CN104487434A - 双环取代的嘧啶类化合物 - Google Patents
双环取代的嘧啶类化合物 Download PDFInfo
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- CN104487434A CN104487434A CN201380039519.4A CN201380039519A CN104487434A CN 104487434 A CN104487434 A CN 104487434A CN 201380039519 A CN201380039519 A CN 201380039519A CN 104487434 A CN104487434 A CN 104487434A
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- 125000002619 bicyclic group Chemical group 0.000 title abstract description 21
- 150000003230 pyrimidines Chemical class 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 192
- 150000003839 salts Chemical class 0.000 claims abstract description 45
- 239000003814 drug Substances 0.000 claims abstract description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 206010071289 Lower urinary tract symptoms Diseases 0.000 claims abstract description 5
- 201000001880 Sexual dysfunction Diseases 0.000 claims abstract description 3
- 231100000872 sexual dysfunction Toxicity 0.000 claims abstract description 3
- -1 amino, hydroxyl Chemical group 0.000 claims description 195
- 230000001681 protective effect Effects 0.000 claims description 175
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 105
- 125000001424 substituent group Chemical group 0.000 claims description 88
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 65
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 62
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 51
- 239000007789 gas Substances 0.000 claims description 43
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 43
- 125000005842 heteroatom Chemical group 0.000 claims description 42
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 40
- 125000005843 halogen group Chemical group 0.000 claims description 37
- 229910052801 chlorine Inorganic materials 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
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- 125000004429 atom Chemical group 0.000 claims description 25
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- 229910052731 fluorine Inorganic materials 0.000 claims description 24
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 150000002118 epoxides Chemical class 0.000 claims description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims description 13
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
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- 125000003545 alkoxy group Chemical group 0.000 claims description 5
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- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
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- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 4
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 claims description 4
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 claims description 3
- ZABMHLDQFJHDSC-UHFFFAOYSA-N 2,3-dihydro-1,3-oxazole Chemical compound C1NC=CO1 ZABMHLDQFJHDSC-UHFFFAOYSA-N 0.000 claims description 3
- 206010037211 Psychomotor hyperactivity Diseases 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 3
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 3
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- 230000002265 prevention Effects 0.000 claims description 3
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 3
- 125000005958 tetrahydrothienyl group Chemical group 0.000 claims description 3
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002677 5-alpha reductase inhibitor Substances 0.000 claims description 2
- 108060003345 Adrenergic Receptor Proteins 0.000 claims description 2
- 102000017910 Adrenergic receptor Human genes 0.000 claims description 2
- JBMKAUGHUNFTOL-UHFFFAOYSA-N Aldoclor Chemical class C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC=NS2(=O)=O JBMKAUGHUNFTOL-UHFFFAOYSA-N 0.000 claims description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 2
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 2
- 206010057671 Female sexual dysfunction Diseases 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 2
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 102000030484 alpha-2 Adrenergic Receptor Human genes 0.000 claims description 2
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 claims description 2
- 239000002876 beta blocker Substances 0.000 claims description 2
- 229940097320 beta blocking agent Drugs 0.000 claims description 2
- 239000000480 calcium channel blocker Substances 0.000 claims description 2
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 claims description 2
- 239000002804 dopamine agent Substances 0.000 claims description 2
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 claims description 2
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- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 claims description 2
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- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
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- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 4
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- QPUMEZIFDXYGPG-UHFFFAOYSA-N piperazine 1H-pyrrole Chemical compound N1CCNCC1.N1C=CC=C1 QPUMEZIFDXYGPG-UHFFFAOYSA-N 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical class OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical class NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- ZFCHNZDUMIOWFV-UHFFFAOYSA-N pyrimidine-2-carboxylic acid Chemical class OC(=O)C1=NC=CC=N1 ZFCHNZDUMIOWFV-UHFFFAOYSA-N 0.000 description 1
- ALVVERXWBOWPKK-UHFFFAOYSA-N pyrimidine-5-carboxamide hydrochloride Chemical class Cl.NC(=O)C1=CN=CN=C1 ALVVERXWBOWPKK-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 229910052704 radon Inorganic materials 0.000 description 1
- SYUHGPGVQRZVTB-UHFFFAOYSA-N radon atom Chemical compound [Rn] SYUHGPGVQRZVTB-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 102000000568 rho-Associated Kinases Human genes 0.000 description 1
- 108010041788 rho-Associated Kinases Proteins 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960000835 tadalafil Drugs 0.000 description 1
- WOXKDUGGOYFFRN-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 WOXKDUGGOYFFRN-IIBYNOLFSA-N 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- ZBCMUHWEHQJMNT-UHFFFAOYSA-N tert-butyl 2-methylnonanoate Chemical class CCCCCCCC(C)C(=O)OC(C)(C)C ZBCMUHWEHQJMNT-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BQMKAHQKDSZAIQ-UHFFFAOYSA-N tetrasodium;iron(3+);nitroxyl anion;pentacyanide Chemical compound [Na+].[Na+].[Na+].[Na+].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].O=[N-] BQMKAHQKDSZAIQ-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 229940043263 traditional drug Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229960003223 tripelennamine Drugs 0.000 description 1
- 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 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 229940094720 viagra Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- KAKZBPTYRLMSJV-UHFFFAOYSA-N vinyl-ethylene Natural products C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged systems
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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Abstract
Description
Claims (16)
- 权 利 要 求、 通式 ( I ) 所示的化合 受的盐或其立体异构体-其中. R1选自通过 N连接到嘧啶环上的任选被取代基取代的 6-7元的含氮稠杂 环基、 7- 12元的含氮嫘杂环基或 7- 12元的含氮桥杂环基,所述取代基选自卤素原子、 氰基、 氨基、 羟基、 烷基、 卤代 C ;烷基、 羟基 C 垸基、 C,.6烷氧基、 d.6烷基羰基或 d.6烷氧基羰基,其中取代基的个数为 1 -4个;R2选自氢原子, 羟基,氨基, 氰基, 烷基氨基, 二 (C^焼基)氨基, .6烷基, 卤代 垸基, 羟基 烷基或 d.6垸氧基;R3、 R4分别独立地选自氢原子或 -M-R7 ,M选自一条单键, 或任选被取代基1^取代的 d.6亚烷基,R7选自任选被取代基 L2取代的 3- 14元环状基团,或者 R3、 R4与它们连接的氮原子共同形成任选被取代基 L3取代的 5-6元的含氮 杂环基,所述取代基 、 L2、 ^选自卤素原子、 羟基、 氮基、 氨基、 C,.6烷基氨基、 二 (Cw垸基)氨基、 氧代、 d.6烷基、 羟基 C,.6烷基、 卤代 Cl-6烷基、 Cl-6烷氧基、 d.6浣 基羰基、 C L6烷基磺酰基或二 (d.6烷基)膦基, 其中取代基的个数为 1 -4个;R5、 R6分别独立地选自氢原子或 -Q-R8,Q选自一条单键, 或任选被取代基 取代的 d.6亚垸基,R8选自任选被取代基 L5取代的 6- 14元芳基、 5-7元单杂环基、 8-9元稠环基或 8-9元稠杂环基,所述取代基 L4、 L5选自卤素原子、 羟基、 烷基、 卤代 烷基、 羧基 Ci.6焼 基、 烯基、 C2.6炔基、 垸氧基、 卤代 d.6垸氧基、 氨基、 垸基氨基、 二 (Cw 垸基)氨基、 氰基、 硝基、 d.6垸基羰基、 磺酰氨基或 烷基磺酰氨基, 其中取代 基的个数为 1-4个。
- 2、 权利要求 1所述的化合物、 其药学上可接受的盐或其立体异构体: 其中, R<sup>2</sup>选自氢原子, 羟基或甲基;选自氢原子:R6选自氢原子。
- 3、 如权利要求 2所述的化合物、 其药学上可接受的盐或其立体异构体: 其中, R<sup>5</sup>选自 -Q-R<sup>8</sup> 'Q选自 C,.6亚垸基,R8选自任选被取代基 L5取代的 6-10元芳基、 5-7元单杂环基、 8-9元稠环基或 8-9元稠杂环基,所述取代基 L5选自卤素原子、 羟基、 d.6焼基、 卤代 d.6烷基、 羧基 垸基、 C,_6垸氧基、 卤代 烷氧基、 氨基、 垸基氨基、 二 (d.6垸基)氨基、 氰基、 硝基、 d.6烷基羰基、 磺酰氨 ¾或(^.6烷基磺酰氨基, 其中取代基的个数为 1-4个。
- 4、 权利要求 3所述的化合物、 其药学上可接受的盐或其立体异构体: 其中, R<sup>1</sup>选自通过 N连接到嘧啶环上的任选被取代基取代的 6-7元的含氮稠杂 环基、 7·12元的含 螺杂环基或 7-12元的含氮桥杂环基,所述取代基选自卤素原子、 氰基、 氨基、 羟基、 垸基、 卤代 烷基、 羟基 d.6烷基、 d.6烷氧基、 烷基羰基或 CM焼氧基羰基,其中取代基的个数为 1-4个。
- 5、 权利要求 4所述的化合物、 其药学上可接受的盐或其立体异构体- 其中, R'选自通过 N连接到嘧啶环上的任选被取代基取代的 6-7元含氮稠杂环 基、 7-10元含 螺杂环基或 7·8元含氮桥杂环基,所述取代基选自卤素原子、 氰基、 氨基、 羟基、 C 6烷基、 卤代 d.6烷基、 羟基 烷基或 烷氧基, 其中取代基的个数为 1-4个;R3选自 -M-R7 ,M选自一条单键或 d.6亚烷基, R7选自任选被取代基 L2取代的苯基、 5-7元单杂环基、 4-7元环烷基、 8-9元稠 环基、 7-】0元螺环基、 7-10元桥环基、 7-10元嫘杂环基或 7-10元桥杂环基,或者 R3、 R4与它们连接的氮原子共同形成任选被取代基 L3取代的 5-6元含氮杂 环基,所述取代基 L2、 ^选自卤素原子、 羟基、 钗基、 氨基、 垸基氨基、 二 (d.6垸 基)氨基、 氧代、 C,-6烷基、 羟基 C L6垸基、 卤代 d.6烷基、 d.6烷氧基, 其中取代基 的个数为 1-4个;Rs选自 -Q-R8,Q选自亚甲基或亚乙基,R8选自任选被取代基 L5取代的苯基、 5-7元单杂环基、 8-9元稠环基或 8-9元稠 杂环基,所述取代基!^选自氟、 氯、 甲基、 三氟甲基、 甲氧基、 乙氧基、 三氟甲氧基、 二甲氨基或羧甲基, 其中取代基的个数为 1-4个;R2选自氢原子; R4选自氢原子; R6选自氢原子。
- 6、 权利要求 5所述的化合物、 其药学上可接受的盐或其立体异构体: 其中,R7选自任选被取代基 取代的苯基、 四氢呋喃基、 四氢噻吩基、 四氢吡咯基、 咪唑烷基、 吡唑烷基、 哌啶基、 吗啉基、 哌嗪基、 2-氧代氮杂环庚垸基、 2-氧代哌 嗪基呋喃基、 二氢噻吩基、 二氢吡咯基、 二氢噁唑基、 二氢吡唑基、 噻吩基、 吡咯 基、 咪^基、 噻唑基、 吡唑基、 嘧啶基、 吡啶基、 吡嗪基、 噁唑基、 环丁烷基、 环 戊垸基、 环己垸基、 环庚烷基、 萘基、 吲哚基、 苯并咪唑基、 2,3-二氢苯并呋喃基、 喹啉基、苯并 [ [1,3]间二氧杂环戊烯、 7-10元螺环基、 7-10元桥环基、 7-10元螺杂 环基或 7· 10元桥杂环基,或者 R3、 R4与它们连接的氮原子共同形成任选被取代基 L3取代的 5-6元含缀杂 环基,所述取代基 L2、 1^3选自卤素原子、 羟基、 氰基、 氮基、 C !.6烷基氨基、 二 (C,-6 垸基)氨基、 氧代、 垸基、 羟基 垸基、 卤代 烷基、 烷氧基' 其中取代 基的个数为 1 -4个;R8选自任选被取代基 L5取代的苯基、 8-9元稠环棊或 8-9元稠杂环基, 所述取代基 1^5选自氟、 氯、 甲基、 三氟甲基、 甲氧基、 乙氧基、 三氟甲氧基、 二甲氨基或羧甲基, 其中取代基的个数为】-4个。
- 7、 权利要求 6所述的化合物、 其药学上可接受的盐或其立体异构体: 其中, R<sup>1</sup>选自通过 N连接到嘧啶环上的任选被取代基取代的 6-7元含氮稠杂环 基、 7- 10元含氮螺杂环基或 7·8元含氣桥杂环基,所述取代基选自氟原子、 氯原子、 氨基、 羟基、 .6烷基或羟基 烷基, 其 中取代基的个数为 1 -2个;R]选自 -M-R7 ,M选自一条单键、 亚甲基或亚乙基,R7选自任选被取代基 L2取代的环戊烷基、 环己烷基或环庚垸基,所述取代基 L2选自氟原子、 氣原子、 羟基、 氨基、 甲氨基、 二甲氨基、 甲基、 乙基或甲氧基, 其中取代基的个数为 1 -2个;R5选自 -Q-R8 ,Q选自亚甲基或亚乙基,R8选自任选被取代基 L5取代的笨基,所述取代基 L5选自锒、 氣、 甲基、 三氣甲基、 甲氧基、 乙氧基或三氟甲氧基, 其中取代基的个数为 1 -4个。
- 8、 权利要求 6所述的化合物、 其药学上可接受的盐或其立体异构体: 其中, R<sup>1</sup>选自通过 N连接到嘧啶环上的任选被取代基取代的 6-7元含氮稠杂环 基或 7- 10元含氮螺杂环基,所述取代基选自氟原子、 氯原子、 氨基、 羟基、 C ,.6垸華或羟基 C 垸基, 其 中取代基的个数为〖-2个:R3选自 -M-R7 ,M选自一条单键、 亚甲基或亚乙基,R7选自任选被取代基 1^取代的哌啶基、吗啉基、哌嗪基、 2-氧代氮杂环庚烷基、 2-氧代哌嗪基呋喃基或 7- 10元螺环基,或者 R]、 R4与它们连接的氮原子共同形成任选被取代基 L3取代的哌啶基、哌嗪 基或吗啉基,所述取代基 L2、 L3选自氟原子、 氯原子、 羟基、 氨基、 甲氨基、 二甲氨基、 氧 代、 三氟甲基、 甲基、 乙基或甲氧基. 其中取代基的个数为 1 -2个;R5选自 -Q-R8 ,Q选自亚甲基或亚乙基,R8选自任选被取代基 L5取代的苯基,所述取代基 L5选自氟、 氯、 甲基、 三氟甲基、 甲氧基、 乙氧基或三氟甲氧基, 其中取代基的个数为 1 -4个。
- 9、 权利要求 6所述的化合物、 其药学上可接受的盐或其立体异构体: 其中, R<sup>1</sup>选自通过 N连接到嘧啶环上的任选被取代基取代的 6-7元含氮稠杂环 基、 7- 10元含氮嫘杂环基或 7-8元含氮桥杂环基,所述取代基选自氟原子、 氯原子、 氨基、 羟基、 CL6烷基或羟基 垸基, 其 中取代基的个数为 1 -2个:R3选自 -M-R7 ,M选自一条单键、 亚甲基或亚乙基,R7选自任选被取代基 L2取代的苯基、 噻吩基、 吡咯基、 咪唑基、 噻唑基、 吡唑 基、 嘧啶基、 吡啶基、 吡嗪基、 噁唑基、 萘基、 吲哚基、 喹啉基或 7-10元桥环基, 或者 R3、 R4与它们连接的氮原子共同形成任选被取代基 L3取代的哌啶基、 哌嗪 基或吗啉基,所述取代基 L2、 L3选自氟原子、 氯原子、 羟基、 氨基、 甲氨基、 二甲氨基、 氧 代、 三氟甲基、 甲基、 乙基或甲氧基, 其中取代基的个数为 1 -2个;R5选自 -Q-R8 ,Q选自亚甲基或亚乙基,RS选自任选被取代基 L5取代的苯基或 8-9元稠环基,所述取代基!^选自氟、 氯、 甲基、 三氟甲基、 甲氧基、 乙氧基或三氟甲氧基' 其中取代基的个数为 1 -4个。
- 10、 如权利要求 6所述的化合物、 其药学上可接受的盐或其立体异构体: 其中, R<sup>1</sup>选自下式基团:3与 R4与它们连接的氮原子共同形成:5选自下式基团:
- 1 1、 如权利要求 10所述的化合物、 其药学上可接受的盐或其立体异构体 其中, R<sup>1</sup>选自下式基团-R3与 R4与它们连接的氮原子共同形成:、CH5选自下式基团:
- 12、 权利要求 7或权利要求 1 1 中所述的化合物、 其药学上可接受的盐或其立 体异构体, 所述化合物选自:CS6000/CT0ZN3/X3d ■9t9請 ΪΟΖ OAV
- 13、 权利要求 8或权利要求 11 中所述的化合物、 其药学上可接受的盐或其立 体异构体, 所述化合物选自-•136--137- -8Π-CS6000/CT0ZN3/X3d 9爾 ΪΟΖ Ο -6CI-■9t9請 ΪΟΖ OAVCS6000/CT0ZN3/X3d ■9t9請 ΪΟΖ OAV15、 药物制剂, 含有权利要求 1-14任一项权利要求所述的化合物、其药学上可 接受的盐或其立体异构体, 以及一种或多种药用载体和 /或稀释剂。 16、含有权利要求卜】 4任一项权利要求所述的化合物、其药学上可接受的盐或 其立体异构体的药物组合物,其特征在于,进一步包含一种或多种第二治疗活性剂, 选自血管扩张剂, 前列腺素 E l, 前列环素, α-肾上腺素受体阻滞剂, 混合的 α,β- 阻断剂, α-阻断剂, 5α-还原酶抑制剂, α2-肾上腺素受体阻滞剂, ACE抑制剂, ΝΕΡ 抑制剂, 中枢多巴胺剂, 血管活性肠肽, 钙通道阻滞剂, 噻嗪类, 或它们的混合物。
- 17、权利要求 1 -】4任一项权利要求所述的化合物、其药学上可接受的盐或其立 体异构体在制备药物中的应用, 所述的药物为 PDE-5 抑制剂, 用于治疗和 /或预防 性功能障碍疾病及下尿路症状的疾病。
- 18、权利要求 1 - 14任一项权利要求所述的化合物、其药学上可接受的盐或其立 体异构体在制备药物中的应用,所述的药物治疗和 /或预防选自下述的疾病:高血压、 心力衰竭、 肺动脉高压、 勃起功能障碍、 膀胱过度活化、 前列腺增生以及女性性功 能障碍。
- 19、 权利要求 17或 18所述的应用, 其中所述的疾病是勃起功能障碍、 膀胱过 度活化及良性前列腺增生。
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US20150232474A1 (en) | 2015-08-20 |
EP2886540A4 (en) | 2015-06-24 |
EP2886540A1 (en) | 2015-06-24 |
KR101794321B1 (ko) | 2017-12-01 |
JP2015524828A (ja) | 2015-08-27 |
EP2886540B1 (en) | 2017-07-26 |
WO2014026467A1 (zh) | 2014-02-20 |
JP6037489B2 (ja) | 2016-12-07 |
KR20150042846A (ko) | 2015-04-21 |
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