OA11502A - Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction. - Google Patents

Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction. Download PDF

Info

Publication number: OA11502A
Authority: OA; OAPI
Prior art keywords: pyridin; title compound; compound; préparation; formula
Prior art date: 1998-04-20

Application number

OA1200000284A

Other languages

English (en)

Inventor

Mark Edward Bunnage

John Paul Mathias

Stephen Derek Albert Street

Anthony Wood

Original Assignee

Pfizer

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

1998-04-20

Filing date

2000-10-13

Publication date

2004-05-10

1998-04-20 Priority claimed from GBGB9808315.7A external-priority patent/GB9808315D0/en

1998-06-30 Priority claimed from GBGB9814187.2A external-priority patent/GB9814187D0/en

2000-10-13 Application filed by Pfizer filed Critical Pfizer

2004-05-10 Publication of OA11502A publication Critical patent/OA11502A/en

Links

ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 title claims description 18
229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 title claims description 7
239000002590 phosphodiesterase V inhibitor Substances 0.000 title claims description 7
201000001880 Sexual dysfunction Diseases 0.000 title claims description 3
231100000872 sexual dysfunction Toxicity 0.000 title claims description 3
DOTPSQVYOBAWPQ-UHFFFAOYSA-N pyrazolo[4,3-d]pyrimidin-3-one Chemical compound N1=CN=C2C(=O)N=NC2=C1 DOTPSQVYOBAWPQ-UHFFFAOYSA-N 0.000 title abstract description 3
238000011282 treatment Methods 0.000 title description 6
150000001875 compounds Chemical class 0.000 claims abstract description 581
-1 NR5R6 Chemical group 0.000 claims abstract description 54
125000000217 alkyl group Chemical group 0.000 claims abstract description 44
125000001424 substituent group Chemical group 0.000 claims abstract description 19
125000003545 alkoxy group Chemical group 0.000 claims abstract description 16
229910052757 nitrogen Inorganic materials 0.000 claims abstract description 16
125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 15
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 15
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
125000003386 piperidinyl group Chemical group 0.000 claims abstract description 7
125000002757 morpholinyl group Chemical group 0.000 claims abstract description 5
125000004076 pyridyl group Chemical group 0.000 claims abstract description 5
125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 4
125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims abstract description 3
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims abstract description 3
125000002541 furyl group Chemical group 0.000 claims abstract description 3
125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 3
125000003718 tetrahydrofuranyl group Chemical group 0.000 claims abstract description 3
125000001412 tetrahydropyranyl group Chemical group 0.000 claims abstract 2
239000000203 mixture Substances 0.000 claims description 227
238000000034 method Methods 0.000 claims description 121
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 13
206010057671 Female sexual dysfunction Diseases 0.000 claims description 13
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 10
208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 10
230000008569 process Effects 0.000 claims description 10
206010020751 Hypersensitivity Diseases 0.000 claims description 9
208000006011 Stroke Diseases 0.000 claims description 9
230000007815 allergy Effects 0.000 claims description 9
125000005843 halogen group Chemical group 0.000 claims description 9
238000004519 manufacturing process Methods 0.000 claims description 9
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
238000009472 formulation Methods 0.000 claims description 7
238000011321 prophylaxis Methods 0.000 claims description 7
206010002383 Angina Pectoris Diseases 0.000 claims description 6
201000001320 Atherosclerosis Diseases 0.000 claims description 6
206010071445 Bladder outlet obstruction Diseases 0.000 claims description 6
206010007559 Cardiac failure congestive Diseases 0.000 claims description 6
206010013935 Dysmenorrhoea Diseases 0.000 claims description 6
208000010412 Glaucoma Diseases 0.000 claims description 6
206010019280 Heart failures Diseases 0.000 claims description 6
206010020772 Hypertension Diseases 0.000 claims description 6
206010021639 Incontinence Diseases 0.000 claims description 6
241001465754 Metazoa Species 0.000 claims description 6
208000018262 Peripheral vascular disease Diseases 0.000 claims description 6
208000003800 Urinary Bladder Neck Obstruction Diseases 0.000 claims description 6
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
208000023819 chronic asthma Diseases 0.000 claims description 6
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
201000010099 disease Diseases 0.000 claims description 6
208000035475 disorder Diseases 0.000 claims description 6
230000010243 gut motility Effects 0.000 claims description 6
208000002815 pulmonary hypertension Diseases 0.000 claims description 6
208000010228 Erectile Dysfunction Diseases 0.000 claims description 5
210000004204 blood vessel Anatomy 0.000 claims description 5
206010006451 bronchitis Diseases 0.000 claims description 5
238000009109 curative therapy Methods 0.000 claims description 5
201000001881 impotence Diseases 0.000 claims description 5
208000037805 labour Diseases 0.000 claims description 5
239000008194 pharmaceutical composition Substances 0.000 claims description 5
125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 5
206010039083 rhinitis Diseases 0.000 claims description 5
208000006673 asthma Diseases 0.000 claims description 4
125000002393 azetidinyl group Chemical group 0.000 claims description 4
125000001309 chloro group Chemical group Cl* 0.000 claims description 4
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
WAJNANMQOPCIPO-UHFFFAOYSA-N pyrazolo[4,3-d]pyrimidin-7-one Chemical compound O=C1N=CN=C2C=NN=C12 WAJNANMQOPCIPO-UHFFFAOYSA-N 0.000 claims description 4
125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 4
125000000623 heterocyclic group Chemical group 0.000 claims description 3
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 2
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
125000004429 atom Chemical group 0.000 claims description 2
125000001589 carboacyl group Chemical group 0.000 claims description 2
239000003085 diluting agent Substances 0.000 claims description 2
125000004438 haloalkoxy group Chemical group 0.000 claims description 2
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
SGPGESCZOCHFCL-UHFFFAOYSA-N Tilisolol hydrochloride Chemical compound [Cl-].C1=CC=C2C(=O)N(C)C=C(OCC(O)C[NH2+]C(C)(C)C)C2=C1 SGPGESCZOCHFCL-UHFFFAOYSA-N 0.000 claims 3
MPNWKIDRINJSMK-UHFFFAOYSA-N 3-ethyl-5-[5-(4-ethyl-4-oxidopiperazin-4-ium-1-yl)sulfonyl-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-ylmethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound N1=C(C(NC(=N2)C=3C(=NC=C(C=3)S(=O)(=O)N3CC[N+]([O-])(CC)CC3)OCCOC)=O)C2=C(CC)N1CC1=CC=CC=N1 MPNWKIDRINJSMK-UHFFFAOYSA-N 0.000 claims 1
RUKLJDUBNXUMRI-HXUWFJFHSA-N 3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-[(2r)-1-methoxypropan-2-yl]oxypyridin-3-yl]-2-[(6-methylpyridin-2-yl)methyl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1CN(CC)CCN1S(=O)(=O)C1=CN=C(O[C@H](C)COC)C(C=2NC(=O)C3=NN(CC=4N=C(C)C=CC=4)C(CC)=C3N=2)=C1 RUKLJDUBNXUMRI-HXUWFJFHSA-N 0.000 claims 1
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
INFYRZAJYPRAJM-UHFFFAOYSA-N 5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(2-methoxyethoxy)pyridin-3-yl]-3-propyl-2-(pyridin-2-ylmethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound N1=C(C(NC(=N2)C=3C(=NC=C(C=3)S(=O)(=O)N3CCN(CC)CC3)OCCOC)=O)C2=C(CCC)N1CC1=CC=CC=N1 INFYRZAJYPRAJM-UHFFFAOYSA-N 0.000 claims 1
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
150000003839 salts Chemical class 0.000 abstract description 11
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 abstract description 4
230000015572 biosynthetic process Effects 0.000 abstract description 3
238000003786 synthesis reaction Methods 0.000 abstract description 3
125000003342 alkenyl group Chemical group 0.000 abstract description 2
125000004193 piperazinyl group Chemical group 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 643
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 437
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 299
239000000243 solution Substances 0.000 description 203
239000007787 solid Substances 0.000 description 182
238000002360 preparation method Methods 0.000 description 169
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 126
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 118
239000000741 silica gel Substances 0.000 description 112
229910002027 silica gel Inorganic materials 0.000 description 112
229960001866 silicon dioxide Drugs 0.000 description 112
238000004440 column chromatography Methods 0.000 description 102
235000019439 ethyl acetate Nutrition 0.000 description 101
229940093499 ethyl acetate Drugs 0.000 description 100
239000011541 reaction mixture Substances 0.000 description 83
238000010828 elution Methods 0.000 description 77
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 76
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 66
HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 64
239000003921 oil Substances 0.000 description 61
235000019198 oils Nutrition 0.000 description 61
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 60
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 60
238000006243 chemical reaction Methods 0.000 description 60
239000006260 foam Substances 0.000 description 56
239000012267 brine Substances 0.000 description 50
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 50
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 43
238000010992 reflux Methods 0.000 description 42
UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 42
239000012071 phase Substances 0.000 description 41
239000000284 extract Substances 0.000 description 40
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 38
239000000725 suspension Substances 0.000 description 38
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
239000007832 Na2SO4 Substances 0.000 description 32
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
229910052938 sodium sulfate Inorganic materials 0.000 description 32
235000011152 sodium sulphate Nutrition 0.000 description 32
239000002253 acid Substances 0.000 description 31
IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 31
239000008346 aqueous phase Substances 0.000 description 30
238000004587 chromatography analysis Methods 0.000 description 29
239000012043 crude product Substances 0.000 description 29
239000000706 filtrate Substances 0.000 description 28
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 25
FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 24
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
239000000499 gel Substances 0.000 description 23
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 22
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 22
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
239000011734 sodium Substances 0.000 description 21
235000011121 sodium hydroxide Nutrition 0.000 description 21
229940083608 sodium hydroxide Drugs 0.000 description 21
239000012258 stirred mixture Substances 0.000 description 21
239000000047 product Substances 0.000 description 20
229910052708 sodium Inorganic materials 0.000 description 20
235000017557 sodium bicarbonate Nutrition 0.000 description 20
229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 19
239000010410 layer Substances 0.000 description 19
229960001407 sodium bicarbonate Drugs 0.000 description 19
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 18
239000002904 solvent Substances 0.000 description 18
102100024085 Alpha-aminoadipic semialdehyde dehydrogenase Human genes 0.000 description 17
239000012074 organic phase Substances 0.000 description 17
229910052700 potassium Inorganic materials 0.000 description 17
239000011591 potassium Substances 0.000 description 17
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
101710135349 Venom phosphodiesterase Proteins 0.000 description 16
229910021529 ammonia Inorganic materials 0.000 description 16
HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 16
CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 15
XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 14
229920006395 saturated elastomer Polymers 0.000 description 14
150000001408 amides Chemical class 0.000 description 13
ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 description 13
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 13
FRDAATYAJDYRNW-UHFFFAOYSA-N 3-methyl-3-pentanol Chemical compound CCC(C)(O)CC FRDAATYAJDYRNW-UHFFFAOYSA-N 0.000 description 12
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 12
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
229910000024 caesium carbonate Inorganic materials 0.000 description 12
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 12
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical compound COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 description 10
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
150000001412 amines Chemical group 0.000 description 10
239000007864 aqueous solution Substances 0.000 description 10
238000004128 high performance liquid chromatography Methods 0.000 description 10
239000002244 precipitate Substances 0.000 description 10
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
229960000583 acetic acid Drugs 0.000 description 9
239000002585 base Substances 0.000 description 9
XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 description 9
238000002425 crystallisation Methods 0.000 description 9
239000000543 intermediate Substances 0.000 description 9
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 8
229910000029 sodium carbonate Inorganic materials 0.000 description 8
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
235000011114 ammonium hydroxide Nutrition 0.000 description 7
NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 7
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 7
235000017550 sodium carbonate Nutrition 0.000 description 7
229940001593 sodium carbonate Drugs 0.000 description 7
239000000758 substrate Substances 0.000 description 7
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 7
238000001665 trituration Methods 0.000 description 7
PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 6
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 6
NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 6
229910000564 Raney nickel Inorganic materials 0.000 description 6
239000006071 cream Substances 0.000 description 6
239000012362 glacial acetic acid Substances 0.000 description 6
229960005235 piperonyl butoxide Drugs 0.000 description 6
AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 6
229910000104 sodium hydride Inorganic materials 0.000 description 6
LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
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150000001298 alcohols Chemical class 0.000 description 1
230000029936 alkylation Effects 0.000 description 1
238000005804 alkylation reaction Methods 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
125000006242 amine protecting group Chemical group 0.000 description 1
150000001413 amino acids Chemical class 0.000 description 1
125000003277 amino group Chemical group 0.000 description 1
IMUDHTPIFIBORV-UHFFFAOYSA-N aminoethylpiperazine Chemical compound NCCN1CCNCC1 IMUDHTPIFIBORV-UHFFFAOYSA-N 0.000 description 1
VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
239000000908 ammonium hydroxide Substances 0.000 description 1
238000004458 analytical method Methods 0.000 description 1
150000001450 anions Chemical class 0.000 description 1
238000003556 assay Methods 0.000 description 1
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
235000019400 benzoyl peroxide Nutrition 0.000 description 1
235000019445 benzyl alcohol Nutrition 0.000 description 1
AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
125000001246 bromo group Chemical group Br* 0.000 description 1
244000309464 bull Species 0.000 description 1
229910052792 caesium Inorganic materials 0.000 description 1
TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
229910052791 calcium Inorganic materials 0.000 description 1
BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
239000000292 calcium oxide Substances 0.000 description 1
ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
150000001718 carbodiimides Chemical class 0.000 description 1
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
239000003054 catalyst Substances 0.000 description 1
229940125810 compound 20 Drugs 0.000 description 1
108010041382 compound 20 Proteins 0.000 description 1
JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
OQRBCLLVAUWAKU-UHFFFAOYSA-L copper;sulfate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O OQRBCLLVAUWAKU-UHFFFAOYSA-L 0.000 description 1
229960003280 cupric chloride Drugs 0.000 description 1
YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
229960002887 deanol Drugs 0.000 description 1
230000006735 deficit Effects 0.000 description 1
239000011928 denatured alcohol Substances 0.000 description 1
230000001419 dependent effect Effects 0.000 description 1
230000036576 dermal application Effects 0.000 description 1
FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
229960001760 dimethyl sulfoxide Drugs 0.000 description 1
239000012971 dimethylpiperazine Substances 0.000 description 1
UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
238000006073 displacement reaction Methods 0.000 description 1
238000004090 dissolution Methods 0.000 description 1
229940079593 drug Drugs 0.000 description 1
239000003814 drug Substances 0.000 description 1
239000003937 drug carrier Substances 0.000 description 1
230000004064 dysfunction Effects 0.000 description 1
FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
ZPSRHLWRTVNGSM-UHFFFAOYSA-N ethyl 2-methyl-5-propylpyrazole-3-carboxylate Chemical compound CCCC=1C=C(C(=O)OCC)N(C)N=1 ZPSRHLWRTVNGSM-UHFFFAOYSA-N 0.000 description 1
NIMKIMUBJFWPTD-UHFFFAOYSA-N ethyl 5,5-dimethyl-2,4-dioxohexanoate Chemical compound CCOC(=O)C(=O)CC(=O)C(C)(C)C NIMKIMUBJFWPTD-UHFFFAOYSA-N 0.000 description 1
HXSGCLZNDKQJGQ-UHFFFAOYSA-N ethyl 5-(4-ethylpiperazin-1-yl)sulfonyl-2-(propylamino)pyridine-3-carboxylate Chemical compound C1=C(C(=O)OCC)C(NCCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 HXSGCLZNDKQJGQ-UHFFFAOYSA-N 0.000 description 1
XSNYQCXIGIJDQN-AWEZNQCLSA-N ethyl 5-(4-ethylpiperazin-1-yl)sulfonyl-2-[(3s)-oxolan-3-yl]oxypyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC(S(=O)(=O)N2CCN(CC)CC2)=CN=C1O[C@H]1CCOC1 XSNYQCXIGIJDQN-AWEZNQCLSA-N 0.000 description 1
TZEXUTQSDJTATA-UHFFFAOYSA-N ethyl 5-amino-2-ethoxypyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC(N)=CN=C1OCC TZEXUTQSDJTATA-UHFFFAOYSA-N 0.000 description 1
YFONSBZEAHNVCW-UHFFFAOYSA-N ethyl 5-ethyl-1h-pyrazole-3-carboxylate Chemical compound CCOC(=O)C=1C=C(CC)NN=1 YFONSBZEAHNVCW-UHFFFAOYSA-N 0.000 description 1
FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
238000001640 fractional crystallisation Methods 0.000 description 1
230000005714 functional activity Effects 0.000 description 1
STJIISDMSMJQQK-UHFFFAOYSA-N furan-3-ylmethanol Chemical compound OCC=1C=COC=1 STJIISDMSMJQQK-UHFFFAOYSA-N 0.000 description 1
239000011521 glass Substances 0.000 description 1
JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
210000001308 heart ventricle Anatomy 0.000 description 1
238000010438 heat treatment Methods 0.000 description 1
XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
150000004688 heptahydrates Chemical class 0.000 description 1
150000004678 hydrides Chemical class 0.000 description 1
206010020718 hyperplasia Diseases 0.000 description 1
JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
238000001727 in vivo Methods 0.000 description 1
230000001939 inductive effect Effects 0.000 description 1
239000003112 inhibitor Substances 0.000 description 1
230000002401 inhibitory effect Effects 0.000 description 1
230000005764 inhibitory process Effects 0.000 description 1
229940030980 inova Drugs 0.000 description 1
239000007926 intracavernous injection Substances 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
125000002346 iodo group Chemical group I* 0.000 description 1
239000003456 ion exchange resin Substances 0.000 description 1
229920003303 ion-exchange polymer Polymers 0.000 description 1
ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
239000008101 lactose Substances 0.000 description 1
229910052744 lithium Inorganic materials 0.000 description 1
229910000103 lithium hydride Inorganic materials 0.000 description 1
238000001819 mass spectrum Methods 0.000 description 1
238000005259 measurement Methods 0.000 description 1
230000001404 mediated effect Effects 0.000 description 1
RHMQNXNXUZLEIY-UHFFFAOYSA-N methanol;2-propan-2-yloxypropane Chemical compound OC.CC(C)OC(C)C RHMQNXNXUZLEIY-UHFFFAOYSA-N 0.000 description 1
ILIZIRZNLURXBS-UHFFFAOYSA-N methyl 5-(4-methylpiperazin-1-yl)sulfonyl-2-propoxypyridine-3-carboxylate Chemical compound C1=C(C(=O)OC)C(OCCC)=NC=C1S(=O)(=O)N1CCN(C)CC1 ILIZIRZNLURXBS-UHFFFAOYSA-N 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
239000002808 molecular sieve Substances 0.000 description 1
HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
150000002772 monosaccharides Chemical class 0.000 description 1
210000003205 muscle Anatomy 0.000 description 1
HHQJWDKIRXRTLS-UHFFFAOYSA-N n'-bromobutanediamide Chemical compound NC(=O)CCC(=O)NBr HHQJWDKIRXRTLS-UHFFFAOYSA-N 0.000 description 1
BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-UHFFFAOYSA-N 0.000 description 1
AEXITZJSLGALNH-UHFFFAOYSA-N n'-hydroxyethanimidamide Chemical compound CC(N)=NO AEXITZJSLGALNH-UHFFFAOYSA-N 0.000 description 1
SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
230000018791 negative regulation of catalytic activity Effects 0.000 description 1
150000002825 nitriles Chemical class 0.000 description 1
XITQUSLLOSKDTB-UHFFFAOYSA-N nitrofen Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC1=CC=C(Cl)C=C1Cl XITQUSLLOSKDTB-UHFFFAOYSA-N 0.000 description 1
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
238000005580 one pot reaction Methods 0.000 description 1
229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
LMYJGUNNJIDROI-UHFFFAOYSA-N oxan-4-ol Chemical compound OC1CCOCC1 LMYJGUNNJIDROI-UHFFFAOYSA-N 0.000 description 1
238000007254 oxidation reaction Methods 0.000 description 1
229910052760 oxygen Inorganic materials 0.000 description 1
239000001301 oxygen Substances 0.000 description 1
230000020477 pH reduction Effects 0.000 description 1
229910052763 palladium Inorganic materials 0.000 description 1
QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
150000004686 pentahydrates Chemical class 0.000 description 1
150000002978 peroxides Chemical class 0.000 description 1
239000000546 pharmaceutical excipient Substances 0.000 description 1
238000003408 phase transfer catalysis Methods 0.000 description 1
UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
108091008695 photoreceptors Proteins 0.000 description 1
235000002651 pink gum Nutrition 0.000 description 1
244000087877 pink gum Species 0.000 description 1
229920000166 polytrimethylene carbonate Polymers 0.000 description 1
239000011736 potassium bicarbonate Substances 0.000 description 1
235000015497 potassium bicarbonate Nutrition 0.000 description 1
229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
235000015320 potassium carbonate Nutrition 0.000 description 1
NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
229910000105 potassium hydride Inorganic materials 0.000 description 1
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
159000000001 potassium salts Chemical class 0.000 description 1
239000002243 precursor Substances 0.000 description 1
SUVIGLJNEAMWEG-UHFFFAOYSA-N propane-1-thiol Chemical compound CCCS SUVIGLJNEAMWEG-UHFFFAOYSA-N 0.000 description 1
238000000746 purification Methods 0.000 description 1
JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 1
239000002516 radical scavenger Substances 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
230000004044 response Effects 0.000 description 1
210000002027 skeletal muscle Anatomy 0.000 description 1
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
229910000033 sodium borohydride Inorganic materials 0.000 description 1
239000012279 sodium borohydride Substances 0.000 description 1
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
235000009518 sodium iodide Nutrition 0.000 description 1
AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
235000019345 sodium thiosulphate Nutrition 0.000 description 1
235000015096 spirit Nutrition 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
238000003756 stirring Methods 0.000 description 1
238000010998 test method Methods 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
238000012546 transfer Methods 0.000 description 1
230000009466 transformation Effects 0.000 description 1
238000000844 transformation Methods 0.000 description 1
238000005406 washing Methods 0.000 description 1
235000005074 zinc chloride Nutrition 0.000 description 1
239000011592 zinc chloride Substances 0.000 description 1

Classifications

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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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OA1200000284A 1998-04-20 2000-10-13 Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction. OA11502A (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
GBGB9808315.7A GB9808315D0 (en)	1998-04-20	1998-04-20	Therapeutic agents
GBGB9814187.2A GB9814187D0 (en)	1998-06-30	1998-06-30	Therapeutic agents

Publications (1)

Publication Number	Publication Date
OA11502A true OA11502A (en)	2004-05-10

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ID=26313490

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OA1200000284A OA11502A (en)	1998-04-20	2000-10-13	Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction.

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EP (2)	EP1371647B1 (de)
JP (2)	JP3721077B2 (de)
KR (1)	KR100449790B1 (de)
CN (2)	CN1134442C (de)
AP (1)	AP1022A (de)
AR (2)	AR015770A1 (de)
AT (2)	ATE247117T1 (de)
AU (1)	AU748352B2 (de)
BG (1)	BG104949A (de)
BR (1)	BR9909808A (de)
CA (1)	CA2329077C (de)
CO (1)	CO5271649A1 (de)
DE (2)	DE69910368T2 (de)
DK (2)	DK1371647T3 (de)
DZ (1)	DZ2773A1 (de)
EA (1)	EA200000969A1 (de)
ES (2)	ES2242124T3 (de)
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HR (1)	HRP20000712A2 (de)
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ID (1)	ID27036A (de)
IL (2)	IL138907A0 (de)
IS (1)	IS5650A (de)
MA (1)	MA26622A1 (de)
NO (1)	NO20005255L (de)
OA (1)	OA11502A (de)
PA (1)	PA8470501A1 (de)
PE (1)	PE20000463A1 (de)
PL (1)	PL343794A1 (de)
PT (2)	PT1371647E (de)
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SI (2)	SI1371647T1 (de)
SK (1)	SK15532000A3 (de)
TN (1)	TNSN99073A1 (de)
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TW (1)	TW593310B (de)
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1999
- 1999-03-25 DE DE69910368T patent/DE69910368T2/de not_active Expired - Fee Related
- 1999-03-25 CN CNB998072885A patent/CN1134442C/zh not_active Expired - Fee Related
- 1999-03-25 PT PT03013988T patent/PT1371647E/pt unknown
- 1999-03-25 EA EA200000969A patent/EA200000969A1/ru unknown
- 1999-03-25 BR BR9909808-3A patent/BR9909808A/pt not_active Application Discontinuation
- 1999-03-25 HR HR20000712A patent/HRP20000712A2/hr not_active Application Discontinuation
- 1999-03-25 AT AT99907805T patent/ATE247117T1/de not_active IP Right Cessation
- 1999-03-25 PL PL99343794A patent/PL343794A1/xx not_active IP Right Cessation
- 1999-03-25 DE DE69926154T patent/DE69926154T2/de not_active Expired - Fee Related
- 1999-03-25 EP EP03013988A patent/EP1371647B1/de not_active Expired - Lifetime
- 1999-03-25 SI SI9930802T patent/SI1371647T1/xx unknown
- 1999-03-25 HU HU0102543A patent/HUP0102543A3/hu unknown
- 1999-03-25 PT PT99907805T patent/PT1073658E/pt unknown
- 1999-03-25 AT AT03013988T patent/ATE299503T1/de not_active IP Right Cessation
- 1999-03-25 CN CNB031579582A patent/CN1229349C/zh not_active Expired - Fee Related
- 1999-03-25 ES ES03013988T patent/ES2242124T3/es not_active Expired - Lifetime
- 1999-03-25 TR TR2000/03039T patent/TR200003039T2/xx unknown
- 1999-03-25 WO PCT/IB1999/000519 patent/WO1999054333A1/en not_active Ceased
- 1999-03-25 DK DK03013988T patent/DK1371647T3/da active
- 1999-03-25 KR KR10-2000-7011569A patent/KR100449790B1/ko not_active Expired - Fee Related
- 1999-03-25 JP JP2000544672A patent/JP3721077B2/ja not_active Expired - Fee Related
- 1999-03-25 RS YUP-635/00A patent/RS50011B/sr unknown
- 1999-03-25 US US09/402,242 patent/US6251904B1/en not_active Expired - Fee Related
- 1999-03-25 DK DK99907805T patent/DK1073658T3/da active
- 1999-03-25 ES ES99907805T patent/ES2203078T3/es not_active Expired - Lifetime
- 1999-03-25 IL IL13890799A patent/IL138907A0/xx not_active IP Right Cessation
- 1999-03-25 AU AU27425/99A patent/AU748352B2/en not_active Ceased
- 1999-03-25 CA CA002329077A patent/CA2329077C/en not_active Expired - Fee Related
- 1999-03-25 SI SI9930361T patent/SI1073658T1/xx unknown
- 1999-03-25 ID IDW20002117A patent/ID27036A/id unknown
- 1999-03-25 EP EP99907805A patent/EP1073658B1/de not_active Expired - Lifetime
- 1999-03-25 SK SK1553-2000A patent/SK15532000A3/sk unknown
- 1999-03-26 TW TW088104856A patent/TW593310B/zh not_active IP Right Cessation
- 1999-04-07 PA PA19998470501A patent/PA8470501A1/es unknown
- 1999-04-13 GT GT199900053A patent/GT199900053A/es unknown
- 1999-04-15 AP APAP/P/1999/001514A patent/AP1022A/en active
- 1999-04-16 AR ARP990101780A patent/AR015770A1/es active IP Right Grant
- 1999-04-16 CO CO99022946A patent/CO5271649A1/es not_active Application Discontinuation
- 1999-04-16 PE PE1999000322A patent/PE20000463A1/es not_active Application Discontinuation
- 1999-04-19 DZ DZ990073A patent/DZ2773A1/xx active
- 1999-04-19 MA MA25542A patent/MA26622A1/fr unknown
- 1999-04-19 TN TNTNSN99073A patent/TNSN99073A1/fr unknown
- 1999-04-20 UY UY25484A patent/UY25484A1/es not_active Application Discontinuation
2000
- 2000-09-29 IS IS5650A patent/IS5650A/is unknown
- 2000-10-05 IL IL138907A patent/IL138907A/en unknown
- 2000-10-13 OA OA1200000284A patent/OA11502A/en unknown
- 2000-10-19 NO NO20005255A patent/NO20005255L/no not_active Application Discontinuation
- 2000-11-15 BG BG104949A patent/BG104949A/xx unknown
2001
- 2001-04-30 US US09/845,420 patent/US6458951B2/en not_active Expired - Fee Related
2003
- 2003-11-20 JP JP2003390698A patent/JP2004099620A/ja not_active Withdrawn
2006
- 2006-11-24 AR ARP060105188A patent/AR057934A2/es unknown

Also Published As

Publication number	Publication date
AP1022A (en)	2001-11-14
DE69926154T2 (de)	2006-03-23
JP3721077B2 (ja)	2005-11-30
US20010039271A1 (en)	2001-11-08
DZ2773A1 (fr)	2003-12-01
IL138907A0 (en)	2001-11-25
CA2329077C (en)	2007-09-18
UY25484A1 (es)	1999-11-17
TW593310B (en)	2004-06-21
HUP0102543A3 (en)	2002-01-28
PA8470501A1 (es)	2000-09-29
DK1073658T3 (da)	2003-12-08
DK1371647T3 (da)	2005-10-17
ATE299503T1 (de)	2005-07-15
AR057934A2 (es)	2007-12-26
CO5271649A1 (es)	2003-04-30
ATE247117T1 (de)	2003-08-15
CN1229349C (zh)	2005-11-30
PT1371647E (pt)	2005-10-31
EP1371647B1 (de)	2005-07-13
CA2329077A1 (en)	1999-10-28
DE69910368D1 (de)	2003-09-18
ES2242124T3 (es)	2005-11-01
AP9901514A0 (en)	1999-06-30
DE69910368T2 (de)	2004-03-25
SK15532000A3 (sk)	2001-12-03
TNSN99073A1 (fr)	2005-11-10
CN1495169A (zh)	2004-05-12
DE69926154D1 (de)	2005-08-18
US6458951B2 (en)	2002-10-01
US6251904B1 (en)	2001-06-26
SI1371647T1 (en)	2005-10-31
SI1073658T1 (en)	2003-12-31
HUP0102543A2 (hu)	2001-11-28
JP2004099620A (ja)	2004-04-02
KR20010042815A (ko)	2001-05-25
PL343794A1 (en)	2001-09-10
HK1064670A1 (en)	2005-02-04
JP2002512248A (ja)	2002-04-23
AU2742599A (en)	1999-11-08
CN1305478A (zh)	2001-07-25
NO20005255D0 (no)	2000-10-19
HRP20000712A2 (en)	2001-06-30
WO1999054333A1 (en)	1999-10-28
EP1073658A1 (de)	2001-02-07
EP1073658B1 (de)	2003-08-13
EP1371647A2 (de)	2003-12-17
GT199900053A (es)	2000-10-04
ES2203078T3 (es)	2004-04-01
ID27036A (id)	2001-02-22
KR100449790B1 (ko)	2004-09-22
MA26622A1 (fr)	2004-12-20
TR200003039T2 (tr)	2001-01-22
AR015770A1 (es)	2001-05-16
IL138907A (en)	2007-08-19
PT1073658E (pt)	2003-12-31
BR9909808A (pt)	2000-12-26
RS50011B (sr)	2008-09-29
YU63500A (sh)	2002-11-15
BG104949A (en)	2001-06-29
EP1371647A3 (de)	2004-07-28
IS5650A (is)	2000-09-29
AU748352B2 (en)	2002-06-06
NO20005255L (no)	2000-12-19
CN1134442C (zh)	2004-01-14
PE20000463A1 (es)	2000-05-26
EA200000969A1 (ru)	2001-06-25

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JPWO1991018893A1 (ja)	1993-02-04	新規１，４―チアジン誘導体及びそれを有効成分とする強心剤