group- Phenyl)-2,2,4-trimethylammonium-1,2,3,4-tetrahydroquinoline-6-yl]-acid amides
According to general step B, with the compound (800mg) described among the embodiment 1e with 5-chloro thiophene-2-carboxylic acid (456mg), DMA (768 μ l) and HATU (1.1g) at CH
2Cl
2Handle (10ml).By silica gel chromatography purifying title compound, use heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent.
Yield: 1.0g.
(b).
5-chloro-thiophene-2-carboxylic acid [1-ethanoyl-5-hydroxyl-7-methoxyl group-4-(4-methoxy Base-phenyl)-2,2,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
According to general step D, use boron tribromide (350 μ l) at CH the compound of describing among the embodiment 7a (200mg)
2Cl
2Handle (25ml), but temperature is no more than-30 ℃ in the present embodiment.Title compound uses heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent by the silica gel chromatography purifying, and then handles (method A) by preparation property HPLC.
Yield: 35mg; MS-ESI:[M+H]
+=529.2; HPLC:R
t=28.24 minutes (method 2).
Embodiment 8
Xenyl-4-carboxylic acid [1-ethanoyl-5-hydroxyl-7-methoxyl group-4-(4-methoxyl group-benzene
Base)-2,2,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
According to general step D, use boron tribromide (100 μ l) at CH the compound of describing among the embodiment 4 (50mg)
2Cl
2Handle (4ml), but temperature is no more than 0 ℃ in the present embodiment.Reaction mixture also contains the product of describing among the embodiment 10.By silica gel chromatography purifying title compound, use heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent.
Yield: 43mg; MS-ESI:[M+H]
+=565.4; HPLC:R
t=32.53 minutes (method 2).
Embodiment 9
Xenyl-4-carboxylic acid [1-ethanoyl-5,7-dihydroxyl-4-(4-hydroxyl-phenyl)-2,2,4-
Trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
According to general step D, use boron tribromide (100 μ l) at CH the compound of describing among the embodiment 4 (50mg)
2Cl
2Handle (4ml), but temperature is no more than 15 ℃ in the present embodiment.By silica gel chromatography purifying title compound, use heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent.
Yield: 33mg; MS-ESI:[M+H]
+=537.4; HPLC:R
t=24.16 minutes (method 2).
Embodiment 10
Xenyl-4-carboxylic acid [1-ethanoyl-5-hydroxyl-4-(4-hydroxyl-phenyl-7-methoxyl group
-2,2,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
According to general step D, use boron tribromide (800 μ l) at CH the compound of describing among the embodiment 4 (400mg)
2Cl
2Handle (25ml), but temperature is no more than 0 ℃ in the present embodiment.By silica gel chromatography purifying title compound (by product of describing among=the embodiment 8), use heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent.
Yield: 50mg; MS-ESI:[M+H]
+=551.4; HPLC:R
t=27.58 minutes (method 2).
Embodiment 11
4,5-dimethyl-furans-2-carboxylic acid [1-ethanoyl-5-hydroxyl-7-methoxyl group-4-(4-first
Oxygen base-phenyl)-2,2,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
According to general step D, use boron tribromide (336 μ l) at CH the compound of describing among the embodiment 2 (200mg)
2Cl
2Handle (25ml), but temperature remains on-78 ℃ in the present embodiment.By preparation property HPLC purifying title compound (method A).
Yield: 51mg; MS-ESI:[M+H]
+=507.4; HPLC:R
t=24.32 minutes (method 1).
Embodiment 12
N-[1-ethanoyl-5-hydroxyl-4-(4-hydroxyl-phenyl)-7-methoxyl group-2,2, the 4-trimethylammonium
-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-3,5-two chloro-benzamide
According to general step D, use boron tribromide (38 μ l) at CH the compound of describing among the embodiment 6a (75mg)
2Cl
2Handle (5ml).By preparation property HPLC purifying title compound (method A).
Yield: 11mg; MS-ESI:[M+H]
+=543.4; HPLC:R
t=25.66 minutes (method 2).
Embodiment 13
N-[1-ethanoyl-5-hydroxyl-7-methoxyl group-4-(4-methoxyl group-phenyl)-2,2, the 4-front three
Base-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-3,5-dimethyl-benzamide
(a).
N-[1-ethanoyl-5,7-dimethoxy-4 '-(4-p-methoxy-phenyl)-2,2,4-three Methyl isophthalic acid, 2,3,4-tetrahydroquinoline-6-yl]-3,5-dimethyl-benzamide
According to general step B, with 3,5-mesitylenic acid (330mg), DMA (768 μ l) and HATU (1.1g) are at CH with the compound (800mg) described among the embodiment 1e
2Cl
2Acidylate (10ml).By silica gel chromatography purifying title compound, use heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent.
Yield: 1.18g.
(b).
N-[1-ethanoyl-5-hydroxyl-7-methoxyl group-4-(4-methoxyl group-benzene Base)-2,2,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-3,5-dimethyl-benzoyl Amine
According to general step D, use boron tribromide (513 μ l) at CH the compound of describing among the embodiment 13a (300mg)
2Cl
2Handle (25ml), but temperature is no more than-40 ℃ in the present embodiment.By preparation property HPLC purifying title compound (method A).
Yield: 41mg; MS-ESI:[M+H]
+=517.4; HPLC:R
t=13.89 minutes (method 3).
Embodiment 14
N-[1-ethanoyl-5-hydroxyl-7-methoxyl group-4-(4-methoxyl group-phenyl)-2,2, the 4-front three
Base-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-3,5-two bromo-benzamide
(a).
N-[1-ethanoyl-5,7-dimethoxy-4 '-(4-p-methoxy-phenyl)-2,2,4-three Methyl isophthalic acid, 2,3,4-tetrahydroquinoline-6-yl]-3,5-dibromobenzene methane amide
According to general step B, with the compound (800mg) described among the embodiment 1e with 3,5-dibromobenzoic acid (616mg), DMA (768 μ l) and HATU (1.1g) acidylate in DMF (10ml).By silica gel chromatography purifying title compound, use heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent.
Yield: 900mg.
(b).
N-[1-ethanoyl-5-hydroxyl-7-methoxyl group-4-(4-methoxyl group-benzene Base)-2,2,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-3,5-two bromo-benzamide
According to general step D, use boron tribromide (639 μ l) at CH the compound of describing among the embodiment 14a (300mg)
2Cl
2Handle (25ml), but temperature is no more than-60 ℃ in the present embodiment.By preparation property HPLC purifying title compound (method B).
Yield: 28mg; MS-ESI:[M+H]
+=647.2; HPLC:R
t=16.29 minutes (method 3).
Embodiment 15
Xenyl-4-carboxylic acid [1-ethanoyl-2,2,4-trimethylammonium-7-(2-morpholine-4-base-ethoxy
Base-4-phenyl-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
(a).
1-Fmoc-2-methoxyl group-4-N-methyl-p-nitroaniline
THF (30ml) solution of 2-methoxyl group-4-N-methyl-p-nitroaniline (3.0g) and pyridine (1.6ml) is cooled to 0 ℃.Add FmocCl (5.07g) in batches, after reinforced the finishing, remove ice bath, mixture stirred 5 hours.Vacuum is removed THF, and resistates is dissolved in CH
2Cl
2(175ml).Add methyl alcohol (approximately 100ml), vacuum is removed portion C H
2Cl
2Up to forming precipitation.Mixture left standstill 1 hour, and by filtering collecting precipitation, vacuum-drying obtains title compound then.
Yield: 6.32g; MS-ESI:[M+H]
+=391.2
(b).
9-fluorenyl methyl N-(2-methoxyl group-4-aminophenyl) carbamate
General step E: the mixture of the compound (6.07g), acetate (8.9ml) and the THF (150ml) that describe among the embodiment 15a is cooled to 0 ℃.Add zinc powder (20.4g) in batches, remove ice bath.After temperature slowly reaches 10 ℃, rise to 45 ℃ rapidly.After reaction mixture is cooled to room temperature,, add a large amount of CH by removing by filter excessive zinc
2Cl
2(approximately 500ml).Mixture is with saturated NaHCO
3The aqueous solution (3 * 200ml) and salt solution (1 * 200ml) washing.Separate organic layer, dry (MgSO
4), filtration and vacuum concentration are up to forming throw out.Mixture is placed down at 0 ℃ and is spent the night, and collect crystallization by filtering this moment, and vacuum-drying obtains title compound.
Yield: 4.45g.
(c).
(7-methoxyl group-2,2,4-trimethylammonium-1,2-dihydroquinoline-6-yl)-carboxylamine 9H-fluorenes-9-ylmethyl ester
With compound (4.45g), the I that describes among the embodiment 15b
2(157mg), MgSO
4(7.4g), the mixture heating up of 4-tert-butyl catechol (61mg) and acetone (approximately 350ml) refluxed 5 hours.By removing by filter MgSO
4, the filtrate vacuum concentration.Use heptane/ethyl acetate=9/1=＞7/3 (v/v) as eluent by silica gel chromatography, obtain title compound.
Yield: 4.24g.
(d).
(1-ethanoyl-7-methoxyl group-2,2,4-trimethylammonium-1,2-dihydroquinoline-6-yl)- Carboxylamine 9H-fluorenes-9-ylmethyl ester
The pyridine (25ml) and the CH of the compound of in embodiment 15c, describing (4.24g)
2Cl
2(25ml) add a small amount of DMAP (approximately 20mg) in the solution.The CH that slowly adds Acetyl Chloride 98Min. (2.0ml)
2Cl
2(20ml) solution.After reinforced the finishing, mixture CH
2Cl
2(approximately 100ml) dilution, water (3 * 100ml), the 0.1M HCl aqueous solution (3 * 100ml), the 0.5M HCl aqueous solution (1 * 100ml) and salt solution (1 * 100ml) washs.Organic layer drying (MgSO
4) and vacuum concentration.Use heptane/ethyl acetate=9/1=＞7/3 (v/v) as eluent by silica gel chromatography, obtain title compound.
Yield: 3.91g.
(e).
1-ethanoyl-6-amino-7-methoxyl group-2,2,4-trimethylammonium-1,2-dihydroquinoline
Piperidines (8.0ml) is added to the CH of the compound of describing among the embodiment 15d (3.91g)
2Cl
2(80ml) in the solution.1.5 after hour, the reaction mixture vacuum concentration uses heptane/ethyl acetate=9/1=＞7/3 (v/v) as eluent by silica gel chromatography, obtains title compound.
Yield: 2.2g.
(f).
(2-two for 1-ethanoyl-7-methoxyl group-2,2,4-trimethylammonium-1 for xenyl-4-carboxylic acid Hydrogen quinoline-6-yl)-acid amides
General step F: add 4-xenyl carbonyl chloride (2.21g) in the mixture of the compound of in embodiment 15e, describing (2.2g), toluene (45ml) and pyridine (5ml).If incomplete as yet under room temperature after being reflected at 3 hours, add a part of 4-xenyl carbonyl chloride (2.0g) again.Stirred lasting 30 minutes, then the reaction mixture vacuum concentration.Resistates is dissolved in the ethyl acetate (approximately 100ml), uses saturated NaHCO
3The aqueous solution (100ml), the 1M HCl aqueous solution (3 * 100ml) and salt solution (100ml) washing.Organic layer drying (MgSO
4) and vacuum concentration.In resistates, add CH
2Cl
2(approximately 50ml) is by solids removed by filtration and discard.The filtrate vacuum concentration uses heptane/ethyl acetate=1/0=＞1/1 (v/v) as eluent by silica gel chromatography, obtains title compound.
Yield: 3.1g.
(g).
Xenyl-4-carboxylic acid (1-ethanoyl-7-hydroxyl-2,2,4-trimethylammonium-4-phenyl -1,2,3,4-tetrahydroquinoline-6-yl)-acid amides
General step G: add aluminum chloride (5.6g) in benzene (100ml) solution of the compound of describing in embodiment 15f (3.1g), reaction mixture at room temperature stirred 20 hours.Reaction H
2O quencher (approximately 100ml) uses the 2M NaOH aqueous solution to regulate mixture pH to pH8, simultaneously vigorous stirring.Add ethyl acetate (approximately 300ml), organic layer H
2O (2 * 150ml) and salt solution (1 * 150ml) washing, dry (MgSO
4) and vacuum concentration obtain product, it directly uses not repurity.
Yield: 3.5g.
(h).
Xenyl-4-carboxylic acid [1-ethanoyl-2,2,4-trimethylammonium-7-(2-morpholine-4-base- Oxyethyl group)-and 4-phenyl-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
General step H: with compound (70mg), N-(2-chloroethyl)-morpholine hydrochloride (31mg), the Cs that describes among the embodiment 15g
2CO
3And the mixture of DMF (3ml) is residual up to no longer including starting raw material 50 ℃ of stirrings down.Reaction mixture adds entry (approximately 15ml) with ethyl acetate (15ml) dilution.Organic layer wash with water (3 * 15ml), separate dry (MgSO
4), filter and vacuum concentration.By by 1,4-diox and contain the H of HCl
2The mixture lyophilize of O obtains the corresponding hydrochloride form of title compound.
Yield: 63mg (HCl salt); MS-ESI:[M+H]
+=618.6; HPLC:R
t=19.49 minutes (method 4).
Embodiment 16
Xenyl-4-carboxylic acid (1-ethanoyl-7-formyl-dimethylamino methoxyl group-2,2,4-
Trimethylammonium-4-phenyl-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
According to general step H, with compound (79mg) 2-chloro-N,N-dimethylacetamide (23mg) and the Cs that describes among the embodiment 15g
2CO
3(255mg) alkylation in DMF (2ml).By by CH
3The CN crystallization obtains title compound.
Yield: 15mg; MS-ESI:[M+H]
+=590.6; HPLC:R
t=23.58 minutes (method 5).
Embodiment 17
Xenyl-4-carboxylic acid [1-ethanoyl-2,2,4-trimethylammonium-4-phenyl-7-(3-piperidines-1-
Base-propoxy-)-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
According to general step H, with compound (79mg) N-(3-chloropropyl) piperidine hydrochlorate (37.4mg) and the Cs that describes among the embodiment 15g
2CO
3(255mg) alkylation in DMF (2ml).By by CH
3The CN crystallization obtains title compound.
Yield: 83mg (HCl salt); MS-ESI:[M+H]
+=630.8; HPLC:R
t=15.49 minutes (method 5).
Embodiment 18
Xenyl-4-carboxylic acid [1-ethanoyl-2,2,4-trimethylammonium-4-phenyl-7-(pyridine-2-base
Methoxyl group)-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
According to general step H, with compound (79mg) 2-picoline chloride hydrochloride (31mg) and the Cs that describes among the embodiment 15g
2CO
3(255mg) alkylation in DMF (2ml).By by CH
3The CN crystallization obtains title compound.
Yield: 32mg (HCl salt); MS-ESI:[M+H]
+=596.6; HPLC:R
t=22.41 minutes (method 6).
Embodiment 19
Xenyl-4-carboxylic acid [1-ethanoyl-2,2,4-trimethylammonium-4-phenyl-7-(pyridin-3-yl
Methoxyl group)-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
According to general step H, with compound (79mg) picoline chloride hydrochloride (31mg) and the Cs that describes among the embodiment 15g
2CO
3(255mg) alkylation in DMF (2ml).By by CH
3The CN crystallization obtains title compound.
Yield: 36mg (HCl salt); MS-ESI:[M+H]
+=596.6; HPLC:Rt=19.70 minute (method 6).
Embodiment 20
Xenyl-4-carboxylic acid [1-ethanoyl-2,2,4-trimethylammonium-4-phenyl-7-(pyridin-4-yl
Methoxyl group)-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
According to general step H, with compound (79mg) 4-picoline chloride hydrochloride (31mg) and the Cs that describes among the embodiment 15g
2CO
3(255mg) alkylation in DMF (2ml).By by CH
3The CN crystallization obtains title compound.
Yield: 31mg (HCl salt); MS-ESI:[M+H]
+=596.4; HPLC:R
t=17.09 minutes (method 6).
Embodiment 21
Xenyl-4-carboxylic acid [1-ethanoyl-7-(2-dimethylamino-oxyethyl group)-2,2,4-front three
Base-4-phenyl-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-acid amides
According to general step H, with compound (79mg) 2-dimethylamino ethyl chloride thing hydrochloride (27mg) and the Cs that describes among the embodiment 15g
2CO
3(255mg) alkylation in DMF (2ml).By by CH
3The CN crystallization obtains title compound.
Yield: 55mg (HCl salt); MS-ESI:[M+H]
+=576.6; HPLC:R
t=14.94 minutes (method 5).
Embodiment 22
Xenyl-4-carboxylic acid (1-ethanoyl-7-carbamyl ylmethoxy-2,2,4-trimethylammonium
-4-phenyl-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
According to general step H, with compound (79mg) 2-chlor(o)acetamide (18mg) and the Cs that describes among the embodiment 15g
2CO
3(255mg) alkylation in DMF (2ml).By preparation property HPLC purifying title compound (method A).
Yield: 60.2mg; MS-ESI:[M+H]
+=562.4; HPLC:R
t=20.47 minutes (method 5).
Embodiment 23
Morpholine-4-carboxylic acid (3-{1-ethanoyl-6-[(xenyl-4-carbonyl)-amino]-2,2,4-
Trimethylammonium-4-phenyl-1,2,3,4-tetrahydrochysene-quinoline-7-base oxygen base }-propyl group)-acid amides
According to general step H, with compound (79mg) morpholine-4-carboxylic acid (3-chloropropyl) acid amides (40mg) and the Cs that describes among the embodiment 15g
2CO
3(255mg) alkylation in DMF (2ml).By preparation property HPLC purifying title compound (method A).
Yield: 52.4mg; MS-ESI:[M+H]
+=675.6; HPLC:R
t=22.31 minutes (method 5).
Embodiment 24
Furans-2-carboxylic acid 1-ethanoyl-6-(3,5-two bromo-benzamidos)-2,2, the 4-trimethylammonium
-4-phenyl-1,2,3,4-tetrahydrochysene-quinoline-7-base ester
(a).
1-ethanoyl-7-methoxyl group-2,2,4-trimethylammonium-1,2-dihydroquinoline-6- Base)-3,5-two bromo-benzamide
According to general step F, with 3,5-dibromobenzene formyl chloride (1.72g) is handled in toluene (9ml) and pyridine (1ml) with the compound (1.0g) described among the embodiment 15e.Use heptane/ethyl acetate=8/2 (v/v) as eluent by silica gel chromatography, obtain title compound.
Yield: 1.3g.
(b).
N-(1-ethanoyl-7-hydroxyl-2,2,4-trimethylammonium-4-phenyl-1,2,3,4-first hydrogen Quinoline-6-yl)-3,5-two bromo-benzamide
According to general step G, the compound of describing among the embodiment 24a (1.3g) is used AlCl
3(1.0g) in benzene (50ml), stir.Resultant product directly uses not repurity.
Yield: 1.39g.
(c).
Furans-2-carboxylic acid 1-ethanoyl-6-(3,5-two bromo-benzamidos)-2,2,4- Trimethylammonium-4-phenyl-1,2,3,4-tetrahydrochysene-quinoline-7-base ester
With the mixture of the compound (100mg) described among the embodiment 24b, furoyl chloride (16 μ l) at DIPEA (60 μ l) and CH
2Cl
2Under room temperature, stir (5ml), residual up to no longer including starting raw material.Add entry, separate organic layer, use the salt water washing, dry (MgSO
4) and vacuum concentration.By preparation property HPLC purifying title compound (method A).
Yield: 47mg; MS-ESI:[M+H]
+=681.2; HPLC:R
t=31.6 minutes (method 2).
Embodiment 25
N-[1-ethanoyl-7-(2-amino-oxyethyl group)-2,2,4-trimethylammonium-4-phenyl
-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-3,5-two bromo-benzamide
General step I: the mixture of triphenylphosphine that will contain the compound (100mg) described among the embodiment 24b, N-(2-hydroxyethyl) t-butyl carbamate (29mg), DtBAD (79mg), DIPEA (60 μ l) and excess polymeric constraint (bound) is at CH
2Cl
2Under room temperature, stir (5ml), residual up to no longer including starting raw material.Reaction mixture filters, water and salt water washing.Separate organic layer, dry (MgSO
4) and vacuum concentration.Dissolving crude product is in CH
3Among the CN (approximately 1ml), add the cracking that several TFA promote t-butyl carbamate.By preparation property HPLC purifying title compound (method A).
Yield: 17mg (tfa salt); MS-ESI:[M+H]
+=630.2; HPLC:R
t=15.6 minutes (method 2).
Embodiment 26
{ 2-[1-ethanoyl-6-(3,5-dimethyl-benzamido)-2,2,4-trimethylammonium-4-benzene
Base-1,2,3,4-tetrahydrochysene-quinoline-7-base oxygen base]-ethyl }-t-butyl carbamate
(a).
N-(1-ethanoyl-7-methoxyl group-2,2,4-trimethylammonium-1,2-dihydroquinoline-6- Base)-3,5-dimethyl-benzamide
According to general step F, with 3,5-dimethyl benzoyl chloride (0.97g) is acidylate in toluene (9ml) and pyridine (1ml) with the compound (1.0g) described among the embodiment 15e.Use heptane/ethyl acetate=8/2 (v/v) as eluent by silica gel chromatography, obtain title compound.
Yield: 1.1g.
(b).
N-(1-ethanoyl-7-hydroxyl-2,2,4-trimethylammonium-4-phenyl-1,2,3,4-tetrahydrochysene Quinoline-6-yl)-3, the 5-dimethyl benzamide
According to general step G, the compound of describing among the embodiment 26a (1.1g) is used AlCl
3(1.0g) in benzene (50ml), stir.Resultant product directly uses not repurity.
Yield: 1.3g.
(c).
{ 2-[1-ethanoyl-6-(3,5-dimethyl-benzamido)-2,2,4-trimethylammonium -4-phenyl-1,2,3,4-tetrahydrochysene-quinoline-7-base oxygen base]-ethyl }-t-butyl carbamate
According to general step I, with the compound (100mg) described among the embodiment 26b with the triphenylphosphine of N-(2-hydroxyethyl) t-butyl carbamate (37mg), DtBAD (101mg), DIPEA (77 μ l) and excessive polymer bound at CH
2Cl
2Alkylation (5ml).In the present embodiment not with the t-butyl carbamate cracking, through obtaining title compound after preparation property HPLC (method A) and the lyophilize.
Yield: 38mg; MS-ESI:[M+H]
+=600.4; HPLC:R
t=33.1 minutes (method 2).
Embodiment 27
N-[1-ethanoyl-7-(furans-2-ylmethoxy)-2,2,4-trimethylammonium-4-phenyl
-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-3,5-dimethyl-benzamide
According to general step I, use the triphenylphosphine of 2-(hydroxyethyl) furans (21 μ l), DtBAD (101mg), DIPEA (77 μ l) and polymer bound at CH the compound of describing among the embodiment 26b (100mg)
2Cl
2Alkylation (5ml).By preparation property HPLC purifying title product (method A), lyophilize then.
Yield: 16mg; MS-ESI:[M+H]
+=537.4; HPLC:R
t=32.8 minutes (method 2).
Embodiment 28
N-[1-ethanoyl-2,2,4-trimethylammonium-4-phenyl-7-(pyridin-4-yl methoxy
Base)-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-3,5-two chloro-benzamide
(a).
N-(1-ethanoyl-7-methoxyl group-2,2,4-trimethylammonium-1,2-dihydroquinoline-6- Base)-3,5-two chloro-benzamide
According to general step F, with 3,5-dichlorobenzoyl chloride (1.2g) is acidylate in toluene (9ml) and pyridine (1ml) with the compound (1.0g) described among the embodiment 15e.Use heptane/ethyl acetate=8/2 (v/v) as eluent by silica gel chromatography, obtain title compound.
Yield: 1.47g.
(b).
N-(1-ethanoyl-7-hydroxyl-2,2,4-trimethylammonium-4-phenyl-1,2,3,4-tetrahydrochysene Quinoline-6-yl)-3, the 5-dichloro-benzamide
According to general step G, the compound of describing among the embodiment 28a (1.47g) is used AlCl
3(1.5g) in toluene (75ml), stir.Resultant product directly uses not repurity.
Yield: 1.51g.
(c).
N-[1-ethanoyl-2,2,4-trimethylammonium-4-phenyl-7-(pyridin-4-yl methoxy Base)-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-3,5-two chloro-benzamide
According to general step H, with compound (100mg) 4-picoline chloride hydrochloride (36mg) and the Cs that describes among the embodiment 28b
2CO
3(255mg) at DMF (1ml) and CH
2Cl
2Alkylation in the mixture (4ml).Handle through preparation HPLC (method A), lyophilize obtains the corresponding tfa salt of title compound then.
Yield: 35mg (tfa salt); MS-ESI:[M+H]
+=588.4; HPLC:R
t=18.0 minutes (method 2).
Embodiment 29
N-[1-ethanoyl-2,2,4-trimethylammonium-4-phenyl-7-(2-tetramethyleneimine-1-base-ethoxy
Base)-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-3,5-dimethyl-benzamide
General step J: with the mixture of compound (100mg), 2-chloroethyl pyrrolidine hydrochloride (41mg) and the DIPEA (77 μ l) that describe among the embodiment 26b at CH
2Cl
2Under room temperature, stir (5ml), residual up to no longer including starting raw material.Add entry, separate organic layer, use the salt water washing.Dry (MgSO
4) and vacuum concentration.By preparation property HPLC purifying, lyophilize obtains the corresponding tfa salt of title compound then.
Yield: 104mg (tfa salt); MS-ESI:[M+H]
+=554.4; HPLC:R
t=15.2 minutes (method 2).
Embodiment 30
N-[1-ethanoyl-2,2,4-trimethylammonium-7-(5-methyl-isoxazolyls-3-base methoxy
Base)-and 4-phenyl-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-3,5-dimethyl-benzamide
According to general step J, use (chloromethyl)-5-methyl-isoxazole (32mg) and DIPEA (77 μ l) at CH the compound of describing among the embodiment 26b (100mg)
2Cl
2Alkylation (5ml).By preparation property HPLC purifying (method A), lyophilize obtains title compound then.
Yield: 41mg; MS-ESI:[M+H]
+=552.4; HPLC:R
t=31.3 minutes (method 2).
Embodiment 31
N-[1-ethanoyl-7-(2-diethylin-oxyethyl group)-2,2,4-trimethylammonium-4-phenyl
-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-3,5-dimethyl-benzamide; Have trifluoroacetic acid
Compound
According to general step J, the compound of describing among the embodiment 26b (100mg) is used N, N-diethyllaminoethyl chloride hydrochloride (42mg) and DIPEA (77 μ l) are at CH
2Cl
2Alkylation (5ml).By preparation property HPLC purifying (method A), lyophilize obtains the corresponding tfa salt of title compound then.
Yield: 43mg (tfa salt); MS-ESI:[M+H]
+=556.4; HPLC:R
t=15.2 minutes (method 2).
Embodiment 32
N-[1-ethanoyl-2,2,4-trimethylammonium-4-phenyl-7-(pyridin-4-yl methoxyl group)
-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-5-bromo-2-methylamino--benzamide
(a).
N-(1-ethanoyl-7-methoxyl group-2,2,4-trimethylammonium-1,2-dihydroquinoline-6- Base)-5-bromo-2-methylamino--benzamide
According to general step F, with compound (1.0g) 5-bromo-2-methylamino--Benzoyl chloride (1.43g) acidylate in toluene (9ml) and pyridine (1ml) of describing among the embodiment 15e.Use heptane/ethyl acetate=8/2 (v/v) as eluent by silica gel chromatography, obtain title compound.
Yield: 595mg.
(b).
N-(1-ethanoyl-7-hydroxyl-2,2,4-trimethylammonium-4-phenyl-1,2,3,4-tetrahydrochysene Quinoline-6-yl)-5-bromo-2-methylamino--benzamide
According to general step G, the compound of describing among the embodiment 32a (595mg) is used AlCl
3(0.75g) in benzene (50ml), stir.Resultant product directly uses not repurity.
Yield: 437mg.
(c).
N-[1-ethanoyl-2,2,4-trimethylammonium-4-phenyl-7-(pyridin-4-yl methoxy Base)-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-5-bromo-2-methylamino--benzamide
According to general step H, with compound (44mg) 4-picoline chloride hydrochloride (15mg) and the Cs that describes among the embodiment 32b
2CO
3(approximately 100mg) is at DMF (1ml) and CH
2Cl
2Alkylation in the mixture (4ml).After preparation property HPLC (method B) processing, obtain the corresponding tfa salt of title compound.
Yield: 18mg (tfa salt); MS-ESI:[M+H]
+=629.4; HPLC:R
t=18.1 minutes (method 2).
Embodiment 33
Furans-2-carboxylic acid (1-ethanoyl-7-dimethylamino-2,2,4-trimethylammonium-4-phenyl
-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
(a).
(2,2.4-trimethylammonium-1,2-dihydroquinoline-6-yl)-t-butyl carbamate
With N-Boc-1,4-phenylenediamine (75g), MgSO
4(216g), the mixture of 4-tert-butyl catechol (1.8g) and iodine (4.7g) refluxed 20 hours in anhydrous propanone (600ml).By removing by filter MgSO
4, the filtrate vacuum concentration.Resistates is chromatography on short silica gel plug, uses heptane/ethyl acetate=8/2 (v/v) as eluent, obtains the product into brown oil.
Yield: 41g.
(b).
(1-ethanoyl-2,2,4-trimethylammonium-1,2-dihydroquinoline-6-yl)-carboxylamine The tert-butyl ester
With the compound (41g) described among the embodiment 33a at pyridine (200ml) and CH
2Cl
2Solution (200ml) is cooled to 0 ℃.The CH that dropwise adds Acetyl Chloride 98Min. (21ml)
2Cl
2(50ml) solution.After reinforced the finishing, mixture at room temperature stirred 3 hours.Add ethyl acetate (2 liters) and H
2O (2 liters) separates organic layer, dry (MgSO
4) and vacuum concentration.By obtaining title compound by the ethyl acetate crystallization.
Yield: 23g.
(c).
1-ethanoyl-6-amino-2,2,4-trimethylammonium-4-phenyl-1,2,3,4-tetrahydrochysene quinoline Quinoline
According to general step G, the compound of describing among the embodiment 33b (33.3g) is used AlCl
3(40.4g) in benzene (700ml), stir.Product uses heptane/ethyl acetate=8/2 (v/v) as eluent by the silica gel chromatography purifying.
Yield: 22.4g.
D). (1-ethanoyl-2,2,4-trimethylammonium-4-phenyl-1,2,3,4-tetrahydroquinoline-6-
Base)-carboxylamine 9-fluorenyl methyl ester
Pyridine (6.4ml) is added in THF (300ml) solution of the compound of describing among the embodiment 33c (22.4g), mixture is cooled to 0 ℃.THF (100ml) solution that dropwise adds FmocCl (20.7g), after reinforced the finishing, mixture at room temperature stirred 1 hour.The reaction mixture vacuum concentration adds the ethyl acetate (800ml) and the 0.3M HCl aqueous solution (500ml).Separate organic layer, with 0.3M HCl (2 * 500ml), H
2O (500ml) and salt solution (500ml) washing, dry then (MgSO
4) and vacuum concentration.Product directly uses not repurity in next step.
Yield: 43g.
(e).
(1-ethanoyl-2,2,4-trimethylammonium-7-nitro-4-phenyl-1,2,3,4-tetrahydrochysene quinoline Quinoline-6-yl)-carboxylamine 9-fluorenyl methyl ester
Nitrosonitric acid (3.07ml) was added to the compound (43g) described among the embodiment 33d and acetate (230ml) at CH in 10 minutes
2Cl
2In the mixture (230ml).Reaction mixture stirs and transforms fully up to starting raw material, adds entry (150ml) then.Separate water layer, use CH
2Cl
2(150ml) extraction.The saturated NaHCO of organic layer that merges
3The aqueous solution (3 * 200ml) and salt solution (200ml) washing, use MgSO then
4Dry also filtration.Add methyl alcohol (approximately 200ml), careful vacuum is removed CH
2Cl
2, then with mixture standing over night at room temperature.Collect the glassy yellow crystallization by filtering, and vacuum-drying (MgSO
4).
Yield: 29.3g.
(f).
(1-ethanoyl-7-amino-2,2,4-trimethylammonium-4-phenyl-1,2,3,4-tetrahydrochysene quinoline Quinoline-6-yl)-carboxylamine 9-fluorenyl methyl ester
According to general step E, compound (20g) reduction in THF (approximately 600ml) with zinc powder (45g) and acetate (20ml) with describing among the embodiment 33e obtains product, and it directly uses in next step.
(g).
(1-ethanoyl-7-dimethylamino-2,2,4-trimethylammonium-4-phenyl-1,2,3,4- Tetrahydroquinoline-6-yl)-carboxylamine 9-fluorenyl methyl ester
With the aqueous solution of formaldehyde (37%, 3.8ml) be added in methyl alcohol (200ml) solution of compound (12g), acetate (15.7ml) and the sodium cyanoborohydride (2.9g) described among the embodiment 33f, thermopositive reaction takes place, form white precipitate.Add a certain amount of methyl alcohol again in order to promote to stir.Stir after 15 minutes, by filtering collecting precipitation, with methanol=1/1 (v/v) washing.The filtrate partial concentration obtains more solid matter, collects.The solid CH that merges
2Cl
2/ MeOH recrystallization obtains dimethylated compound.
Yield: 9.7g.
(h).
1-ethanoyl-6-amino-7-dimethylamino-2,2,4-trimethylammonium-4-phenyl -1,2,3, the 4-tetrahydroquinoline
Piperidines (7.7ml) is added to the CH of the compound of describing among the embodiment 33g (4.5g)
2Cl
2(70ml) in the solution.After 24 hours, reaction mixture CH
2Cl
2(100ml) dilution, with the 0.5M HCl aqueous solution (2 * 150ml), water (100ml) and salt solution (1ml) washs.Organic layer drying (MgSO
4), being diluted to cumulative volume then is 200ml.In further reacting, use the stock solution (approximately 13.8mg/ml) of this title compound.
(i).
Furans-2-carboxylic acid (1-ethanoyl-7-dimethylamino-2,2,4-trimethylammonium-4-phenyl -1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
Triethylamine (38 μ l) and 2-furoyl chloride (27 μ l) are added to the CH of the compound of describing among the embodiment 33h (96.6mg)
2Cl
2(10ml) in the solution, resulting mixture stirs and transforms fully up to starting raw material, by silica gel chromatography purifying title compound, uses heptane/ethyl acetate 1/0=＞0/1 (v/v) as eluent.
Yield: 5.5mg.MS-ESI:[M+H]
+=446.2; HPLC:R
t=19.02 minutes (method 2).
Embodiment 34
5-methyl-thiophene-2-carboxylic acid (1-ethanoyl-7-dimethylamino-2,2,4-trimethylammonium-4-benzene
Base-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
According to general step A, with the compound (96.6mg) described among the embodiment 33h with 5-thiotolene-2-carboxylic acid (39.1mg), HATU (157mg) and DIPEA (239 μ l) at CH
2Cl
2Acidylate (10ml).By preparation property HPLC purifying title compound (method B).
Yield: 35.5mg; MS-ESI:[M+H] +=476.2; HPLC:R
t=21.26 minutes (method 2).
Embodiment 35
Xenyl-4-carboxylic acid (1-ethanoyl-7-dimethylamino-2,2,4-trimethylammonium-4-phenyl
-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
According to general step A, with the compound (96.6mg) described among the embodiment 33h with 4-xenyl carboxylic acid (54.4mg), HATU (157mg) and DIPEA (239 μ l) at CH
2Cl
2Acidylate (10ml).By preparation property HPLC purifying title compound (method B).
Yield: 31.5mg; MS-ESI:[M+H]
+=532.4; HPLC:R
t=24.92 minutes (method 2).
Embodiment 36
N-(1-ethanoyl-7-dimethylamino-2,2,4-trimethylammonium-4-phenyl-1,2,3, the 4-tetrahydrochysene-
Quinoline-6-yl)-3,5-two bromo-benzamide
According to general step A, with 3,5-dibromobenzoic acid (77mg), HATU (157mg) and DIPEA (239 μ l) are at CH with the compound (96.6mg) described among the embodiment 33h
2Cl
2Acidylate (10ml).By by CH
2Cl
2/ CH
3CN crystallization purifying title compound.
Yield: 24.3mg; MS-ESI:[M+H]
+=614.2; HPLC:R
t=27.71 minutes (method 2).
Embodiment 37
Cyclopentane carboxylic acid (1-ethanoyl-7-dimethylamino-2,2,4-trimethylammonium-4-phenyl
-1,2.3.4-tetrahydrochysene-quinoline-6-base-acid amides
According to general step A, with the compound (137mg) described among the embodiment 33h with Cyclopentane carboxylic acid (128 μ l), HATU (224mg) and DIPEA (400 μ l) at CH
2Cl
2Acidylate (10ml).By silica gel chromatography purifying title compound, use heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent.
Yield: 148mg; MS-ESI:[M+H]
+=448.4; HPLC:R
t=12.93 minutes (method 1).
Embodiment 38
N-(1-ethanoyl-7-dimethylamino-2,2,4-trimethylammonium-4-phenyl-1,2,3, the 4-tetrahydrochysene-
Quinoline-6-yl)-isobutyramide
According to general step A, with the compound (137mg) described among the embodiment 33h with isopropylformic acid (110 μ l), HATU (224mg) and DIPEA (400 μ l) at CH
2Cl
2Acidylate (10ml).Title compound uses heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent by the silica gel chromatography purifying.
Yield: 43mg; MS-ESI:[M+H]
+=422.4; HPLC:R
t=9.99 minutes (method 1).
Embodiment 39
Furans-2-carboxylic acid (1-ethanoyl-7-furans-2-base carbonylamino-2,2,4-trimethylammonium-4-
Phenyl-1,2,3,4-tetrahydroquinoline-6-yl)-acid amides
The CH of compound of in embodiment 33f, describing (150mg) and triethylamine (43 μ l)
2Cl
2(1ml) add 2-furoyl chloride (30 μ l) in the solution.After the starting raw material completely consumed is intact, add the 1M HCl aqueous solution, separate organic layer, add piperidines (1ml) then, resulting mixture stirs and spends the night.Reaction mixture separates organic layer with 1M HCl solution washing, dry (MgSO
4) and vacuum concentration.By silica gel chromatography purifying title compound, use heptane/ethyl acetate=1/0=＞0/1 (v/v) as eluent, handle by preparation property HPLC (method A) then.
Yield: 18mg; MS-ESI:[M+H]
+=512.4; HPLC:R
t=19.92 minutes (method 2).
Embodiment 40
5-methyl-thiophene-2-carboxylic acid (1-ethanoyl-2,2,4-trimethylammonium-4-phenyl-7-third amino
-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
(a).
1-ethanoyl-6-amino-2,2,4-trimethylammonium-4-phenyl-7-third amino -1,2,3, the 4-tetrahydroquinoline
General step K: add propionic aldehyde (94.2 μ l) in the mixture of the compound of in embodiment 33f, describing (750mg), acetate (953 μ l), sodium cyanoborohydride (135mg) and MeOH (10ml).Mixture stirred 18 hours, added entry, by filtering collecting precipitation.With resolution of precipitate in CH
2Cl
2(10ml), add piperidines (1ml), resulting mixture stirred 18 hours.Reaction mixture separates organic layer with 1M HCl solution washing, and to be diluted to cumulative volume be 50ml.Directly use in the reaction below of this solution.
(b).
5-methyl-thiophene-2-carboxylic acid (1-ethanoyl-2,2,4-trimethylammonium-4-phenyl-7- Third amino-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
According to general step A, with the compound (100mg) described among the 40a with 5-thiotolene-2-carboxylic acid (39.1mg), HATU (157mg) and DIPEA (239ul) at CH
2Cl
2Acidylate (10ml).By preparation property HPLC purifying title compound and lyophilize.
Yield: 18.3mg; MS-ESI:[M+H]
+=490.4; HPLC:R
t=23.96 minutes (method 2).
Embodiment 41
Xenyl-4-carboxylic acid (1-ethanoyl-7-ethylamino-2,2,4-trimethylammonium-4-phenyl
-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
(a).
1-ethanoyl-6-amino-7-ethylamino-2,2,4-trimethylammonium-4-phenyl -1,2,3, the 4-tetrahydroquinoline
According to general step K,,, obtain the CH of title compound after processing and the dilution with piperidines (1ml) deprotection with compound (750mg) acetaldehyde (the 73.3 μ l) acidylate of describing among the embodiment 33f
2Cl
2Solution.
(b).
Xenyl-4-carboxylic acid (1-ethanoyl-7-ethylamino-2,2,4-trimethylammonium-4-phenyl -1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
According to general step A, with the compound (100mg) described among the 41a with 4-xenyl carboxylic acid (54.4mg), HATU (157mg) and DIPEA (239 μ l) at CH
2Cl
2Acidylate (10ml).By preparation property HPLC purifying title compound and lyophilize.
Yield: 9.8mg; MS-ESI:[M+H]
+=532.4; HPLC:R
t=25.55 minutes (method 2).
Embodiment 42
5-methyl-thiophene-2-carboxylic acid { 1-ethanoyl-2,2,4-trimethylammonium-4-phenyl-7-[(pyridine
-4-ylmethyl)-and amino]-1,2,3,4-tetrahydrochysene-quinoline-6-yl }-acid amides
(a).
1-ethanoyl-6-amino-2,2,4-trimethylammonium-4-phenyl-7-[(pyridin-4-yl first Base)-and amino]-1,2,3, the 4-tetrahydroquinoline
According to general step K,,, obtain the CH of title compound after processing and the dilution with piperidines (1ml) deprotection with compound (750mg) 4-pyridylaldehyde (the 125 μ l) acidylate of describing among the embodiment 33f
2Cl
2Solution.
(b).
5-methyl-thiophene-2-carboxylic acid { 1-ethanoyl-2,2,4-trimethylammonium-4-phenyl -7-[(pyridin-4-yl methyl)-and amino]-1,2,3,4-tetrahydrochysene-quinoline-6-yl }-acid amides
According to general step A, with the compound (114mg) described among the 42a with 5-thiotolene-2-carboxylic acid (39.1mg), HATU (157mg) and DIPEA (239 μ l) at CH
2Cl
2Acidylate (10ml).By preparation property HPLC purifying title compound and lyophilize.
Yield: 51mg; MS-ESI:[M+H]
+=539.4; HPLC:R
t=13.19 minutes (method 2).
Embodiment 43
5-methyl-thiophene-2-carboxylic acid { 1-ethanoyl-2,2,4-trimethylammonium-4-phenyl-7-[(pyridine
-3-ylmethyl)-and amino]-1,2,3,4-tetrahydrochysene-quinoline-6-yl }-acid amides
(a).
1-ethanoyl-6-amino-2,2,4-trimethylammonium-4-phenyl-7-[(pyridin-3-yl first Base)-and amino]-1,2,3, the 4-tetrahydroquinoline
According to general step K,,, obtain the CH of title compound after processing and the dilution with piperidines (1ml) deprotection with compound (750mg) 3-pyridylaldehyde (the 125 μ l) acidylate of describing among the embodiment 33f
2Cl
2Solution.
(b).
5-methyl-thiophene-2-carboxylic acid { 1-ethanoyl-2,2,4-trimethylammonium-4-phenyl -7-[(pyridin-3-yl methyl)-and amino]-1,2,3,4-tetrahydrochysene-quinoline-6-yl }-acid amides
According to general step A, with the compound (114mg) described among the embodiment 43a with 5-thiotolene-2-carboxylic acid (39.1mg), HATU (157mg) and DIPEA (239 μ l) at CH
2Cl
2Acidylate (10ml).By preparation property HPLC purifying title compound and lyophilize.
Yield: 44mg; MS-ESI:[M+H]
+=539.4; HPLC:R
t=13.45 minutes (method 2).
Embodiment 44
N-(1-ethanoyl-7-isobutyl amino-2,2,4-trimethylammonium-4-phenyl-1,2,3, the 4-tetrahydrochysene-
Quinoline-6-yl)-3,5-two bromo-benzamide
(a).
1-ethanoyl-6-amino-7-isobutyl amino-2,2,4-trimethylammonium-4-phenyl -1,2,3, the 4-tetrahydroquinoline
According to general step K,,, obtain the CH of title compound after processing and the dilution with piperidines (1ml) deprotection with compound (750mg) isobutyric aldehyde (the 119 μ l) acidylate of describing among the embodiment 33f
2Cl
2Solution.
(b).
N-(1-ethanoyl-7-isobutyl amino-2,2,4-trimethylammonium-4-phenyl-1,2,3,4- Tetrahydrochysene-quinoline-6-yl)-3,5-two bromo-benzamide
According to general step A, with 3,5-dibromobenzoic acid (77mg), HATU (157mg) and DIPEA (239 μ l) are at CH with the compound (114mg) described among the embodiment 44a
2Cl
2Acidylate (10ml).By preparation property HPLC purifying title compound and lyophilize.
Yield: 54mg; MS-ESI:[M+H]
+=642.4; HPLC:R
t=29.47 minutes (method 2).
Embodiment 45
Xenyl-4-carboxylic acid (1-ethanoyl-7-benzyl amino-2,2,4-trimethylammonium-4-phenyl
-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
(a).
1-ethanoyl-6-amino-7-benzyl amino-2,2,4-trimethylammonium-4-phenyl -1,2,3, the 4-tetrahydroquinoline
According to general step K,,, obtain the CH of title compound after processing and the dilution with piperidines (1ml) deprotection with compound (750mg) phenyl aldehyde of describing among the embodiment 33f (133 μ l)
2Cl
2Solution.
(b).
Xenyl-4-carboxylic acid (1-ethanoyl-7-benzyl amino-2,2,4-trimethylammonium-4-phenyl -1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
According to general step A, with the compound (113mg) described among the embodiment 45a with 4-xenyl carboxylic acid (54.4mg), HATU (157mg) and DIPEA (239 μ l) at CH
2Cl
2Acidylate (10ml).By preparation property HPLC purifying title compound and lyophilize.
Yield: 114mg; MS-ESI:[M+H]
+=594.4; HPLC:R
t=26.46 minutes (method 2).
Embodiment 46
5-methyl-thiophene-2-carboxylic acid (1-ethanoyl-7-benzyl amino-2,2,4-trimethylammonium-4-phenyl
-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
According to general step A, with the compound (113mg) described among the embodiment 45a with 5-thiotolene-2-carboxylic acid (39.1mg), HATU (157mg) and DIPEA (239 μ l) at CH
2Cl
2Acidylate (10ml).By preparation property HPLC purifying title compound and lyophilize.
Yield: 107mg; MS-ESI:[M+H]
+=538.4; HPLC:R
t=18.59 minutes (method 2).
Embodiment 47
N-{1-ethanoyl-2,2,4-trimethylammonium-4-phenyl-7-[(pyridin-3-yl methyl)-ammonia
Base]-1,2,3,4-tetrahydrochysene-quinoline-6-yl }-3,5-two bromo-benzamide
According to general step A, with 3,5-dibromobenzoic acid (77mg), HATU (157mg) and DIPEA (239 μ l) are at CH with the compound (114mg) described among the embodiment 43a
2Cl
2Acidylate (10ml).By preparation property HPLC purifying title compound and lyophilize.
Yield: 41mg; MS-ESI:[M+H]
+=677.2; HPLC:R
t=14.88 minutes (method 2).
Embodiment 48
N-(1-ethanoyl-7-dimethylamino-4-methyl-4-phenyl-1,2,3,4-tetrahydrochysene-quinoline
-6-yl)-3,5-two bromo-benzamide
(a).
The 4-methyl isophthalic acid, the 2-dihydroquinoline
The THF solution of 4-toluquinoline (10.0g) is cooled to-78 ℃, adds BH then
3The THF of THF (1M, 70ml) solution.After 2 hours, add toluene (3.5M, 40ml) solution, the reaction mixture continuation stirring 2 hours of two (2-methoxyl group-oxyethyl group) aluminum dihydride sodium.Add entry, mixture dilutes with ethyl acetate, separates organic layer, dry (MgSO
4) and partial vacuum concentrate, make the title compound crystallization separate out.Collect crystallization by filtering, obtain 3.5g after the vacuum-drying.Remaining mother liquor vacuum concentration, resistates use heptane/ethyl acetate=0/1=＞1/0 (v/v) as eluent, the 4.4g title compound of getting back by the silica gel chromatography purifying.
Yield: 7.9g.
(b).
1-ethanoyl-4-methyl isophthalic acid, the 2-dihydroquinoline
According to general step C, use Acetyl Chloride 98Min. (11.8ml) and DMA (34ml) at CH the compound of describing among the embodiment 48a (7.9g)
2Cl
2(50ml) in 0 ℃ of following acidylate.Title compound uses heptane/ethyl acetate=6/4 as eluent by the silica gel chromatography purifying.
Yield: 8.8g.
(c).
1-ethanoyl-4-methyl-4-phenyl-1,2,3, the 4-tetrahydroquinoline
According to general step G, the compound of describing among the embodiment 48b (8.8g) is used AlCl
3(18.8g) in benzene (250ml), stir.Resulting product directly uses not repurity.
Yield: 12.0g.
(d).
1-ethanoyl-4-methyl-6-nitro-4-phenyl-1,2,3, the 4-tetrahydroquinoline
The CH of compound of in embodiment 48c, describing (5.0g) and diacetyl oxide (189 μ l)
2Cl
2(50ml) dropwise add the HNO of being fuming in the solution
3(9.4ml).After reacting completely, add entry, organic layer salt water washing separates and vacuum concentration.Title compound uses heptane/ethyl acetate=6/4 (v/v) as eluent by the silica gel chromatography purifying.
Yield: 3.86g.
(e).
1-ethanoyl-6-amino-4-methyl-4-phenyl-1,2,3, the 4-tetrahydroquinoline
According to general step E, reduction in THF (approximately 250ml) obtains product, its crude product of use in next step with zinc powder (16g) and acetate (7ml) with the compound (3.86g) described among the embodiment 48d.
Yield: 2.2g.
(f).
(1-ethanoyl-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)-amino Formic acid 9-fluorenyl methyl esters
Pyridine (314 μ l) is added in THF (10ml) solution of the compound of describing among the embodiment 48e (1.0g), reaction mixture is cooled to 0 ℃.Add FmocCl (1.01g), mixture at room temperature stirred 18 hours, then with the reaction mixture vacuum concentration.By silica gel chromatography purifying title compound, use heptane/ethyl acetate=6/4 (v/v) as eluent.
Yield: 950mg.
(g).
(1-ethanoyl-4-methyl-7-nitro-4-phenyl-1,2,3,4-tetrahydroquinoline-6- Base)-carboxylamine 9-fluorenyl methyl esters
The CH of compound of in embodiment 48f, describing (850mg) and diacetyl oxide (17 μ l)
2Cl
2(5ml) dropwise add the HNO of being fuming in the solution
3(842 μ l).After reacting completely, add entry, organic layer salt water washing separates and vacuum concentration.By silica gel chromatography purifying title compound, use heptane/ethyl acetate=9/1=＞0/1 (v/v) as eluent.
Yield: 714mg.
(h).
(1-ethanoyl-7-amino-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinoline-6- Base)-carboxylamine 9-fluorenyl methyl ester
According to general step E, use the reduction in THF (approximately 50ml) of zinc powder (5.6g) and acetate (2.4ml) to obtain product the compound of describing among the embodiment 48g (2.37g), in next step, directly use its crude product.
Yield: 2.66g.
(i).
(1-ethanoyl-7-dimethylamino-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinoline -6-yl)-carboxylamine 9-fluorenyl methyl esters
The aqueous solution (37%, 650 μ l) of formaldehyde is added in methyl alcohol (50ml) solution of compound (2.66g), acetate (3.1ml) and the sodium cyanoborohydride (232mg) described among the embodiment 48h, and resulting mixture stirred 18 hours.Reaction mixture vacuum concentration, resistates are dissolved in the ethyl acetate, water and salt water washing.Separate organic layer, dry (MgSO
4) and vacuum concentration.Title compound uses heptane/ethyl acetate=9/1=＞0/1 (v/v) as eluent by the silica gel chromatography purifying.
Yield: 1.0g.
(j).
1-ethanoyl-6-amino-7-dimethylamino-4-methyl-4-phenyl-1,2,3,4-four The hydrogen quinoline
Piperidines (1.8ml) is added to the CH of the compound of describing among the embodiment 48i (1g)
2Cl
2(20ml) in the solution, it is residual up to no longer including starting raw material to stir the mixture.Reaction mixture vacuum concentration, title compound use heptane/ethyl acetate=9/1=＞0/1 (v/v) as eluent by the silica gel chromatography purifying.
Yield: 370mg.
(k).
N-(1-ethanoyl-7-dimethylamino-4-methyl-4-phenyl-1,2,3, the 4-tetrahydrochysene- Quinoline-6-yl)-3,5-two bromo-benzamide
According to general step A, with 3,5-dibromobenzoic acid (70mg), HATU (131mg) and DIPEA (120 μ l) are at CH with the compound (74mg) described among the embodiment 48j
2Cl
2Acidylate (3ml).By preparation property HPLC purifying title compound and lyophilize.
Yield: 82mg; MS-ESI:[M+H]
+=586.2; HPLC:R
t=22.40 minutes (method 2).
Embodiment 49
5-bromo-thiophene-2-carboxylic acid (1-ethanoyl-7-dimethylamino-4-methyl-4-phenyl
-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
According to general step A, with the compound (74mg) described among the embodiment 48j with 5-bromothiophene-2-carboxylic acid (52mg), HATU (131mg) and DIPEA (120 μ l) at CH
2Cl
2Acidylate (3ml).By preparation property HPLC purifying title compound and lyophilize.
Yield: 69mg; MS-ESI:[M+H]
+=514.2; HPLC:R
t=17.01 minutes (method 2).
Embodiment 50
5-chloro-thiophene-2-carboxylic acid (1-ethanoyl-7-dimethylamino-4-methyl-4-phenyl
-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-acid amides
According to general step A with the compound (74mg) described among the embodiment 48j with 5-chlorothiophene-2-carboxylic acid (52mg), HATU (131mg) and DIPEA (120 μ l) at CH
2Cl
2Acidylate (3ml).By preparation property HPLC purifying title compound and lyophilize.
Yield: 81mg; MS-ESI:[M+H]
+=468.2; HPLC:R
t=17.49 minutes (method 2).
Embodiment 51
CHO-FSH external biological activity
The FSH activity of in human fsh receptor stable transfection and Chinese hamster ovary (CHO) cell, having tested compound with cAMP response part (CRE)/promotor (instructing the expression of Photinus pyralis LUC reporter gene) cotransfection.Part combines with Gs-link coupled fsh receptor and causes cAMP to increase, and it causes that conversely the trans-activation of luciferase reporter gene construction increases.In order to test antagonistic properties, (rec-hFSH, 10mU/ml), its concentration is not for there being to induce under the situation of test compounds 80% concentration of about cAMP accumulation maximal stimulation to have added Recombinant FSH.Utilize luminescent counter to quantize the luciferase signal.Calculated the EC of test compounds
50Value (the test compounds concentration when causing half (50%) maximal stimulation or reduction).Used software program GraphPad PRISM, 3.0 editions (GraphPad software Inc.San Diego) for this reason.
All embodiment compounds all have less than 10 in independent excitement or antagonism mensuration or two kinds of mensuration
-5The EC of M
50(IC
50) value.Embodiment 5-8,10-14,16,18-20,33-35,37,38,41 and the 45-50 compound at least a said determination, demonstrate less than 10
-7The EC of M
50Value.
Claims (12)
1. according to tetrahydroquinoline derivative or its pharmacologically acceptable salt of formula I,
Formula I
Wherein
R
1And R
2Be H or Me;
R
3Be H, hydroxyl or C
1-4Alkoxyl group;
R
4Be H, OH or C
1-4Alkoxyl group;
R
5Be OH, C
1-4Alkoxyl group or R
7
Condition is: if R
4Be H, R so
5Not OH or C
1-4Alkoxyl group;
R
6Be C
2-5Heteroaryl, C
6Aryl, C
3-8Cycloalkyl or C
1-6Alkyl;
R
7Be amino, two (C
1-4Alkyl) amino, C
2-5Heteroaryl carbonylamino, C
2-5Heteroaryl carbonyl oxygen base, R
8-C
2-4Alkylamino, R
8-C
2-4Alkoxyl group, R
9-methylamino or R
9-methoxyl group;
R
8Be hydroxyl, amino, C
1-4Alkoxyl group, two (C
1-4Alkyl) amino, C
2-6Heterocyclylalkyl, C
2-6Heterocyclylalkyl carbonylamino, two (C
1-4Alkyl) amino carbonyl amino, C
1-4Alkoxycarbonyl amido; And
R
9Be aminocarboxyl, C
2-5Heteroaryl or C
6Aryl.
2. the tetrahydroquinoline derivative of claim 1, wherein R
7Be two (C
1-4Alkyl) amino, C
2-5Heteroaryl carbonyl oxygen base, R
8-C
2-4Alkoxyl group, R
9-methylamino or R
9-methoxyl group.
3. the tetrahydroquinoline derivative of claim 2, wherein R
8Be amino, two (C
1-4Alkyl) amino, C
2-6Heterocyclylalkyl or C
2-6The Heterocyclylalkyl carbonylamino.
4. the tetrahydroquinoline derivative of claim 1, wherein R
7Be two (C
1-4Alkyl) amino, R
8-C
2-4Alkoxyl group, R
9-methylamino or R
9-methoxyl group.
5. the tetrahydroquinoline derivative of claim 1, wherein R
8Be amino, two (C
1-4Alkyl) amino or C
2-6Heterocyclylalkyl.
6. the tetrahydroquinoline derivative of claim 1, wherein R
8Be two (C
1-4Alkyl) amino or C
2-6Heterocyclylalkyl.
7. the tetrahydroquinoline derivative of claim 1, wherein R
6Be C
2-5Heteroaryl or C
6Aryl.
8. the tetrahydroquinoline derivative of claim 1, wherein R
6Be C
4-5Heteroaryl or C
6Aryl, R
9Be aminocarboxyl, C
3-5Heteroaryl or C
6Aryl.
9. the tetrahydroquinoline derivative of claim 3, wherein R
7Be two (C
1-4Alkyl) amino, R
8-oxyethyl group, R
9-methylamino or R
9-methoxyl group, and R
9Be aminocarboxyl, C
3-5Heteroaryl or C
6Aryl.
10. the tetrahydroquinoline derivative of claim 9, wherein R
8Be two (C
1-4Alkyl) amino, C
4-5Heterocyclylalkyl.
11. a pharmaceutical composition, it contains tetrahydroquinoline derivative any among the claim 1-10 and pharmaceutically suitable assistant agent.
12. the purposes that any one tetrahydroquinoline derivative or its pharmacologically acceptable salt are used to prepare the medicine of regulating fertility among the claim 1-10.
Applications Claiming Priority (3)
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|---|---|---|---|
| US43504002P | 2002-12-20 | 2002-12-20 | |
| US60/435,040 | 2002-12-20 | ||
| EP02102866.7 | 2002-12-20 |
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| CN102993094B (en) * | 2011-09-08 | 2014-07-23 | 中国石油大学(北京) | Synthesizing method of tetrahydroquinoline derivative |
| CN102627578B (en) * | 2011-10-20 | 2014-06-11 | 南京大学 | Phenyl benzylamine compound and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000008015A2 (en) * | 1998-08-07 | 2000-02-17 | Applied Research Systems Ars Holding N.V. | Fsh mimetics for the treatment of infertility |
| US6200963B1 (en) * | 1999-03-31 | 2001-03-13 | American Home Products Corporation | Aryl sulfonic acids as FSH antagonists |
-
2003
- 2003-12-16 CN CNB2003801066985A patent/CN100404508C/en not_active Expired - Fee Related
-
2005
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000008015A2 (en) * | 1998-08-07 | 2000-02-17 | Applied Research Systems Ars Holding N.V. | Fsh mimetics for the treatment of infertility |
| US6200963B1 (en) * | 1999-03-31 | 2001-03-13 | American Home Products Corporation | Aryl sulfonic acids as FSH antagonists |
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