WO1997019947A1 - COMPOSES 2'-[[4'-HALO-[1,1'-BIPHENYL]-4-YL]METHYL]-5'-METHYL-SPIRO[CYCLOPENTANE-1,7'(8'H)-[3H]IMIDAZO[2,1-b]PURIN]-4'(5'H)-ONES - Google Patents

COMPOSES 2'-[[4'-HALO-[1,1'-BIPHENYL]-4-YL]METHYL]-5'-METHYL-SPIRO[CYCLOPENTANE-1,7'(8'H)-[3H]IMIDAZO[2,1-b]PURIN]-4'(5'H)-ONES Download PDF

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Publication number
WO1997019947A1
WO1997019947A1 PCT/US1996/018550 US9618550W WO9719947A1 WO 1997019947 A1 WO1997019947 A1 WO 1997019947A1 US 9618550 W US9618550 W US 9618550W WO 9719947 A1 WO9719947 A1 WO 9719947A1
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WO
WIPO (PCT)
Prior art keywords
methyl
compound
spiro
biphenyl
imidazo
Prior art date
Application number
PCT/US1996/018550
Other languages
English (en)
Inventor
Brian A. Mckittrick
Deen Tulshian
Original Assignee
Schering Corporation
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.)
Filing date
Publication date
Application filed by Schering Corporation filed Critical Schering Corporation
Priority to JP9520543A priority Critical patent/JP2000501095A/ja
Priority to EP96941401A priority patent/EP0863902A1/fr
Priority to AU10555/97A priority patent/AU1055597A/en
Publication of WO1997019947A1 publication Critical patent/WO1997019947A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/34—Gestagens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/36—Antigestagens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/42—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of mineralocorticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to 2'-[[4'-halo-[1 ,1 '-biphenyl]-4- yl]methyl]-5'-methyl-spiro[cyclopentane-1 ,7'(8 ⁇ )-[3H]imidazo[2,1 -b]purin]- 4'(5'H)-ones, their use in treating cardiovascular and pulmonary disorders, and pharmaceutical compositions comprising them.
  • Phosphodiesterase inhibitory compounds of this invention were generically but not specifically disclosed in PCT publication WO91/19717, published December 26, 1991 , and related compounds were generically and specifically disclosed in WO94/19351 , published September 17 1994. We have found that the compounds of the present invention show unexpectedly superior plasma levels compared to the compounds of the prior publications when administered intravenously, subcutaneously or orally.
  • the present invention is directed to 2'-[[4'-halo-[1 ,1'- biphenyl]-4-yl]methyl]-5'-methyl-spiro[cyclopentane-1 ,7'(8 ⁇ )-[3H]imidazo- [2,1 -b]purin]-4'(5 ⁇ )-ones of the formula 1:
  • the compounds of formula I are useful as antihypertensive, bronchodilating and blood platelet inhibiting agents.
  • Compounds of the invention are useful in inhibiting phosphodiesterase enzymes; the inhibition of vascular phosphodiesterase is associated with vasodilation and vasorelaxation, and therefore is expected to induce antihypertensive and antianginal activity.
  • Compounds of formula I can also serve as smooth muscle relaxants and are therefore useful in the treatment of bronchoconstriction.
  • Such compounds also can inhibit smooth muscle proliferation, vascular growth and platelet function and are useful in treating conditions such as restenosis post angioplasty, atherosclerosis and conditions which benefit from inhibiting platelet function.
  • compounds of formula I are also useful in treating ischemia and peripheral vascular diseases.
  • the compounds of the present invention are not as readily metabolized. They demonstrate good selectivity of inhibition of Type I and Type V phosphodiesterase isozymes while maintaining high blood levels and demonstrating antiplatelet and vasodilator activity.
  • the present invention is also directed toward a pharmaceutical composition containing a compound of formula I in an amount effective to inhibit phosphodiesterase enzymes, smooth muscle proliferation, vascular growth or platelet function, or to relax smooth muscle.
  • the present invention is also directed toward a pharmaceutical composition containing an anti-hypertensive, an anti-anginal, a bronchodilating or a platelet inhibiting effective amount of a compound of formula I.
  • the present invention is also directed toward a method for treating hypertension, angina, bronchoconstriction, restenosis post angioplasty, atherosclerosis, ischemia, peripheral vascular diseases, or diseases benefitting from platelet inhibition in a mammal comprising administering to a mammal in need of such treatment an amount of a compound of formula I effective to treat any of the above diseases.
  • the present invention is also directed toward a method for maintaining guanosine 3',5'-cyclic monophosphate (cGMP) levels in a mammal by administering an amount of a compound of formula I effective to maintain or increase cGMP levels.
  • cGMP guanosine 3',5'-cyclic monophosphate
  • Compounds of the invention have a basic nitrogen containing moiety, and can form pharmaceutically acceptable salts with organic and inorganic acids.
  • suitable acids for such salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • the compounds of the present invention can be prepared by several routes, such as those described in WO91/19717 and WO94/19351.
  • the following examples show typical procedures, but those skilled in the art will recognize that the preparation of these compounds is not Iimited to these procedures.
  • Me refers to methyl
  • Bn refers to benzyl
  • Ph refers to phenyl
  • SEM refers to trimethylsilylethoxymethyl.
  • Step 1
  • Example 1 Use the procedure of Example 1 , Step 2, heating with sulfur and morpholine for 4 h, to convert ketone 9 (50.93 g, 0.19 mol) to acid 10 (51.3 g, 95%), a white solid.
  • the compounds of formula I can be combined with a suitable pharmaceutical carrier to prepare a pharmaceutical composition suitable for parenteral or oral administration.
  • a suitable pharmaceutical carrier to prepare a pharmaceutical composition suitable for parenteral or oral administration.
  • Such pharmaceutical compositions are useful in the treatment of cardiovascular and pulmonary disorders such as mammalian hypertension and bronchoconstriction.
  • the effective daily antihypertensive dose (ED50) of the present compounds will typically be in the range of about 1 to about 100 mg/kg of mammalian body weight, administered in single or divided doses.
  • the exact dosage to be administered can be determined by the attending clinician and is dependent upon where the particular compound lies within the above cited range, as well as upon the age, weight and condition of the individual.
  • the present compounds can be administered in a dosage range of about 10 to about 500 mg per patient generally given a number of times per day, providing a total daily dosage of from about 10 to about 2000 mg per day.
  • compositions of the present invention can be administered orally or parenterally.
  • Typical injectable formulations include solutions and suspensions.
  • Typical oral formulations include tablets, capsules, syrups, suspensions and elixirs.
  • mechanical delivery systems e.g. transdermal dosage forms.
  • the typical acceptable pharmaceutical carriers for use in the formulations described above are exemplified by sugars such as lactose, sucrose, mannitol and sorbitol; starches such as cornstarch, tapioca starch and potato starch; cellulose and derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone, polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate and calcium stearate, stearic acid, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationic and anionic surfactants; ethylene glycol polymers; beta-cyclodextrin; fatty alcohols and hydrolyzed cereal solids; as well as other non-toxic compatible fillers
  • the present compounds are useful in inhibiting phosphodiesterase enzymes, in particular phosphodiesterase isozymes Types I and V. These phosphodiesterase enzymes are known to hydrolyze cGMP in smooth muscle. High levels of cGMP are associated with the relaxation of vascular smooth muscle, with a consequent subsequent reduction in blood pressure. Thus, it is believed that by inhibiting these phosphodiesterase enzymes, cGMP levels in muscle will be either maintained or increased, with a subsequent reduction in blood pressure. In vivo antihypertensive activity is determined orally in spontaneously hypertensive rats (SHR).
  • SHR spontaneously hypertensive rats
  • cGMP cyclic guanosine monophosphate
  • the first enzyme calcium-calmodulin dependent phosphodiesterase (CaM-PDE)
  • CaM-PDE calcium-calmodulin dependent phosphodiesterase
  • the enzyme is activated several fold by Ca-calmodulin and is selective for cGMP, although it will also hydrolyze cAMP.
  • the second enzyme, cGMP phosphodiesterase (cGMP- PDE) is a homogeneous enzyme obtained from bovine lung and purified by ion-exchange chromatography, gel filtration, and sucrose gradient centrifugation.
  • cGMP-PDE is highly selective for cGMP.
  • Bovine aorta homogenates and primary cultures of bovine aortic endothelial and vascular smooth muscle cells contain an enzyme with properties very similar to the lung isozyme. The enzyme assay is performed using a Biomek Automated
  • the negatively charged substrates are then separated from guanosine by binding to an anion-exchange resin (AG1 - X8) and centrifugation or filtration, and the product is quantitated by scintillation counting in counts per minute (cpm) of the remaining soluble material. Percent inhibition is calculated as follows:
  • % lnhibition 100-[(cpm compound-blank)/(cpm control-blank)X100]
  • Activity is expresssed as the IC50 value, ie. the concentration required to inhibit activity of enzyme by 50 per cent.
  • SHR conscious spontaneously hypertensive rats
  • SHR males are purchased from Taconic Farms, Germantown New York and are approximately 16-18 weeks old when anesthetized with ether.
  • the caudal (ventral tail) artery is cannulated with polyethylene tubing (PE50) and blood pressure and heart rate are recorded as described by Baum, T. et. al, J. Cardiovasc. Pharmacol. Vol 5, pp. 655-667, (1983). Rats are placed into plastic cylindrical cages where they rapidly recover consciousness. Blood pressure and heart rate are allowed to stabilize for approximately 90 minutes prior to compound administration.
  • PE50 polyethylene tubing
  • Compounds are administered orally as solutions or suspensions in 0.4% aqueous methylcellulose vehicle via a feeding needle.
  • the compound or 0.4% aqueous methylcellulose vehicle are given in a volume of 4 ml/kg to SHRs that had been fasted overnight.
  • Activity is expressed as the fall in mean blood pressure (MBP) in millimeters of mercury (mm Hg).
  • MBP mean blood pressure
  • mm Hg millimeters of mercury
  • Plasma levels were plotted versus hours post dosing and the area under the curve (AUC, ⁇ ghr/ml) was calculated.
  • test results are compared to a previously- known compound, 2'-[[(4'-methoxy-1 ,1 '-biphenyl)-4-yl]methyl]-5'-methyl- spiro[cyclopentane-1 ⁇ ( ⁇ HSHjimidazo- ⁇ .l -b]purin]-4'(5'H)-one (Ref. Cpd.).

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  • 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)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Cette invention concerne des composés antihypertenseur et bronchodilateur de formule (I) ou un de leurs sels pharmaceutiquement acceptables. Dans la formule, X représente fluoro, chloro ou bromo.
PCT/US1996/018550 1995-11-28 1996-11-26 COMPOSES 2'-[[4'-HALO-[1,1'-BIPHENYL]-4-YL]METHYL]-5'-METHYL-SPIRO[CYCLOPENTANE-1,7'(8'H)-[3H]IMIDAZO[2,1-b]PURIN]-4'(5'H)-ONES WO1997019947A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP9520543A JP2000501095A (ja) 1995-11-28 1996-11-26 ２’‐［［４’‐ハロ‐［１，１’‐ビフェニル］‐４‐イル］メチル］‐５’‐メチル‐スピロ［シクロペンタン‐１，７’（８’Ｈ）‐［３Ｈ］イミダゾ［２，１‐ｂ］プリン］‐４’（５’Ｈ）‐オン類
EP96941401A EP0863902A1 (fr) 1995-11-28 1996-11-26 COMPOSES 2'- 4'-HALO- 1,1'-BIPHENYL]-4-YL]METHYL]-5'-METHYL-SPIRO CYCLOPENTANE-1,7'(8'H)- 3H]IMIDAZO 2,1-b]PURIN]-4'(5'H)-ONES
AU10555/97A AU1055597A (en) 1995-11-28 1996-11-26 2'-{{4'-halo-{1,1'-biphenyl}-4-yl}methyl}-5'-methyl-spiro{cy clopentane-1,7'(8'h)-{3h}imidazo{2,1-b}purin}-4'(5'h)-ones

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US56371795A 1995-11-28 1995-11-28
US08/563,717 1995-11-28

Publications (1)

Publication Number Publication Date
WO1997019947A1 true WO1997019947A1 (fr) 1997-06-05

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PCT/US1996/018550 WO1997019947A1 (fr) 1995-11-28 1996-11-26 COMPOSES 2'-[[4'-HALO-[1,1'-BIPHENYL]-4-YL]METHYL]-5'-METHYL-SPIRO[CYCLOPENTANE-1,7'(8'H)-[3H]IMIDAZO[2,1-b]PURIN]-4'(5'H)-ONES

Country Status (8)

Country Link
EP (1) EP0863902A1 (fr)
JP (1) JP2000501095A (fr)
AR (1) AR004752A1 (fr)
AU (1) AU1055597A (fr)
CA (1) CA2237956A1 (fr)
CO (1) CO4480029A1 (fr)
WO (1) WO1997019947A1 (fr)
ZA (1) ZA969888B (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6326379B1 (en) 1998-09-16 2001-12-04 Bristol-Myers Squibb Co. Fused pyridine inhibitors of cGMP phosphodiesterase
US6683081B2 (en) 1999-12-24 2004-01-27 Bayer Aktiengesellschaft Triazolotriazinones and the use thereof
US6777416B2 (en) 1999-12-24 2004-08-17 Bayer Aktiengesellschaft Isoxazolo pyrimidinones and the use thereof
US6803365B2 (en) 1999-12-24 2004-10-12 Bayer Aktlengesellschaft Imidazo[1,3,5]triazinones and the use thereof
US10981916B2 (en) 2016-12-28 2021-04-20 Dart Neuroscience, Llc Substituted pyrazolopyrimidinone compounds as PDE2 inhibitors
US11434247B1 (en) 2017-11-27 2022-09-06 Dart Neuroscience Llc Substituted furanopyrimidine compounds as PDE1 inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991019717A1 (fr) * 1990-06-21 1991-12-26 Schering Corporation Derives polycycliques de guanine
WO1994019351A1 (fr) * 1993-02-26 1994-09-01 Schering Corporation Derives de guanine 2-benzyle-polycyclique et procede de preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991019717A1 (fr) * 1990-06-21 1991-12-26 Schering Corporation Derives polycycliques de guanine
WO1994019351A1 (fr) * 1993-02-26 1994-09-01 Schering Corporation Derives de guanine 2-benzyle-polycyclique et procede de preparation

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6326379B1 (en) 1998-09-16 2001-12-04 Bristol-Myers Squibb Co. Fused pyridine inhibitors of cGMP phosphodiesterase
US6683081B2 (en) 1999-12-24 2004-01-27 Bayer Aktiengesellschaft Triazolotriazinones and the use thereof
US6777416B2 (en) 1999-12-24 2004-08-17 Bayer Aktiengesellschaft Isoxazolo pyrimidinones and the use thereof
US6803365B2 (en) 1999-12-24 2004-10-12 Bayer Aktlengesellschaft Imidazo[1,3,5]triazinones and the use thereof
US7091203B2 (en) 1999-12-24 2006-08-15 Bayer Healthcare Ag Imidazo[1,3,5]triazinones and their use
US10981916B2 (en) 2016-12-28 2021-04-20 Dart Neuroscience, Llc Substituted pyrazolopyrimidinone compounds as PDE2 inhibitors
US11999738B2 (en) 2016-12-28 2024-06-04 Dart Neuroscience, Llc Substituted pyrazolopyrimidinone compounds as PDE2 inhibitors
US11434247B1 (en) 2017-11-27 2022-09-06 Dart Neuroscience Llc Substituted furanopyrimidine compounds as PDE1 inhibitors
US12006325B2 (en) 2017-11-27 2024-06-11 Dart Neuroscience, Llc Substituted furanopyrimidine compounds as PDE1 inhibitors

Also Published As

Publication number Publication date
EP0863902A1 (fr) 1998-09-16
JP2000501095A (ja) 2000-02-02
CA2237956A1 (fr) 1997-06-05
CO4480029A1 (es) 1997-07-09
AR004752A1 (es) 1999-03-10
AU1055597A (en) 1997-06-19
MX9804198A (es) 1998-10-31
ZA969888B (en) 1997-05-26

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