CA1095519A - Esters of 1,4-ethano-10-hydroxy-5-oxo-5h-[1] benzopyrano [3,4-b] pyridine - Google Patents
Esters of 1,4-ethano-10-hydroxy-5-oxo-5h-[1] benzopyrano [3,4-b] pyridineInfo
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- CA1095519A CA1095519A CA297,028A CA297028A CA1095519A CA 1095519 A CA1095519 A CA 1095519A CA 297028 A CA297028 A CA 297028A CA 1095519 A CA1095519 A CA 1095519A
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- oxo
- ethano
- pyridine
- tetrahydro
- octyl
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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
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- 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
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- 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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- General Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
Abstract
Abstract of the Disclosure Disclosed are compounds of the formula useful in reducing the intra-ocular pressure in mammalian patients wherein R is a straight or branched chain alkanoyl group having from 2-8 carbon atoms or with Y being a straight or branched chain alkylene group having from 1-8 carbon atoms; a is an integer from 1-4;
b is an integer from 1-4; X is CH2, O, S, or NR1 with R1 being hydrogen or lower alkyl with the limitation 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.
b is an integer from 1-4; X is CH2, O, S, or NR1 with R1 being hydrogen or lower alkyl with the limitation 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.
Description
lg Summary of the Invention This invention relates to compounds of the formula OR
wherein R is a straight or branched chain alkanoyl group having from 2-8 carbon atoms or (CH2)a -C-Y-N X
(CH2)b ., with Y being a straight or branched chai.n alk~lene group having from 1-8 carbon atoms; a is an integer fr~m 1-4;
b is an integer from 1-4; X is CH2, O, S, or NRl with Rl being hydrogen or lower alkyl with the limitation that when X is O, S, or NRl, the sum of a and b is 3 or 4, and pharmaceutically acceptable acid addition salts thereof.
wherein R is a straight or branched chain alkanoyl group having from 2-8 carbon atoms or (CH2)a -C-Y-N X
(CH2)b ., with Y being a straight or branched chai.n alk~lene group having from 1-8 carbon atoms; a is an integer fr~m 1-4;
b is an integer from 1-4; X is CH2, O, S, or NRl with Rl being hydrogen or lower alkyl with the limitation that when X is O, S, or NRl, the sum of a and b is 3 or 4, and pharmaceutically acceptable acid addition salts thereof.
-2-"' ~ jb ~$ ~, iS15~
The term "pharmaceutically acceptable acid addition salts" refers to an acid addition salt of the desired acid. Representative salts include the hydro-chloride, hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, succinate, tartrate and the like.
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.
Detailed Description The conpounds of this invention can be pre-pared using the methods described in U.S. Patent 3,4~3,579, lS issued February 3, 1970, 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 OH
o~\~gNlg being described in Example 1 thereof.
Representative compounds which can be pre-pared are exemplified in the following examples.
o Compound of formula A wherein R is -CCH3 1,4-Ethano-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro 5H-[l] benzo~yrano [3,4-~] pyridine-10-acetate h~ydrochloride
The term "pharmaceutically acceptable acid addition salts" refers to an acid addition salt of the desired acid. Representative salts include the hydro-chloride, hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, succinate, tartrate and the like.
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.
Detailed Description The conpounds of this invention can be pre-pared using the methods described in U.S. Patent 3,4~3,579, lS issued February 3, 1970, 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 OH
o~\~gNlg being described in Example 1 thereof.
Representative compounds which can be pre-pared are exemplified in the following examples.
o Compound of formula A wherein R is -CCH3 1,4-Ethano-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro 5H-[l] benzo~yrano [3,4-~] pyridine-10-acetate h~ydrochloride
3.0 g (0.0074 mole) of the pyrone -HCl, Formula B, prepared as described in U.S. Patent 3,493,579, issued February 3, 1970, 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 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 NaCl solution, then dried over MgSO4 and evaporated.
The HCl-salt was prepared in the conven-tional mann~r. Obtained 2.3 g of a white solid, recrystallized from an ethanol/ether mixture, m.p.
237-239C. (69% yield).
Analy~is: Calculated for C25H33NO4 HCl:
C, 67.18; H, 7.67; N, 3.13. Found: C, 67.40;
H, 7.92; Nt 3.16.
~0~
The infra-red and NMR Spectra were consistent with the proposed structure.
EX~PLE 2 !0l Compound of formula A wherein R is -CC2H5 . ~c~ I
l,4-Ethano-3-(3-me-thyl-2-es~y~)-5-oxo-l,2,3,4-tetrahydro-5H-rll benzopyrano ~3,4-b] pyridine-lO-propionate hydro-chloride . . . ~
The pyrone-HCI (3.0 g, 0.0074 mole) starting material was dissolved in chloroform, washed with dilute potassium-bicarbonate solution, then washed wi-th saturLated NaCl solution, dried over MgSO4 and evapora-ted to yield the free base as a yellow glassy residue.
The free base was dissolved in 75 ml of dry p r ~ p j ~n ~ ¦
benzene, then 0.68 g (0.0074 mole) oE _ 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-HCl. The filtrate was then evaporated to give a glassy solid which was taken up in dry ether and etheral-MCl 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 130C.
jk/
~09~9 Analysis: Calculated for C26H35NO4-HCl:
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 con-sistent with the proposed structure.
1,4-Ethano-8-(3-methyl-2-octyl)-5~oxo-1,2,3,4-tetrahydro 5H-[l] benzopyrano [3,4-bl pyridine-10-octanoate hydrochloride In like manner, using ~he method of Example 2 when octanoyl chloride was used in place of propionyl chloride, o the compound in which R is -C(CH2)6CH3 was obtained.
Obtained 3.4 g (86% yield) of a white crystaline solid having a m.p. of 143-145C.
Analysis: Calculated for C31H45NO4 HCl:
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.
~1~9~i;51~
1,4-Ethano-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1] benzopyrano 13,4-b]pyridine-10-trimethylacetate hydro-chloride When trimethylacetyl chloride was used in place O CH~
of propionyl chloride, the compound in which R is -C-C-CH3 was obtained. CH3 Obtained 3.6 g (99% yield) of a white crystaline solid, m.p. 178-180C.
Analysis: Calculated for C28H39NO4 HCl:
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.
~C19S~l~
Il ~\
Compound of formula A wherein R is R's -C(CH2)3 N
where Y = (CH2)3 , a + b = 4, X=CH2 1,4-~thano-10~4-(1-piperidino) butyryloxy]-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5~-[1] benzopyrano [3,4-b]
pyridine hydrochloride_ _ .:
The HCl-salt was prepared in the conven-tional mann~r. Obtained 2.3 g of a white solid, recrystallized from an ethanol/ether mixture, m.p.
237-239C. (69% yield).
Analy~is: Calculated for C25H33NO4 HCl:
C, 67.18; H, 7.67; N, 3.13. Found: C, 67.40;
H, 7.92; Nt 3.16.
~0~
The infra-red and NMR Spectra were consistent with the proposed structure.
EX~PLE 2 !0l Compound of formula A wherein R is -CC2H5 . ~c~ I
l,4-Ethano-3-(3-me-thyl-2-es~y~)-5-oxo-l,2,3,4-tetrahydro-5H-rll benzopyrano ~3,4-b] pyridine-lO-propionate hydro-chloride . . . ~
The pyrone-HCI (3.0 g, 0.0074 mole) starting material was dissolved in chloroform, washed with dilute potassium-bicarbonate solution, then washed wi-th saturLated NaCl solution, dried over MgSO4 and evapora-ted to yield the free base as a yellow glassy residue.
The free base was dissolved in 75 ml of dry p r ~ p j ~n ~ ¦
benzene, then 0.68 g (0.0074 mole) oE _ 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-HCl. The filtrate was then evaporated to give a glassy solid which was taken up in dry ether and etheral-MCl 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 130C.
jk/
~09~9 Analysis: Calculated for C26H35NO4-HCl:
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 con-sistent with the proposed structure.
1,4-Ethano-8-(3-methyl-2-octyl)-5~oxo-1,2,3,4-tetrahydro 5H-[l] benzopyrano [3,4-bl pyridine-10-octanoate hydrochloride In like manner, using ~he method of Example 2 when octanoyl chloride was used in place of propionyl chloride, o the compound in which R is -C(CH2)6CH3 was obtained.
Obtained 3.4 g (86% yield) of a white crystaline solid having a m.p. of 143-145C.
Analysis: Calculated for C31H45NO4 HCl:
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.
~1~9~i;51~
1,4-Ethano-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1] benzopyrano 13,4-b]pyridine-10-trimethylacetate hydro-chloride When trimethylacetyl chloride was used in place O CH~
of propionyl chloride, the compound in which R is -C-C-CH3 was obtained. CH3 Obtained 3.6 g (99% yield) of a white crystaline solid, m.p. 178-180C.
Analysis: Calculated for C28H39NO4 HCl:
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.
~C19S~l~
Il ~\
Compound of formula A wherein R is R's -C(CH2)3 N
where Y = (CH2)3 , a + b = 4, X=CH2 1,4-~thano-10~4-(1-piperidino) butyryloxy]-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5~-[1] benzopyrano [3,4-b]
pyridine hydrochloride_ _ .:
4.05 g (0.01 mole) of the pyrone-HCl was dis-solved in NaHCO3 solution and extracted with methylene chloride. The methylene chloride was washed with saturated NaCl 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 ~-piperidino butyric acid-HCl (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 beore 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 0C., then the by product (dicyclohexylurea) was filtered off.
The filtrate was then concentrated to dryness, leaving an oily residue which immediately crystalized.
1~39~5~91 The solid residue was then taken up in hot CH2C12 and dry ether added until the solution was just turbid. The solution was allowed to sit at room temperature whereupon solid product preclpitated out of solution. The solid was collected and vacuum oven dried to obtain 4.1 g of white solid, m.p.
165-167C. (73% yield) NMR and IR were consistent with the desired product.
Analysis: Calculated for C32H46~4O4 HCl 1/2 H2O: C, 67.642; H, 8.515; N, 4.930. Found: C, 67.89;
H, 8.47; Nt 5-04-Il ,~
Compound of Formula A wherein R is -C(CH2)3 N O
1,4-Ethano-10[4-(4-morpholino) butyryloxy]-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[l~ benzQpyrano [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'-Dicyclohexyl-carbodiimide as described in Example 5 to obtain the above compound.
_9_ :~ogs5~
O
Compound of Formula A wherein R is -C(CH2)3- N N-CH3 1,4-Ethano-10[4-~4-methylpiperazino) butyryloxy]-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[l] benzo-~yrano [3,4-b] ~yridine 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 reaclings, separated by at least 30 minutes, were obtained from each eye using a Bausch and Lomb Appla-matic 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 ~SS19 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 S 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 O ~ .
-C(CH2)3 N~ applied topically as 0.05% 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 per-sisted for at least ~0 minutes. Pilocarpine hydrochloride was active at a concentration of 0.5%, producing a 26%
decrease in intraocular pressure at 60 minutes. Epine-phrine was not active at a concentration of 0.05~ but at 0.1% 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 dose~related decrease in intraocular pres-sure. Maximum effects ranged from 20% at a 0.05 mg/kg dose ~ ~ 5 ~ ~ 9 to -45% 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 5~.0 mg/kg, p.o., the compound was inactive in lowering intraocular pressure and did not produce a statistically signifi~ant change in intraocular pressure when administered intra-muscularly. O
The compound of Formula A in which R is -C'CH3 produced a 28% reduction in intraocular pressure when applied topically as a 0. l~/o solution; the compound in o which R is -C(CH2)6CH3 produced a 6~/o reduction in pres-Il l sure; and the compound in which R is -C-C-CH3 a 33%
increase in pressure (not confirmed), all in comparison to a placebo control.
It is apparent that the compounds of the pre-sent 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 is O ~
~ \
C(CH2)3 N ~ (Example 5) was found to be effective as a tranquilizer. Aggressive behavior of biting, evading, running, and vocalizing was decreased when administered 1~9~g orally to a monkey at a dose level of 10 mg/kg. Like-wise, when administered orally to a hooded rat at a dose level of 5.0 mg/kg, a 34% decrease in Desoxyn induced activity resulted.
The free base was then taken up in 155 ml. of dry methylene chloride and 2.07 g (0.01 mole) of ~-piperidino butyric acid-HCl (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 beore 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 0C., then the by product (dicyclohexylurea) was filtered off.
The filtrate was then concentrated to dryness, leaving an oily residue which immediately crystalized.
1~39~5~91 The solid residue was then taken up in hot CH2C12 and dry ether added until the solution was just turbid. The solution was allowed to sit at room temperature whereupon solid product preclpitated out of solution. The solid was collected and vacuum oven dried to obtain 4.1 g of white solid, m.p.
165-167C. (73% yield) NMR and IR were consistent with the desired product.
Analysis: Calculated for C32H46~4O4 HCl 1/2 H2O: C, 67.642; H, 8.515; N, 4.930. Found: C, 67.89;
H, 8.47; Nt 5-04-Il ,~
Compound of Formula A wherein R is -C(CH2)3 N O
1,4-Ethano-10[4-(4-morpholino) butyryloxy]-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[l~ benzQpyrano [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'-Dicyclohexyl-carbodiimide as described in Example 5 to obtain the above compound.
_9_ :~ogs5~
O
Compound of Formula A wherein R is -C(CH2)3- N N-CH3 1,4-Ethano-10[4-~4-methylpiperazino) butyryloxy]-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[l] benzo-~yrano [3,4-b] ~yridine 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 reaclings, separated by at least 30 minutes, were obtained from each eye using a Bausch and Lomb Appla-matic 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 ~SS19 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 S 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 O ~ .
-C(CH2)3 N~ applied topically as 0.05% 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 per-sisted for at least ~0 minutes. Pilocarpine hydrochloride was active at a concentration of 0.5%, producing a 26%
decrease in intraocular pressure at 60 minutes. Epine-phrine was not active at a concentration of 0.05~ but at 0.1% 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 dose~related decrease in intraocular pres-sure. Maximum effects ranged from 20% at a 0.05 mg/kg dose ~ ~ 5 ~ ~ 9 to -45% 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 5~.0 mg/kg, p.o., the compound was inactive in lowering intraocular pressure and did not produce a statistically signifi~ant change in intraocular pressure when administered intra-muscularly. O
The compound of Formula A in which R is -C'CH3 produced a 28% reduction in intraocular pressure when applied topically as a 0. l~/o solution; the compound in o which R is -C(CH2)6CH3 produced a 6~/o reduction in pres-Il l sure; and the compound in which R is -C-C-CH3 a 33%
increase in pressure (not confirmed), all in comparison to a placebo control.
It is apparent that the compounds of the pre-sent 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 is O ~
~ \
C(CH2)3 N ~ (Example 5) was found to be effective as a tranquilizer. Aggressive behavior of biting, evading, running, and vocalizing was decreased when administered 1~9~g orally to a monkey at a dose level of 10 mg/kg. Like-wise, when administered orally to a hooded rat at a dose level of 5.0 mg/kg, a 34% decrease in Desoxyn induced activity resulted.
Claims (16)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula wherein R is a straight or branched chain alkanoyl group having from 1-8 carbon atoms or wherein Y is a straight or branched chain alkylene group having from 1-8 carbon atoms, a is an integer from 1-4, b is an integer from 1-4, X is CH2, O, S, or NR1 with R1 being hydrogen or lower alkyl, with the proviso that when X is O, S, or NR1, the sum of a and b is 3 or 4, said process being selected from the group consisting of:
(a) dissolving 1,4-ethano-10-hydroxy-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano-[3,4b]
pyridine in an organic solvent, adding R-halide, where R is as defined above, together with an equimolar amount of an acid acceptor, refluxing the reaction mixture, cooling the reaction mixture, filtering off the acid acceptor salt which is formed and recovering the desired compound from the filtrate, and (b) dissolving 1,4-ethano-10-hydroxy-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1] benzypyrano-[3,4b]
pyridine in an organic solvent, reacting with RCOOH, where R
is as defined above, and with N,N'dicyclohexylcarbodiimide, cooling the reaction mixture, filtering off the dicyclohexylurea which is formed and recovering the desired compound from the filtrate.
(a) dissolving 1,4-ethano-10-hydroxy-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano-[3,4b]
pyridine in an organic solvent, adding R-halide, where R is as defined above, together with an equimolar amount of an acid acceptor, refluxing the reaction mixture, cooling the reaction mixture, filtering off the acid acceptor salt which is formed and recovering the desired compound from the filtrate, and (b) dissolving 1,4-ethano-10-hydroxy-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1] benzypyrano-[3,4b]
pyridine in an organic solvent, reacting with RCOOH, where R
is as defined above, and with N,N'dicyclohexylcarbodiimide, cooling the reaction mixture, filtering off the dicyclohexylurea which is formed and recovering the desired compound from the filtrate.
2. A process according to Claim 1, procedure (a), wherein the R-halide is acetyl chloride.
3. A process according to Claim 1, procedure (a), wherein the R-halide is propionyl chloride.
4. A process according to Claim 1, procedure (a), wherein the R-halide is octanoyl chloride.
5. A process according to Claim 1, procedure (a), wherein the R-halide is trimethylacetyl chloride.
6. A process according to Claim 1, procedure (b), wherein the RCOOH is y-piperidino butyric acid.
7. A process according to Claim 1, procedure (b), wherein the RCOOH is 4-morpholino butyric acid.
8. A process according to Claim 1, procedure (b) 3 wherein the RCOOH is 4-methylpiperazino butyric acid.
9. A compound of the formula wherein R is a straight or branched chain alkanoyl group having from 2-8 carbon atoms or wherein Y is a straight or branched chain alkylene group having from 1-8 carbon atoms, a is an integer from 1-4, b is an integer from l-4, X is CH2, O, S, or NR1 with R1 being hydrogen or lower alkyl, with the proviso that when X is O, S, or NR1, the sum of a and b is 3 or 4, whenever prepared according to the method of Claim 1, or by an obvious chemical equivalent.
10. 1,4-Ethano-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1] benzopyrano-[3,4b] pyridine-10-acetate, whenever prepared according to the method of Claim 2, or by an obvious chemical equivalent.
11. 1,4-Ethano-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1] benzopyrano-[3,4b] pyridine-10-propionate, whenever prepared according to the method of Claim 3, or by an obvious chemical equivalent.
12. 1,4-Ethano-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1] benzopyrano-[3,4b] pyridine-10-octanoate, whenever prepared according to the method of Claim 4, or by an obvious chemical equivalent.
13. 1,4-Ethano-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1] benzopyrano-[3,4b] pyridine-10-trimethyl-acetate, whenever prepared according to the method of Claim 5, or by an obvious chemical equivalent.
14. 1,4-Ethano-10[4-(1-piperidino) butyryloxy]-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1] benzopyrano [3,4b] pyridine, whenever prepared according to the method of Claim 6, or by an obvious chemical equivalent.
15. 1,4-Ethano-10[4-(4-morpholino) butyryloxy]-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1] benzopyrano 13,4b] pyridine, whenever prepared according to the method of Claim 7, or by an obvious chemical equivalent.
16. 1,4-Ethano-10[4-(4-methylpiperazino) butyryloxy]-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1] benzopyrano [3,4b] pyridine, whenever prepared according to the method of Claim 8, or by an obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US77775677A | 1977-03-14 | 1977-03-14 | |
| US777,756 | 1977-03-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1095519A true CA1095519A (en) | 1981-02-10 |
Family
ID=25111162
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA297,028A Expired CA1095519A (en) | 1977-03-14 | 1978-02-16 | Esters of 1,4-ethano-10-hydroxy-5-oxo-5h-[1] benzopyrano [3,4-b] pyridine |
Country Status (13)
| Country | Link |
|---|---|
| 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) |
Families Citing this family (2)
| 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 |
| US5952338A (en) * | 1996-07-05 | 1999-09-14 | Takeda Chemical Industries, Ltd. | Agent for prophylaxis and treatment of disturbance of visual function |
Family Cites Families (2)
| 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 |
-
1978
- 1978-02-16 CA CA297,028A patent/CA1095519A/en not_active Expired
- 1978-02-23 ZA ZA00781074A patent/ZA781074B/en unknown
- 1978-03-01 PH PH20839A patent/PH13723A/en unknown
- 1978-03-01 AU AU33718/78A patent/AU516613B2/en not_active Expired
- 1978-03-08 JP JP2554378A patent/JPS53130698A/en active Pending
- 1978-03-10 GR GR55685A patent/GR65603B/en unknown
- 1978-03-13 GB GB9857/78A patent/GB1577304A/en not_active Expired
- 1978-03-13 NO NO780880A patent/NO780880L/en unknown
- 1978-03-13 FR FR7807152A patent/FR2383948A1/en active Granted
- 1978-03-13 DK DK111378A patent/DK111378A/en not_active Application Discontinuation
- 1978-03-13 SE SE7802841A patent/SE7802841L/en unknown
- 1978-03-13 DE DE19782810801 patent/DE2810801A1/en not_active Withdrawn
- 1978-03-14 CH CH277878A patent/CH628633A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DE2810801A1 (en) | 1978-09-21 |
| AU516613B2 (en) | 1981-06-11 |
| NO780880L (en) | 1978-09-15 |
| PH13723A (en) | 1980-09-09 |
| FR2383948B1 (en) | 1981-07-31 |
| SE7802841L (en) | 1978-09-15 |
| FR2383948A1 (en) | 1978-10-13 |
| GR65603B (en) | 1980-10-14 |
| DK111378A (en) | 1978-09-15 |
| AU3371878A (en) | 1979-09-06 |
| GB1577304A (en) | 1980-10-22 |
| ZA781074B (en) | 1979-04-25 |
| CH628633A5 (en) | 1982-03-15 |
| JPS53130698A (en) | 1978-11-14 |
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