GB1577304A - Ester of 1,4-ethano-10-hydroxy-5-oxo-5h-(1)benzopyrano(3,5-b)pyridine - Google Patents

Ester of 1,4-ethano-10-hydroxy-5-oxo-5h-(1)benzopyrano(3,5-b)pyridine Download PDF

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GB1577304A
GB1577304A GB9857/78A GB985778A GB1577304A GB 1577304 A GB1577304 A GB 1577304A GB 9857/78 A GB9857/78 A GB 9857/78A GB 985778 A GB985778 A GB 985778A GB 1577304 A GB1577304 A GB 1577304A
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compound
intraocular pressure
formula
carbon atoms
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Abbott Laboratories
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—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
    • C07D491/12—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 three hetero rings
    • C07D491/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Ophthalmology & Optometry (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyridine Compounds (AREA)

Abstract

A description is given of esters of 1,4-ethano-10-hydroxy-5-oxo-5H-[1]benzopyrano[3,4-b]pyridine derivatives of formula: <IMAGE> where R represents a straight or branched alkanoyl radical containing 2 to 8 carbon atoms, or a radical of formula: <IMAGE> where Y represents a straight or branched alkylene radical containing 1 to 8 carbon atoms, a is an integer from 1 to 4, b is an integer from 1 to 4, X represents CH2, O, S or NR1, where R1 represents a hydrogen atom or a lower alkyl radical, with the proviso that, when X represents O, S or NR1, the sum of a and b is equal to 3 or 4; and of their acid addition salts which are suitable in pharmacy. These compounds constitute medicaments which are useful especially for lowering intraocular pressure and as mild tranquillisers.

Description

(54) ESTERS OF 1,4-ETHANO-10-HYDROXY-5-OXO- 5H-[l]BENZOPYRANO[3,4-b]PYRIDINE (71) We, ABBOTT LABORATORIES, a Corporation organized and existing under the laws of the State of Illinois, United States of America, of 14th Street and Sheridan Road, North Chicago, County of Lake, State of Illinois, United States of America, do hereby declare the invention for which we pray that a Patent may be granted to us and the method by which it is to be performed to be particularly described in and by the following statement: This invention relates to compounds for reducing the intra-occular pressure in mammalian patients.
According to the present invention there is provided a compound of the formula
in which R represents a straight or branched chain alkanoyl group having from 2 to 8 carbon atoms, or
in which Y represents a straight or branched chain alkylene group having from 1 to 8 carbon atoms, a is an integer from 1 to 4, b is an integer from 1 to 4, X is CH2, O, S, or NR1 in which R' represents a hydrogen atom or an alkyl group containing up to 6 carbon atoms, with the proviso that when X is O, S or NR1, the sum of a and b is 3 or 4, and pharmaceutically acceptable acid addition salts thereof.
The term "pharmaceutically acceptable acid addition salts" refers to an acid addition salt of the desired acid.
Representative salts include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, succinate and tartrate.
The compounds of the present invention provide drugs for reducing the intra-ocular pressure in mammalian patients, specifically for use in treating glaucoma. The compounds are also active as mild tranquilizers.
The compounds of this invention can be prepared using the methods described in United States Patent Specification No.
3,493,579, the preparation of the starting material 1,4 - ethano - 10 - hydroxy - 8 (3 - methyl - 2 - octyl) - 5 - oxo - 1,2,3,4 tetrahydro - 5H - [l]benzopyrano - [3,4b] pyridine hydrochloride of the structure
being described in Example 1 thereof.
Representative compounds which can be prepared are exemplified in the following Examples.
EXAMPLE 1 Compound of formula A wherein R is
1,4 - Ethano - 8 - (3 - methyl - 2 octyl) - 5 - oxo - 1,2,3,4 -tetrahydro 5H[l]benzopyranol3,4 - b]pyridine 10 - acetate hydrochloride 3.0 g (0.0074 mole) of the pyrone -HCl, Formula B, prepared as described in United States Patent Specification No. 3,493,579, was placed in a flask with 2.46 g (0.03 mole) of anhydrous sodium acetate and 30 ml of acetic anhydride and heated under reflux overnight. The reaction mixture was then cooled, and the acetic anhydride evaporated. To the residue was added approximately 100 ml of water and the aqueous solution was then extracted with ether. The ether was washed with saturated NaCI solution, then dried over MgSO4 and evaporated.
The HC1-salt was prepared in the conventional manner. Obtained 2.3 g of a white solid, recrystallized from an ethanol/ether mixture, m.p. 237-2390C (69 /" yield).
Analysis: Calculated for C25H33NO4 . HCl: C, 67.18; H, 7.67; N, 3.13.
Found: C, 67.40; H, 7.92; N, 3.16.
The infra-red and NMR Spectra were consistent with the proposed structure.
EXAMPLE 2 Compound of formula A wherein R is
1,4 - Ethano - 8 - (3 - methyl - 2 octyl) - 5 - oxo - 1,2,3,4 - tetrahydro 5H - [I]benzopyrano[3,4 pyridine - 10 - propionate hydrochloride The pyrone-HC1 (3.0 g, 0.0074 mole) starting material was dissolved in chloroform, washed with dilute potassiumbicarbonate solution, then washed with saturated NaCI solution, dried over MgSO4 and evaporated to yield the free base as a yellow glassy residue.
The free base was dissolved in 75 ml of dry benzene, then 0.68 g (0.0074 mole) of propionyl chloride and 0.75 g (0.0074 mole) of triethylamine (ET3N) was added to the solution. The reaction was then refluxed overnight, cooled and filtered to remove the Et3N . HCI. The filtrate was then evaporated to give a glassy solid which was taken up in dry ether and etheral-HC1 then added. The salt precipitated out of solution. A quantative yield of 3.6 g of white solid was obtained giving a softening point of 86 88"C which then melted at 1300C.
Analysis: Calculated for C26H3sNO4. HCI: C, 67.59; H, 7.854; N, 3.032.
Found: C, 67.53; H, 7.81, N, 3.00.
The infra-red and NMR Spectra were consistent with the proposed structure.
EXAMPLE 3 1,4 - Ethano - 8 - (3 - methyl - 2 octyl) - 5 - oxo - 1,2,3,4 tetrahydro - 5H - [l]benzopyrano- [3,4 - b]pyridine - 10 - octanoate hydrochloride In like manner, using the method of Example 2 when octanoyl chloride was used in place of propionyl chloride the compound in which R is
was obtained.
Obtained 3.4 g (86% yield) of a white crystalline solid having a m.p of 143 145 C.
Analysis: Calculated for C3,H4sNO4 . HCI: C, 69.968; H, 8.713; N 2.632.
Found: C, 69.21; H, 8.68; N, 2.56.
Infra-red and NMR Spectra were consistent with the structure.
EXAMPLE 4 1,4 - Ethano - 8 - (3 - methyl - 2 octyl) - 5 -oxo - 1,2,3,4 -tetrahydro 5H - [I]benzopyrano[3,4 pyridine - 10 - trimethylacetate hydrochloride When trimethylacetyl chloride was used in place of propionyl choride, the compound in which R is
was obtained.
Obtained 3.6 g (99 /" yield) of a white crystalline solid, m.p. 178--1806C.
Analysis: Calculated for C28H39NO4 . HCI: C, 68.622; H, 8.190; N, 2.858.
Found: C, 68.28; H, 8.24; N, 2.79.
Infra-red and NMR Spectra were consistent with the structure.
EXAMPLE 5 Compound of formula A wherein R is
where Y=(CH2)3, a+b=4, X=CH2.
1,4 - Ethano - 10[4 - (1 - piperidino) butyryloxyl] - 8 - (3 - methyl - 2 octyl) - 5 - oxo - 1,2,3,4 - tetrahydro 5H - [llbenzopyrano[3,4 - b] pyridine hydrochloride 4.05 g (0.01 mole) of the pyrone-HC1 was dissolved in NaHCO3 solution and extracted with methylene chloride. The methylene chloride was washed with saturated NaCI solution, then dried over MgSO4, and evaporated, yielding a light yellow oil.
The free base was then taken up in 155 ml. of dry methylene chloride and 2.07 g (0.01 mole) of y - piperidino butyric acid-HC1 (Cruickshank and Sheehan, J. Am. Chem.
Soc., 83, 2891, 1961) was added in one portion to the solution. This was allowed to stir for five minutes before 2.26 g (0.011 mole) of N,N' - Dicyclohexylcarbodiimide was added to the solution. The reaction was stirred under a nitrogen atmosphere overnight (18 hours), cooled for 3 hours at 0 C., then the by product (dicyclohexylurea) was filtered off. The filtrate was then concentrated to dryness, leaving an oily residue which immediately crystalized.
The solid residue was then taken up in hot CH2Cl2 and dry ether added until the solution was just turbid. The solution was allowed to sit at room temperature whereupon solid product precipitated out of solution. The solid was collected and vacuum oven dried to obtain 4.1 g of white solid, m.p. 165-1670C. (73 /O yield).
NMR and IR were consistent with the desired product.
Analysis: Calculated for C32H48N4O4 . HCI . 1/2 H2O: C, 67.642; H, 8.515; N, 4.930 Found: C, 67.89; H, 8.47; N, 5.04.
EXAMPLE 6 Compound of Formula A wherein R is
1,4 - Ethano - 10[4 - (4 - morpholino) butyryloxy] - 8 - (3 - methyl - 2 octyl) - 5 - oxo - 1,2,3,4 - tetrahydro 5H - [llbenzopyrano[3,4 - b] pyridine hydrobromide The free base of the compound of Formula B, (4.05 g, .01 mole) is reacted with 2.54 g (.01 mole) of 4 - morpholino butyric acid .HBr [J. Am. Chem. Soc. 83, 2891 (1961)] and 2.26 g (.01 mole) of N,N' Dicyclohexylcarbodiimide as described in Example 5 to obtain the above compound.
EXAMPLE 7 Compound of Formula A wherein R is
1,4 - Ethano - 10[4 - (4 methylpiperazino) butyryloxy] - 8 (3 - methyl - 2 - octyl) - 5 - oxo 1,2,3,4 - tetrahydro - 5H - [I]- benzopyrano[3,4 - b] pyridine hydrobromide In like manner to Example 6, the free base of the Compound of Formula B, (4.05 g, .01 mole) is reacted with 2.67 g (.01 mole) of 4 - methylpiperazino butyric acid .HBr and 2.26 g (.01 mole) of N,N' Dicyclohexylcarbodiimide as described in Example 5 to obtain the desired compound.
The intraocular pressure lowering properties of the compounds of Formula A were evaluated in male albino, New Zealand rabbits, weighing between 2 to 4 kg. The animals were placed in plastic restraining devices and three control readings, separated by at least 30 minutes, were obtained from each eye using a Bausch and Lomb Applamatic Tonometer. Test readings were taken at 30, 60, 90, 120 and 180 minutes after drug administration and were done in the same manner as the control studies. All studies were done on a blinded basis. The statistical procedure used to analyze the data was the one-sided, Mann Whitney, two-sample U-test. P values equal to or less than 0.1 were regarded as indicating statistical significance. The compounds and the reference standards pilocarpine hydrochloride, and epinephrine hydrochloride were prepared in sterile water for topical, intravenous, and intramuscular administration; dry powders were placed in gelatin capsules for the oral studies. Volume doses of the vehicle or an empty gelatin capsule served as placebo controls. The volume of drug instilled for the topical studies was constant at 0.1 ml.
Each compound was tested in four eyes.
The compound of Formula A in which R is
applied topically as 0.05 /n and 0.1 solutions produced a dose-related decrease in intraocular pressure in comparison to the control sample. The maximal effects were -9% and -32%, respectively, for each of the two concentrations. The effect of the 0.1 solution persisted for at least 90 minutes.
Pilocarpine hydrochloride was active at a concentration of 0.5"/,, producing a 260/, decrease in intraocular pressure at 60 minutes. Epinephrine was not active at a concentration of 0.05 but at 0.10/, there was a gradual lowering of intraocular pressure which became statistically significant at 180 minutes after topical application.
Intravenous administration of the compound noted also produced a doserelated decrease in intraocular pressure.
Maximum effects ranged from -200/, at a 0.05 mg/kg dose to 45 /n at 1.0 mg/kg.
Pilocarpine, at a dose of 1 mg/kg, i.v., produced a non-significant increase of intraocular pressure as well as signs of parasympathomimetic-type activity, particularly a profuse salivation.
Over the oral dose range of 1.0 to 50.0 mg/kg, p.o., the compound was inactive in lowering intraocular pressure and did not produce a statistically significant change in intraocular pressure when administered intramuscularly.
The compound of formula A in which R is
produced a 28% reduction in intraocular pressure when applied topically as a 0.1% solution; the compound in which R is
produced a 6% reduction in pressure; and the compound in which R is
a 33% increase in pressure (not confirmed), all in comparison to a placebo control.
It is apparent that the compounds of the present invention are active when applied topically more so than a placebo control or reference compounds pilocarpine or epinephrine.
The compound of Formula A wherein R 1R
(Example 5) was found to be effective as a tranquilizer. Aggressive behaviour of biting, evading, running, and vocalizing was decreased when administered orally to a monkey at a dose level of 10 mg/kg.
Likewise, when administered orally to a hooded rat at a dose level of 5.0 mg/kg, a 34% decrease in Desoxyn induced activity resulted.
WHAT WE CLAIM IS:1. A compound of the formula:
in which R represents a straight or branched chain alkanoyl group having from 2 to 8 carbon atoms, or
in which Y represents a straight or branched chain alkylene group having from 1 to 8 carbon atoms, a is an integer from 1 to 4, b is an integer from 1 to 4, X is CH2, O, S, or NR1, in which R1 represents a hydrogen atom or an alkyl group containing up to 6 carbon atoms, with the proviso that when X is O, S or NR', the sum of a and b is 3 or 4, and pharmaceutically acceptable acid addition salts thereof.
2. A compound as claimed in Claim 1 in which R represents
3. A compound as claimed in Claim 2 in which R represents
4. A compound as claimed in Claim 2 in which R represents
5. A compound as claimed in Claim 2 in which R represents
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (7)

  1. **WARNING** start of CLMS field may overlap end of DESC **.
    significant at 180 minutes after topical application.
    Intravenous administration of the compound noted also produced a doserelated decrease in intraocular pressure.
    Maximum effects ranged from -200/, at a 0.05 mg/kg dose to 45 /n at 1.0 mg/kg.
    Pilocarpine, at a dose of 1 mg/kg, i.v., produced a non-significant increase of intraocular pressure as well as signs of parasympathomimetic-type activity, particularly a profuse salivation.
    Over the oral dose range of 1.0 to 50.0 mg/kg, p.o., the compound was inactive in lowering intraocular pressure and did not produce a statistically significant change in intraocular pressure when administered intramuscularly.
    The compound of formula A in which R is
    produced a 28% reduction in intraocular pressure when applied topically as a 0.1% solution; the compound in which R is
    produced a 6% reduction in pressure; and the compound in which R is
    a 33% increase in pressure (not confirmed), all in comparison to a placebo control.
    It is apparent that the compounds of the present invention are active when applied topically more so than a placebo control or reference compounds pilocarpine or epinephrine.
    The compound of Formula A wherein R 1R
    (Example 5) was found to be effective as a tranquilizer. Aggressive behaviour of biting, evading, running, and vocalizing was decreased when administered orally to a monkey at a dose level of 10 mg/kg.
    Likewise, when administered orally to a hooded rat at a dose level of 5.0 mg/kg, a 34% decrease in Desoxyn induced activity resulted.
    WHAT WE CLAIM IS:1. A compound of the formula:
    in which R represents a straight or branched chain alkanoyl group having from 2 to 8 carbon atoms, or
    in which Y represents a straight or branched chain alkylene group having from 1 to 8 carbon atoms, a is an integer from 1 to 4, b is an integer from 1 to 4, X is CH2, O, S, or NR1, in which R1 represents a hydrogen atom or an alkyl group containing up to 6 carbon atoms, with the proviso that when X is O, S or NR', the sum of a and b is 3 or 4, and pharmaceutically acceptable acid addition salts thereof.
  2. 2. A compound as claimed in Claim 1 in which R represents
  3. 3. A compound as claimed in Claim 2 in which R represents
  4. 4. A compound as claimed in Claim 2 in which R represents
  5. 5. A compound as claimed in Claim 2 in which R represents
  6. 6. A compound as claimed in any preceding claim in the form of a hydrochloride acid addition salt.
  7. 7. A compound as claimed in Claim 1 substantially as herein described with reference to any one of the Examples.
GB9857/78A 1977-03-14 1978-03-13 Ester of 1,4-ethano-10-hydroxy-5-oxo-5h-(1)benzopyrano(3,5-b)pyridine Expired GB1577304A (en)

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JP (1) JPS53130698A (en)
AU (1) AU516613B2 (en)
CA (1) CA1095519A (en)
CH (1) CH628633A5 (en)
DE (1) DE2810801A1 (en)
DK (1) DK111378A (en)
FR (1) FR2383948A1 (en)
GB (1) GB1577304A (en)
GR (1) GR65603B (en)
NO (1) NO780880L (en)
PH (1) PH13723A (en)
SE (1) SE7802841L (en)
ZA (1) ZA781074B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0819431A1 (en) * 1996-07-05 1998-01-21 Takeda Chemical Industries, Ltd. Agent for prophylaxis and treatment of disturbance of visual function

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2645021A1 (en) * 1989-03-30 1990-10-05 Sanofi Sa USE OF A POTASSIC AGONIST IN THE TREATMENT OF GLAUCOMA

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3493579A (en) * 1967-05-29 1970-02-03 Little Inc A 1,4-ethano-5h-(1)benzopyrano (3,4-b)pyridines
US3905969A (en) * 1974-01-17 1975-09-16 Sharps Ass Heterocyclic esters of 5H-{8 1{9 benzopyrano{8 3,4-b{9 pyridines

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0819431A1 (en) * 1996-07-05 1998-01-21 Takeda Chemical Industries, Ltd. Agent for prophylaxis and treatment of disturbance of visual function
US5952338A (en) * 1996-07-05 1999-09-14 Takeda Chemical Industries, Ltd. Agent for prophylaxis and treatment of disturbance of visual function

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CH628633A5 (en) 1982-03-15
AU3371878A (en) 1979-09-06
GR65603B (en) 1980-10-14
CA1095519A (en) 1981-02-10
DE2810801A1 (en) 1978-09-21
AU516613B2 (en) 1981-06-11
DK111378A (en) 1978-09-15
FR2383948B1 (en) 1981-07-31
ZA781074B (en) 1979-04-25
FR2383948A1 (en) 1978-10-13
SE7802841L (en) 1978-09-15
NO780880L (en) 1978-09-15
PH13723A (en) 1980-09-09
JPS53130698A (en) 1978-11-14

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