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US3845061A - Dihydro-3-(4-alkyl or cycloalkyl carbamoyloxy-1-(4-oxo-4-arylbutyl)-4-piperidyl)-2-(3h)-furanones - Google Patents

Dihydro-3-(4-alkyl or cycloalkyl carbamoyloxy-1-(4-oxo-4-arylbutyl)-4-piperidyl)-2-(3h)-furanones Download PDF

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US3845061A
US3845061A US00368863A US36886373A US3845061A US 3845061 A US3845061 A US 3845061A US 00368863 A US00368863 A US 00368863A US 36886373 A US36886373 A US 36886373A US 3845061 A US3845061 A US 3845061A
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piperidyl
dihydro
oxo
furanone
alkyl
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US00368863A
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A Ebnother
E Rissi
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Sandoz AG
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Sandoz AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • v I v I R is lower alkyl or cycloalkyl
  • R is hydrogen, fluorine, chlorine, bromine, lower alkyl or lower alkoxy
  • the present invention relates to furanone derivatives.
  • the invention provides compounds of formula I,
  • a compound of formula I may be obtained by a process comprising reacting a compound of formula II, r R2 wherein R is as defined above, 7 i
  • R,--N o;o f wherein R is as definedabove.
  • the process of the invention is preferably effected in an inert solvent, e.g. an aromatic hydrocarbon such as benzene, toluene or xylene.
  • the reaction temperature is preferably from about to 180 0., preferably to C. Conveniently an excess of an isocyanate of formula III is used.
  • the reaction is preferably effected in a sealed vessel, e.g., an autoclave, especially when low-boiling compounds of formula III or low-boiling solvents are used.
  • the compounds of formula I may be isolated from the reaction mixture and purified in known manner.
  • the free base forms of the compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa.
  • the compounds of formula I are useful because they possess pharmacological activity in animals.
  • the compounds of formula I are useful as analgesic agents, as indicated in standard tests, for example, the hot plate test in mice on p.o. administration of 10 to 50 mg./kg. animal body weight of the compounds, and, as further indicated, by an inhibition of the phenylbenzoquinone syndrome in mice on p.o. administration of 10 to 50 mg./kg. animal body weight of the compounds.
  • the total daily dosage is in the range from about 50 to about 500 mg.
  • dosage forms suitable for oral administration comprise from about 12 mg. to about 250 mg. of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
  • the compounds of formula I are furthermore useful as central nervous system depressants, as indicated in standard tests, for example, the climbing test and the rotating rod test on i.p. administration of 1 to 10 mg./kg. animal body weight, of the compounds, and, as further indicated, by a depression of the rectal temperature in mice on i.p. administration of from 15 to 30 mg./kg. animal body weight of the compounds.
  • the dosage will, of course, vary depending on the compound employed, mode of administration and treatment desired. However, in general, satisfactory results are obtained when administered at a daily dosage of from about 1 mg. to about 30 mg. per kg. animal body weight, conveniently given in divided doses 2 to 4 times a day or in sustained release form.
  • the total daily dosage is in the range from about 50 to about 500 mg.
  • dosage forms suitable for oral administration comprise from about 12 mg. to about 250 mg. of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
  • the compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form.
  • Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventional manner.
  • Representative acid addition salt forms include organic acid salt forms such as the hydrogen maleate, fumarate, tartrate and methane sulphonate and mineral acid salt forms such as the hydrochloride, hydrobromide and sulphate.
  • a pharmaceutical composition may comprise a compound of formula I, in free base form or in pharmaceutically acceptable acid additionsalt form, in association with a pharmaceutical carrier or diluent.
  • Such compositions may be prepared by conventional techniques to be in the form of, for example, capsules, tablets, suppositories, suspensions or solutions, for enteral or parenteral administration.
  • these pharmaceutical compositions may contain suitable preserving, stabilizing, wetting, solubilizing, sweetening, flavouring or colouring agents.
  • the contents of the autoclave are evaporated to dryness, the resulting title compound is dissolved in ethanol and converted into the hydrochloride form by the addition of hydrochloroic acid in ethanol.
  • the crude product is crystallized from methanol for purposes of purification.
  • the hydrochloride form of the title compound has a M.P. of 216-218 (decomp.).
  • Example 2 3- [4-ethylcarbamoyloxy-l- (4-oxo-4-phenylbutyl -4-piperidyl] -dihydro-2 (3H) -furanone 12 g. of dihydro-3-[4-hydroxy-1-(4-oxo-4-phenylbutyl 4-piperidyl]-2(3H)furanone and 30 cc. of ethyl isocyanat-e are heated in 120 cc. of benzene at 140 in an autoclave for 48 hours, and the reaction mixture is worked up as described in Example 1.
  • the hydrochlorideform of the title compound has a M.P. of 205-208 (decomp) from methanol.
  • EXAMPLE 4 3-[1-(4-pfluoropheny1-4-oxobuty1)-4-isopropylcarbamoyloxy 4 piperidyl]-dihydro-2(3H)- furanone 7.5 g. of dihydro-3-[4-hydroxy-l-(4-p-fluorophenyl-4- oxobutyl)-4-piperidyl]-2(3H)-furanone and 11.5 cc. of isopropyl isocyanate are heated in 400 cc. of benzene at 160 in'an autoclave for 21 hours, and the reaction mitxure is worked up as described in Example 1.
  • the hydrochloride form of the title compound has a M.P. of 220-221.5 (decomp.) from methanol.
  • EXAMPLE 5 Dihydr'o-3- [4-methylcarbamoyloxy-l-(4- oxo-4-phenylbutyl)-4 piperidyl]-2(3H)-furanone 8.5 g. of dihydro-3-[4-hydroxy-l- (4-oxo-4-phenylbutyl)-4-piperidyl]-2(3H)-furanone and 7.3 g. of methyl isocyanate are heatedin 1-00 cc'.'of benzene at 120 in an autoclave for 15 hours, and the crude title compound is converted into'its hydrogen maleate form. M.P. 181- 182 from methanol.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

1. A COMPOUND OF THE FORMULA

1-(R2-PHENYLENE-CO-(CH2)3-);4-(R1-NH-COO-),4-(2-(O=)-

TETRAHYDROFUR-3-YL-)-PIPERIDINE

WHEREIN R1 IS ALKYL OF 1 TO 6 CARBON ATOMS OR CYCLOALKYL OF3 TO 8 CARBON ATOMS, AND R2 IS HYDROGEN, OF ATOMIC NUMBER FROM 9 TO 35, ALKYL OF 1 TO 3 CARBON ATOMS OR ALKOXY OF 1 TO 3 CARBON ATOMS, OR A PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT THEREOF.

Description

United States Patent 3,845,061 DIHYDRO 3 [4-ALKYL 0R CYCLOALKYL CAR- BAMOYLOXY 1 (4 OXO-4-'ARYLBUTYL)-4- PIPERlDYL]-2-'(3H)-FURANONES I Anton Ebnother, Arleslleim, and Erwin Rissi, Basel, Switzerland, assignors to Sandoz Ltd., Basel, Switzerland No Drawing. Filed June 11, 1973, Ser. No. 368,863
Claims priority, application Switzerland, June 15, 1972,
Int. C1. 0014 U.S. Cl. 260293.67 '10 Claims ABSTRACT on THE DISCLOSURE This invention concerns novel furanone derivatives of the formula H 0 R -I l 0 i R: i
wherein v I v I R is lower alkyl or cycloalkyl, and
R is hydrogen, fluorine, chlorine, bromine, lower alkyl or lower alkoxy,
useful as analgesic and central nervous system depressant agents.
The present invention relates to furanone derivatives. The invention provides compounds of formula I,
1 I Br-N- 6-0 Rn wherein R is alkyl of 1 to 6 carbon atoms or cycloalkyl, and R is hydrogen, halogen of atomic number from 9 to 35, lower alkyl or lower alkoxy. Further, in accordance with the invention, a compound of formula I may be obtained by a process comprising reacting a compound of formula II, r R2 wherein R is as defined above, 7 i
with a compound of formula IH, H
R,--N= o;o f wherein R is as definedabove. I. i
3,845,061 Patented Oct. 29, 1974 ice The process of the invention is preferably effected in an inert solvent, e.g. an aromatic hydrocarbon such as benzene, toluene or xylene. The reaction temperature is preferably from about to 180 0., preferably to C. Conveniently an excess of an isocyanate of formula III is used. The reaction is preferably effected in a sealed vessel, e.g., an autoclave, especially when low-boiling compounds of formula III or low-boiling solvents are used.
In so far as the production of starting materials is not particularly described these compounds are known or may be produced and purified in accordance with known processes, or in a manner analogous to the processes described herein or to known processes.
The compounds of formula I may be isolated from the reaction mixture and purified in known manner. The free base forms of the compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa.
The compounds of formula I have not been described in the literature.
The compounds of formula I are useful because they possess pharmacological activity in animals. In particular, the compounds of formula I are useful as analgesic agents, as indicated in standard tests, for example, the hot plate test in mice on p.o. administration of 10 to 50 mg./kg. animal body weight of the compounds, and, as further indicated, by an inhibition of the phenylbenzoquinone syndrome in mice on p.o. administration of 10 to 50 mg./kg. animal body weight of the compounds.
For the above mentioned use the dosage will, of course, vary depending on the compound employed, mode of administration and therapy desired. However, in general,
satisfactory results are obtained when administered at a daily dosage of from 1 mg. to about 50 mg. per kg. animal body weight, conveniently given in divided doses 2 to 4 times a day or in sustained release form. For the larger mammals, the total daily dosage is in the range from about 50 to about 500 mg., and dosage forms suitable for oral administration comprise from about 12 mg. to about 250 mg. of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
3-[1-(4-p-fluorophenyl-4-oxobutyl) 4 isopropylcarbamoyloxy-4-piperidyl]dihydro-2(3H)-furanone has particularly interesting properties.
The compounds of formula I are furthermore useful as central nervous system depressants, as indicated in standard tests, for example, the climbing test and the rotating rod test on i.p. administration of 1 to 10 mg./kg. animal body weight, of the compounds, and, as further indicated, by a depression of the rectal temperature in mice on i.p. administration of from 15 to 30 mg./kg. animal body weight of the compounds.
For this use the dosage will, of course, vary depending on the compound employed, mode of administration and treatment desired. However, in general, satisfactory results are obtained when administered at a daily dosage of from about 1 mg. to about 30 mg. per kg. animal body weight, conveniently given in divided doses 2 to 4 times a day or in sustained release form. For the larger mammals, the total daily dosage is in the range from about 50 to about 500 mg., and dosage forms suitable for oral administration comprise from about 12 mg. to about 250 mg. of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventional manner. Representative acid addition salt forms include organic acid salt forms such as the hydrogen maleate, fumarate, tartrate and methane sulphonate and mineral acid salt forms such as the hydrochloride, hydrobromide and sulphate. A pharmaceutical composition may comprise a compound of formula I, in free base form or in pharmaceutically acceptable acid additionsalt form, in association with a pharmaceutical carrier or diluent. Such compositions may be prepared by conventional techniques to be in the form of, for example, capsules, tablets, suppositories, suspensions or solutions, for enteral or parenteral administration. Aside from the usual pharmaceutical diluents or carriers, e.g. water, alcohols, naturalor hardened oils and waxes, these pharmaceutical compositions may contain suitable preserving, stabilizing, wetting, solubilizing, sweetening, flavouring or colouring agents.
In the following non-limitative Examples all temperatures are indicated in degrees Centigrade.
EXAMPLE 1 Dihydro-3- [4-isopropylcarbamoyloxy-1- (4-oxo-4-pheny1butyl) -4-piperidyl] -2 3H) -furanone A solution of g. of dihydro-3-[4-hydroxy-1-(4-oxo- 4-phenylbutyl)-4-piperidyl]-2(3H)-furanone and 11.4 cc. of isopropyl isocyanate in 100 cc. of benzene is heated to 120 for 36 hours in an autoclave. The contents of the autoclave are evaporated to dryness, the resulting title compound is dissolved in ethanol and converted into the hydrochloride form by the addition of hydrochloroic acid in ethanol. The crude product is crystallized from methanol for purposes of purification. The hydrochloride form of the title compound has a M.P. of 216-218 (decomp.).
Analysis:
Calculated: C, 61.0; N, 6.2; H, 7.3%. Found: C, 61.3; N, 6.1; H, 7.5%.
The following compounds of formula I may also be produced in a manner analogous to that described in Example 1, by reacting the corresponding compounds of formula II with isopropyl isocyanate:dihydro-3-[4- isopropylcarbamoyloxy-L(4-oxo o-tolylbutyl)-4-piperidyl] -2 3H) -furanone,
Analysis:
Calculated: C, 67.0; N, 6.5; H, 8.0%. Found: C, 66.7; N, 6.3; H, 8.2%.
3-[l-(4-m-chlorophenyl 4 oxobutyl)-4-isopropylcarbamoyloxy-4-piperidyl] dihydro-2 3H) -furanone,
Analysis:
Calculated: C, 61.3; N, 6.2; H, 6.9%. Found: C, 61.5; N, 6.4; H, 6.8%.
dihydro-3- [4 isopropylcarb amoyloxy 1- (4-p-methoxyphenyl-4 -oxobutyl -4-p i peridyl] -2 3H) -furanone,
Analysis:
Calculated: C, 64.6; N, 6.3; H, 7.7%. Found: C, 64.3; N, 6.5; H, 7.9%.
Example 2: 3- [4-ethylcarbamoyloxy-l- (4-oxo-4-phenylbutyl -4-piperidyl] -dihydro-2 (3H) -furanone 12 g. of dihydro-3-[4-hydroxy-1-(4-oxo-4-phenylbutyl 4-piperidyl]-2(3H)furanone and 30 cc. of ethyl isocyanat-e are heated in 120 cc. of benzene at 140 in an autoclave for 48 hours, and the reaction mixture is worked up as described in Example 1. The hydrochlorideform of the title compound has a M.P. of 205-208 (decomp) from methanol.
EXAMPLE 3 3-[4-cyclohexylcarbamoyloxy-1-(4-oxo- 4-phenylbutyl -4-piperidyl] dihydro-Z 3H) -furanone 12 g. of dihydro-3-[4-hydroxy-1-(4-oxo-4-phenylbutyl)-4-piperidyl]-2(3H)-furanone and 54.6 g. of cyclohexyl isocyanate are heated in 120 cc. of benzene at 140? in an autoclave for 48 hours, and the reaction mixture is worked up as described in Example 1. The hydrochloride form of the title compound has a M.P. of 207-208 (decomp.) from methanol.
EXAMPLE 4: 3-[1-(4-pfluoropheny1-4-oxobuty1)-4-isopropylcarbamoyloxy 4 piperidyl]-dihydro-2(3H)- furanone 7.5 g. of dihydro-3-[4-hydroxy-l-(4-p-fluorophenyl-4- oxobutyl)-4-piperidyl]-2(3H)-furanone and 11.5 cc. of isopropyl isocyanate are heated in 400 cc. of benzene at 160 in'an autoclave for 21 hours, and the reaction mitxure is worked up as described in Example 1. The hydrochloride form of the title compound has a M.P. of 220-221.5 (decomp.) from methanol.
EXAMPLE 5: Dihydr'o-3- [4-methylcarbamoyloxy-l-(4- oxo-4-phenylbutyl)-4 piperidyl]-2(3H)-furanone 8.5 g. of dihydro-3-[4-hydroxy-l- (4-oxo-4-phenylbutyl)-4-piperidyl]-2(3H)-furanone and 7.3 g. of methyl isocyanate are heatedin 1-00 cc'.'of benzene at 120 in an autoclave for 15 hours, and the crude title compound is converted into'its hydrogen maleate form. M.P. 181- 182 from methanol.
EXAMPLE 6: 3- 1-(4 p-fluorophenyl-4-oxobutyl)-4-N- propylcarbamoyloxy 4 piperidyl]-dihydro-2(3H)- furanone R is alkyl vof l to 6 carbon atoms or cycloalkyl of 3 to 8 carbon atoms and R is hydrogen, halogen of atomic number from 9 to 35, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms, I
. or a pharmaceutically acceptable acid addition salt there- 2. The compound of Claim 1, which is dihydro-3-[4- isopropylcarbamoyloxy .1 (4-oxo-4-phenylbutyl)-4- piperidyl] -2(3H)-furanone.
3. The compound of Claim 1, which is dihydro-3-[4- isopropylcarbamoyloxy 1 (4 oxo-4-o-tolylbutyl)-4- piperidyl]-2 3H) -furanone.
4. The compound of Claim 1, which is 3-[1-(4-m-chlorophenyl 4 oxobutyl)-4isopropylcarbamoyloxy-4-piperidyl] dihydro-2(3H)-furanone.
5. The compound of Claim 1, which is dihydro-3- [4-isopropylcarbamoyloxy 1 (4-p-methoxy-phenyl-4- oxobutyl -4-piperidyl] -2 3H) -furanon'e.
6. The compound of Claim 1, which is 3-[4-ethylcarbamoyloxy-1 (4-oxo-4 phenylbutyl)-4-piperidyl]-dihydro -2 (3H)-furanone.'
7. The compound of Claim 1, which is 3-[4-cyclohexyl carba'moyloxy-l-(4-oxo-4-phenylbutyl)-4 piperidyl]-di hydro2(3H)-furanone. v
8. The compound of Claim 1, which is 3-[l-(4-p-fluorophenyl-4-oxobutyl) 4 isopropylcarbamoyloxy-4-piperidyl] -dihydro-2 3H) -furanone.
5 9. The compound of Claim 1, which is dihydro-3-[4- methylcarbamoyloxy-1-(4-oxo 4-phenylbutyl)-4-piperidyl]-2(3H)-furanone.
10. The compound of Claim 1, which is 3-[1-(4-pfluorophenyl-4-oxobutyl)-4 N-propylcarbamoyloxy-4-piperidyl] -dihydro-2 3H) -furanone.
References Cited UNITED STATES PATENTS 6 FOREIGN PATENTS 1/ 1971 Germany 260-29367 OTHER REFERENCES J. Med. Chem. (1970) 13: 1230-1232, Pengman et a1.
US. Cl. X.R.

Claims (1)

1. A COMPOUND OF THE FORMULA
US00368863A 1972-06-15 1973-06-11 Dihydro-3-(4-alkyl or cycloalkyl carbamoyloxy-1-(4-oxo-4-arylbutyl)-4-piperidyl)-2-(3h)-furanones Expired - Lifetime US3845061A (en)

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US (1) US3845061A (en)
JP (1) JPS4949970A (en)
AU (1) AU5700573A (en)
BE (1) BE800858A (en)
DD (1) DD105234A5 (en)
DE (1) DE2329338A1 (en)
FR (1) FR2189031B1 (en)
HU (1) HU165843B (en)
NL (1) NL7308006A (en)
SU (1) SU468415A3 (en)

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AU5700573A (en) 1974-12-19
BE800858A (en) 1973-12-13
NL7308006A (en) 1973-12-18
FR2189031B1 (en) 1977-02-18
DE2329338A1 (en) 1974-01-03
DD105234A5 (en) 1974-04-12
JPS4949970A (en) 1974-05-15
FR2189031A1 (en) 1974-01-25
SU468415A3 (en) 1975-04-25

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