CA2322900C - 2-(hetero)aryl-substituted purin-6-ones as phosphodiesterase inhibitors - Google Patents
2-(hetero)aryl-substituted purin-6-ones as phosphodiesterase inhibitors Download PDFInfo
- Publication number
- CA2322900C CA2322900C CA002322900A CA2322900A CA2322900C CA 2322900 C CA2322900 C CA 2322900C CA 002322900 A CA002322900 A CA 002322900A CA 2322900 A CA2322900 A CA 2322900A CA 2322900 C CA2322900 C CA 2322900C
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- CA
- Canada
- Prior art keywords
- aryl
- alkyl
- optionally substituted
- group
- lower alkyl
- 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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- UYLWKSJTHLRFBX-UHFFFAOYSA-N purin-6-one Chemical class O=C1N=CN=C2N=CN=C12 UYLWKSJTHLRFBX-UHFFFAOYSA-N 0.000 title description 16
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 title description 2
- 239000002571 phosphodiesterase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 322
- 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 claims abstract description 37
- 230000005764 inhibitory process Effects 0.000 claims abstract description 11
- 238000011321 prophylaxis Methods 0.000 claims abstract description 7
- 238000009109 curative therapy Methods 0.000 claims abstract description 6
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 claims abstract description 5
- 101150098694 PDE5A gene Proteins 0.000 claims abstract description 5
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 283
- 125000003118 aryl group Chemical group 0.000 claims description 179
- 125000001424 substituent group Chemical group 0.000 claims description 133
- 125000005843 halogen group Chemical group 0.000 claims description 115
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 90
- 238000006243 chemical reaction Methods 0.000 claims description 77
- -1 Het3 Chemical group 0.000 claims description 62
- 239000000203 mixture Substances 0.000 claims description 62
- 238000002360 preparation method Methods 0.000 claims description 54
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 40
- 229910052757 nitrogen Inorganic materials 0.000 claims description 35
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 34
- 125000000623 heterocyclic group Chemical group 0.000 claims description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 239000001301 oxygen Chemical group 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 18
- 239000011593 sulfur Chemical group 0.000 claims description 17
- 229910052717 sulfur Chemical group 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 16
- 201000001881 impotence Diseases 0.000 claims description 15
- 125000004429 atom Chemical group 0.000 claims description 13
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- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 9
- 208000021663 Female sexual arousal disease Diseases 0.000 claims description 6
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- 206010024419 Libido decreased Diseases 0.000 claims description 6
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- 239000003085 diluting agent Substances 0.000 claims description 6
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- 230000008569 process Effects 0.000 claims description 6
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
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- 230000029936 alkylation Effects 0.000 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
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- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
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- UFZNZKGKBWOSJG-UHFFFAOYSA-N purin-2-one Chemical compound O=C1N=CC2=NC=NC2=N1 UFZNZKGKBWOSJG-UHFFFAOYSA-N 0.000 claims description 3
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 13
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
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- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 description 120
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- 239000000243 solution Substances 0.000 description 55
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
- 230000002829 reductive effect Effects 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 150000003839 salts Chemical class 0.000 description 33
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
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- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 12
- 229920003199 poly(diethylsiloxane) Polymers 0.000 description 12
- 102100024085 Alpha-aminoadipic semialdehyde dehydrogenase Human genes 0.000 description 11
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- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 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
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- 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
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- 229960002613 tamsulosin Drugs 0.000 description 1
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- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
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- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
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- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
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- 230000007306 turnover Effects 0.000 description 1
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- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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- BLGXFZZNTVWLAY-SCYLSFHTSA-N yohimbine Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-SCYLSFHTSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/28—Oxygen atom
- C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9924020.2 | 1999-10-11 | ||
| GBGB9924020.2A GB9924020D0 (en) | 1999-10-11 | 1999-10-11 | Pharmaceutically active compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2322900A1 CA2322900A1 (en) | 2001-04-11 |
| CA2322900C true CA2322900C (en) | 2005-02-08 |
Family
ID=10862516
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002322900A Expired - Fee Related CA2322900C (en) | 1999-10-11 | 2000-10-06 | 2-(hetero)aryl-substituted purin-6-ones as phosphodiesterase inhibitors |
Country Status (7)
| Country | Link |
|---|---|
| US (3) | US6440982B1 (enExample) |
| EP (1) | EP1092718A1 (enExample) |
| JP (2) | JP3727525B2 (enExample) |
| BR (1) | BR0004786A (enExample) |
| CA (1) | CA2322900C (enExample) |
| GB (1) | GB9924020D0 (enExample) |
| MX (1) | MXPA00009938A (enExample) |
Families Citing this family (40)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20030046397A (ko) * | 2000-07-28 | 2003-06-12 | 슬로안-케테링인스티튜트퍼캔서리서치 | 세포증식성 질환 및 바이러스 감염의 치료 방법 |
| US6548508B2 (en) | 2000-10-20 | 2003-04-15 | Pfizer, Inc. | Use of PDE V inhibitors for improved fecundity in mammals |
| EP1335920B1 (en) * | 2000-11-02 | 2013-04-03 | Sloan-Kettering Institute For Cancer Research | Compositions containing purine derivatives for binding to hsp90 |
| JP2004529188A (ja) * | 2001-05-23 | 2004-09-24 | スローン − ケッタリング インスティチュート フォー キャンサー リサーチ | 上昇に関連した癌の治療法 |
| IL161491A0 (en) * | 2001-11-07 | 2004-09-27 | Synthon Bv | Tamsulosin tablets |
| GB0219961D0 (en) | 2002-08-28 | 2002-10-02 | Pfizer Ltd | Oxytocin inhibitors |
| US7323462B2 (en) | 2002-12-10 | 2008-01-29 | Pfizer Inc. | Morpholine dopamine agonists |
| NZ567457A (en) | 2002-12-13 | 2009-08-28 | Warner Lambert Co | Alpha-2-delta ligand to treat lower urinary tract symptoms |
| US20050048573A1 (en) * | 2003-02-03 | 2005-03-03 | Plexxikon, Inc. | PDE5A crystal structure and uses |
| JP4533590B2 (ja) * | 2003-02-28 | 2010-09-01 | ファイザー株式会社 | 脊髄損傷患者における疼痛又は痙性軽減用医薬組成物 |
| CN100374441C (zh) | 2003-06-06 | 2008-03-12 | 天津倍方科技发展有限公司 | 二氢吡咯[2，3-d]嘧啶-4-酮衍生物，其制备方法及其制药用途 |
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| US20030004173A1 (en) | 2003-01-02 |
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| JP3727525B2 (ja) | 2005-12-14 |
| US6440982B1 (en) | 2002-08-27 |
| JP2003128673A (ja) | 2003-05-08 |
| BR0004786A (pt) | 2001-05-22 |
| EP1092718A1 (en) | 2001-04-18 |
| JP2001114782A (ja) | 2001-04-24 |
| MXPA00009938A (es) | 2002-11-04 |
| US6586439B2 (en) | 2003-07-01 |
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