Claims
- 1. A compound named 5,5-dimethyl-10-[2-methyl-4-(2-methylpiperidino) butyryloxy]-8-(3-methyl-2-octyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine or a pharmaceutically acceptable acid addition salt thereof.
- 2. The compound of claim 1 as the dihydrochloride salt.
- 3. A compound named 5,5-dimethyl-10-[2-methyl-4-(morpholino)butyryloxy]-8-(3-methyl-2-octyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano [3,4-d]pyridine or a pharmaceutically acceptable acid addition salt thereof.
- 4. A compound named 5,5-dimethyl-10-[2,2-dimethyl-4-(piperidino)butyryloxy]-8-(3-methyl-2-octyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine or a pharmaceutically acceptable acid addition salt thereof.
- 5. A compound named 5,5-dimethyl-10-[3-(piperidino)propionyloxy]-8-(3-methyl-2-octyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano [3,4-d]pyridine or a pharmaceutically acceptable acid addition salt thereof.
- 6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
- 7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 3 and a pharmaceutically acceptable carrier.
- 8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 4 and a pharmaceutically acceptable carrier.
- 9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 5 and a pharmaceutically acceptable carrier.
- 10. A method of relieving pain comprising administering to a patient in pain a therapeutically effective amount of a compound of claim 1.
- 11. A method of relieving pain comprising administering to a patient in pain a therapeutically effective amount of a compound of claim 3.
- 12. A method of relieving pain comprising administering to a patient in pain a therapeutically effective amount of a compound of claim 4.
- 13. A method of relieving pain comprising administering to a patient in pain a therapeutically effective amount of a compound of claim 5.
CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of our co-pending patent application Ser. No. 311,953 filed Dec. 4, 1972, now U.S. Pat. No. 3,991,194, which in turn is a continuation-in-part of co-pending patent application Ser. No. 212,819, filed Dec. 27, 1971, now abandoned.
This invention relates to novel heterocyclic esters of benzopyranopyridines, to methods of preparing the compounds, to pharmaceutical compositions containing the compounds and to use of the compounds and pharmaceutical compositions containing the compounds for pharmacological and medicinal purposes.
According to one aspect of this invention, compounds are provided which can be represented by the formula ##STR3## WHEREIN R.sub.1 is hydrogen, lower alkyl, lower alkanoyl, cycloalkyl-lower alkyl, cycloalkyl-lower alkanoyl, lower-alkenyl, lower-alkynyl, halo-lower-alkenyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl; R.sub.2 is lower alkyl; R.sub.3 is an alkyl having one to twenty carbon atoms or cycloalkyl-lower alkyl, Y is a straight or branched chain alkylene having one to eight carbon atoms, and R.sub.4 is a group of the formula ##STR4## wherein a is an integer from 1 to 4, b is an integer from 1 to 4 and X is CH.sub.2, O, S or N--R.sub.5, R.sub.5 being hydrogen or lower alkyl, with the limitation that when X is O, S or N--R.sub.5, a and b each must be 2 and R.sub.6 is hydrogen or a lower alkyl group bonded to a carbon in the ring; and the acid addition salts thereof.
The term "lower alkyl" as used herein, refers to C.sub.1 -C.sub.6 straight or branched chain alkyl groups including methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl and the like.
The term "lower alkenyl" refers to straight and branched chain C.sub.2 -C.sub.6 alkyl radicals from which a hydrogen atom has been removed from each of two adjacent carbon atoms to produce ethylenic unsaturation; e.g. vinyl, allyl, methallyl, 1-pentenyl and the like.
The term "lower alkynyl" refers to C.sub.2 -C.sub.6 alkyl groups as defined above, from which two hydrogen atoms have been removed from each of two adjacent carbon atoms to produce acetylenic unsaturation; e.g., ethynyl, propargyl, 2-butynyl, 1-pentynyl and the like groups.
The term "halo" includes chloro, fluoro, bromo and iodo.
The term "lower alkanoyl" refers to saturated, monovalent; aliphatic radicals derived from a monocarboxylic acid, including straight or branched chain radicals of from one to six carbon atoms including the formyl, acetyl, propionyl, .alpha.-methylpropionyl, butyryl, hexanoyl and the like radicals.
"Cycloalkyl," as used herein, refers to cyclic, saturated aliphatic radicals having three to eight carbon atoms in a ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
"Cycloalkyl-lower alkyl" refers to groups such as cyclopropyl-methyl, 2-methylcyclobutyl and the like.
The term "alkyl" refers to straight and branched chain alkyl radicals having from one to 20 carbon atoms such as methyl, n-amyl, 3-methyl-2-octyl, 2-nonyl, 2-eicosanyl and the like.
The term "acid addition salts" refers to non-toxic salts prepared by reacting the basic esters of the benzopyranopyridines with an organic or inorganic acid, or by reacting the benzopyranopyridines with the salt of an appropriate acid. Representative salts include the hydrochloride, hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, succinate, tartrate, napsylate and the like. Such salts are well known in the art and are considered to be "pharmaceutically acceptable."
The compounds provided by the invention considered particularly useful are those of the formula ##STR5## in which R.sub.1 is lower alkynyl, each R.sub.2 is methyl, R.sub.3 is an alkyl group having five to nine carbon atoms, Y is a branched or straight chain alkylene having two to five carbon atoms and, in the groups represented by R.sub.4 in Formula 1, a and b are the same or different integers from 1 to 3 and a + b is an integer from 3 to 5, R.sub.6 is hydrogen or lower alkyl, and X is CH.sub.2 or O. The preferred compounds are those in which R.sub.1 is propargyl, R.sub.3 is 3-methyl-2-octyl or pentyl and the sum of a + b is 3 or 4.
Generally speaking, the esters of this invention are prepared by reacting equimolar quantities of the corresponding benzopyranopyridines, and the appropriate acid or its salt, in the presence of a carbodiimide, such as dicyclohexylcarbodiimide, in a suitable solvent such as methylene chloride, chloroform and the like. This reaction can be represented as follows: ##STR6## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and Y are defined above.
The benzopyranopyridine starting compounds and their preparation are disclosed in U.S. Pat. Nos. 3,576,798 and 3,522,260.
Some of the heterocyclic acids which can be used in the process are:
Reaction between the benzopyranopyridine starting material and the heterocyclic acid, or salt thereof, is readily effected by combining about equimolar amounts of the reactants and a equimolar amount, or slight excess, or a carbodiimide such as dicyclohexylcarbodiimide. The reaction proceeds readily at room temperature and is generally completed in about 4 to 20 hours. After the reaction is terminated, the reaction mixture can be filtered to remove the by-product of dicyclohexylurea, and the solvent can be distilled off using a rotary evaporator. The residue can be directly crystallized from a suitable solvent such as benzene/ether or the residue can be chromatographed and the desired material isolated from the appropriate chromatographic fractions. If the basic esters are obtained, the acid addition salts such as those named above, if desired, can be prepared by methods well known in the art.
The compounds of this invention, in the form of the free bases, can be used as neutralizing agents since they form salts with acids.
The pharmacological activity of the compounds of this invention renders them potentially useful as drugs, both in humans and lower animals, although it should be understood that every compound of the invention will not necessarily have each activity possessed by the others.
The compounds of this invention are useful as analgesic agents, and generally at oral dosages of from 5 to 20 mg./kg. of body weight daily. Lower dosages of the compounds in the range of 0.005 to 5 mg./kg. also induce analgesic activity intravenously and some of the compounds induce this activity at such dosages orally. In test animals, the compounds appear to be in the potency range of .alpha.-d-propoxyphene and codeine.
The compounds additionally exhibit mild tranquilizing activity, and generally at oral dosages of from 0.1 to 20 mg./kg. of body weight.
The compounds also exert anticonvulsant activity and sedative-hypnotic activity in animals.
The amount of active ingredient administered may be varied; however, it is necessary that the amount of active ingredient be such that a suitable dosage is given. The selected dosage depends upon the desired therapeutic effect, on the route of administration and on the duration of treatment.
Specific activity for some of the compounds of the invention will now be presented.
The following references may be referred to for details of test procedures used in pharmacologically evaluating the compounds of this invention:
The compound of Example 1 (SP-106) is a tranquilizing agent in mice at 5 to 10 mg./kg. orally; an analgesic agent at 4 to 12 mg./kg. orally in mice and rats; and a sedative-hypnotic agent in cats and monkeys at 0.5 to 1.0 mg./kg. orally.
The compound of example 2 (SP-112) is a tranquilizing agent in mice at 5 to 10 mg./kg. orally; an analgesic agent in mice and rats at 9 to 12 mg./kg. orally; and a sedative-hypnotic agent at 1 mg./kg. orally in cats and monkeys.
The compound of Example 3 (SP-159) is a tranquilizing agent in mice at 5 and 10 mg./kg. orally and it is an anticonvulsant agent in mice at 30 mg./kg. orally. The compound also showed analgesic activity in the writhing and rat tail flick tests. In the sedative-hypnotic test SP-159 is active at 0.5 mg./kg. orally, and produces an increase in total sleep time over control values.
The compound of Example 4 (SP-158) is a tranquilizing agent in mice at 5 and 10 mg./kg. orally and it is an anticonvulsant agent in mice at 30 mg./kg. orally.
The compound of Example 5 (SP-167) is a tranquilizing agent in mice at 10 mg./kg. orally and it is an anticonvulsant agent in mice at 30 mg./kg. orally.
The compound of Example 6 (SP-171) is a tranquilizing agent in mice at 5 mg./kg. orally.
The compound of Example 8 (SP-178) has analgesic activity. In the mouse hot plate test it had an ED.sub.50 of 4.6 mg./kg. orally; in the acetic acid writhing test it had an ED.sub.50 of 12.2 mg./kg. orally; and, in the rat tail flick test it had an ED.sub.50 of 9.8 mg./kg. orally. SP-178 also has tranquilizing activity in mice at 10 mg./kg. orally. SP-178 is active as a sedative-hypnotic agent at 0.25 to 2.0 mg./kg. orally.
The compound of Example 20 (SP-204) like SP-106 of Example 1 has potent analgesic activity as demonstrated in three tests. SP-204 exhibited an oral ED.sub.50 value of 10.7 mg./kg. in the rat tail flick test, thus showing marked activity. SP-204 exhibited an oral ED.sub.50 value of 7.3 mg./kg. in the acetic acid induced writhing test in mice, thus showing marked activity. In the mouse hot plate test SP-204 had an oral ED.sub.50 of 3.8 mg./kg. When the compound is administered intravenously in this testing procedure, the ED.sub.50 value is 1.2 mg./kg. as compared to an ED.sub.50 value of 4.3 mg./kg. intravenously for morphine.
Unlike SP-106 of Example 1, SP-204 showed little or slight activity in tests which measure potential tranquilizing activity. These testing procedures include the rat motor activity test, the mouse fighting test and the methamphetamine-induced hyperirritability test in rats where SP-204 did not show any significant antagonism at oral doses of 5 to 40 mg./kg.
Both SP-106 and SP-204 show sedative-hypnotic activity in cats, but a definite difference in potency is not now clearly established. In sedative-hypnotic tests in cats, SP-204 was active at oral doses of 0.5 and 1.0 mg./kg.
In summary, SP-106 (Example 1) has potent analgesic activity and significant tranquilizing activity in animals. SP-204 (Example 20) also has potent analgesic activity, but little or slight tranquilizing activity. Thus, SP-204 has the desirable property of good analgesic activity without tranquilizing activity. SP-204 also has a greater comparative stability to hydrolysis and lessened cardiovascular effects as compared to SP-106.
The compound of Example 21 (SP-202) has tranquilizing activity in animals which indicates potential human use. SP-202 was active in the rat motor activity test at oral doses of 0.5 to 5.0 mg./kg. and in the mouse fighting test at a dose of 10 mg./kg. orally. The compound was also active in antagonizing methamphetamine-induced hyperirritability in rats at oral doses of 10 to 40 mg./kg., thus further demonstrating its tranquilizing activity.
SP-202 displayed some analgesic activity in the acetic acid induced writhing test in mice, producing a 21% inhibition of writhing at an oral dose of 10 mg./kg. In sedative-hypnotic tests in cats, SP-202 was active at an oral dose of 0.5 mg./kg.
The compound of Example 22 (SP-205) has analgesic and tranquilizing activity in animals which indicates potential human use. The analgesic activity of SP-205 was demonstrated in the acetic acid induced writhing test in mice, where SP-205 had an oral ED.sub.50 of 14.5 mg./kg. In the rat tail flick test, SP-205 caused a 34% increase in reaction time at an oral dose of 20 mg./kg. The tranquilizing activity of SP-205 was shown in the rat motor activity test where the compound was active at oral doses of 1.25 to 40 mg./kg. At oral doses of 10 to 40 mg./kg., SP-205 antagonized the methamphetamine-induced hyperirritability in rats, thus further demonstrating its tranquilizing activity.
The compound of Example 23 (SP-216) also has tranquilizing and analgesic activity in animals which indicates potential human use. The analgesic activity of SP-216 was shown in the acetic acid induced writhing test in mice where SP-215 had an oral ED.sub.50 value of 12.3 mg./kg. The ED.sub.50 value for SP-216 in the mouse hot plate test is 22.3 mg./kg. SP-216 was active in the rat motor activity test at 5 mg./kg. orally, and in the mouse fighting test at an oral dose of 10 mg./kg. At 5 mg./kg. orally the compound was active in antagonizing the methamphetamine-induced hyperirritability in rats, thus further demonstrating its tranquilizing activity. SP-216 was also active in the sedative-hypnotic test at an oral dose of 0.5 mg./kg.
The active agents of this invention can be administered to animals, including humans, as pure compounds. It is advisable, however, to first combine one or more of the compounds with a suitable pharmaceutical carrier to attain a satisfactory size to dosage relationship and thereby obtain a pharmaceutical composition.
Pharmaceutical carriers which are liquid or solid can be used. Solid carriers such as starch, sugar, talc and the like can be used to form powders. The powders can be used fo direct administration or they may be used to make tablets or to fill gelatin capsules. Suitable lubricants like magnesium stearate, binders such as gelatin, and disintegrating agents like sodium carbonate in combination with critic acid can be used to form tablets. Sweetening and flavoring agents can also be included.
Unit dosage forms such as tablets and capsules can contain any suitable predetermined amount of one or more of the active agents, and they may be administered one or more at a time at regular intervals. Such unit dosage forms, however, should generally contain a concentration of 0.1 to 50 percent by weight of one or more of the active compounds. Unit dosage forms, such as tablets and capsules, generally can contain about 5 to 300 mg. of active agent, although some of the compounds appear to have activity which permits them to be used as low as 0.25 to 1 mg. in a unit dosage form. Thus a range of from a low of about 0.25 to 1 mg. and a high of about 300 mg. may be used.
A typical tablet can have the composition:
The compounds of this invention exhibit both oral and parenteral activity and accordingly can be formulated in dosage forms for either oral or parenteral administration to a patient.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, granules and the like.
Liquid dosage forms for oral administration include emulsions, solutions, suspensions, syrups and the like, containing diluents commonly used in the art such as water. Besides inert diluents, such preparations can also include adjuvants such as wetting agents, emulsifying and suspending agents and sweetening, flavoring and perfuming agents.
Preparations for parenteral administration include sterile aqueous or non-aqueous solutions. Examples of nonaqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. The parenteral preparations are sterilized by conventional methods.
US Referenced Citations (9)
Non-Patent Literature Citations (1)
| Entry |
| Buzas et al., Compt. Rend. 256, 1804-1806 (19639. |
Continuation in Parts (2)
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Number |
Date |
Country |
| Parent |
311953 |
Dec 1972 |
|
| Parent |
212819 |
Dec 1971 |
|
Patent Grant
4042694
