Claims
- 1. A method of producing a positive inotropic effect, delaying coagulation of the blood, causing bronchodilation, or causing vasodilation in a mammal, which comprises the administration to such mammal an effective amount of a compound of the formula ##STR5## or its pharmaceutically acceptable salt, wherein R.sub.1 is hydrogen, C.sub.1 -C.sub.4 alkyl, or chloro;
- R.sub.4 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy; and
- each of R.sub.5 and R.sub.6 is independently hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, allyloxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, hydroxy, halo, cyano, nitro, amino, mono- or di-(C.sub.1 -C.sub.4 alkyl)amino, trifluoromethyl, or Z-Q-substituted C.sub.1 -C.sub.4 alkoxy, wherein Q is oxygen, sulfur, sulfinyl, sulfonyl, or a bond, and Z is C.sub.1 -C.sub.4 alkyl, phenyl, or phenyl substituted with halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, nitro, amino, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, or C.sub.1 -C.sub.4 alkylsulfonyl.
- 2. The method of claim 1 wherein the compound is 2-(2-methoxy-4-methylsulfinylphenyl)imidazo[4,5-c]pyridine or a pharmaceutically acceptable salt thereof.
- 3. The method of claim 1 wherein the compound is 2-(2-methoxy-4-methylsulfonylphenyl)imidazo[4,5-c]pyridine or a pharmaceutically acceptable salt thereof.
- 4. The method of claim 1 wherein the compound is 2-(2-methyoxy-4-trifluoromethylphenyl)imidazo[4,5-c]pyridine or a pharmaceutically acceptable salt thereof.
- 5. A pharmaceutical composition useful for producing an inotropic effect in mammals which comprises a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of the formula ##STR6## or its pharmaceutically acceptable salt, wherein R.sub.1 is hydrogen, C.sub.1 -C.sub.4 alkyl, or chloro;
- R.sub.4 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy; and
- each of R.sub.5 and R.sub.6 is independently hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, allyloxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, hydroxy, halo, cyano, nitro, mono- or di-(C.sub.1 -C.sub.4 alkyl)-amino, trifluoromethyl, or Z-Q-substituted C.sub.1 -C.sub.4 alkoxy, wherein Q is oxygen, sulfur, sulfinyl, sulfonyl, or a bond, and Z is C.sub.1 -C.sub.4 alkyl, phenyl, or phenyl substituted with halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, nitro, amino C.sub.1 -C.sub.4 alkylsulfonyl.
- 6. The composition of claim 5 wherein the compound is 2-(2-methoxy-4-methylsulfinylphenyl)imidazo[4,5-c]pyridine or a pharmaceutically acceptable salt thereof.
- 7. The composition of claim 5 wherein the compound is 2-(2-methoxy-4-methylsulfonylphenyl)imidazo[4,5-c]pyridine or a pharmaceutically acceptable salt thereof.
- 8. The composition of claim 5 wherein the compound is 2-(2-methoxy-4-trifluoromethylphenyl)imidazo[4,5-c]pyridine or a pharmaceutically acceptable salt thereof.
CROSS-REFERENCE
This application is a continuation of copending application Ser. No. 569,364, filed Jan. 9, 1984, now abandoned which is a continuation-in-part of application Ser. No. 469,883, filed Feb. 25, 1983, now abandoned, which is a continuation-in-part of application Ser. No. 373,932, filed May 3, 1982, now abandoned.
The cardiac glycosides and the sympathomimetic amines are the principal inotropic agents used in the management of congestive heart failure. Although the cardiac glycosides, especially digitalis, are among the most frequently prescribed drugs, they have numerous liabilities such as a low therapeutic index and erratic absorption, and are associated with life-threatening arrhythmias and deleterious drug-drug interactions. In addition, many patients either do not respond, or become refractory to these agents. The sympathomimetic amines, such as dopamine and epinephrine, have limited utility due to positive chronotropic effects, arrhythmogenic properties, and oral ineffectiveness.
More recently, new classes of inotropic agents have been found. Among these, certain 2-phenylimidazo[4,5-b]pyridines (U.S. Pat. Nos. 3,985,891 and 4,327,100) have been shown to possess inotropic and anticoagulant activity. U.S. Pat. Nos. 4,299,834 and 4,353,909 describe similarly substituted purine and 6-hydroxy-imidazo[4,5-b]pyridine derivatives.
Weidenhagen and Weeden (Ber., 71B, 2347 (1938); CA 33:984(6)) describe the preparation of 2-phenylimidazo[4,5-c]pyridine and the p-methoxyphenyl and p-aminophenyl analogs.
Middleton and Wibberly (J. Het. Chem., 17, 1757 (1980)) describe the preparation of a variety of substituted imidazopyridines including o-hydroxy-, o-nitro-, m-chloro-, p-chloro-, p-nitro-, and p-amino-substituted 2-phenylimidazo[4,5-c]pyridines, and o-methyl-, o-chloro-, m-chloro-, m-nitro-, p-methyl-, p-bromo-, p-chloro-, p-nitro-, and m,m-dinitro-substituted 2-phenyl-4-chloroimidazo[4,5-c]pyridines. Some of these compounds were found to be active mutagens in the Ames test (Middleton, et al., Mutation Research, 78, 323 (1980)).
Both Lee, et al., Org. Prep. Proced. Int., 12 (3-4), 234 (1980) and Haskell, et al., J. Med. Chem., 13(4), 697 (1970) describe the preparation of 2-(2aminophenyl)imidazo[4,5-c]pyridine.
Yutilov and Shcherbina, Deposited Doc., 1980, VINITI 5441-80, reported in CA 96:68900f, have prepared 2-phenylimidazo[4,5-c]pyridines substituted in the phenyl ring with hydrogen, 4-methoxy, 4-dimethylamino, 4,3- and 2,3-hydroxy-methoxy, and 3,4- and 2,5-dimethoxy.
The preparation of 2-(2-hydroxyphenyl)imidazo[4,5-c]pyridine was reported by Spector and Joullie' in J. Het. Chem., 6(5), 605 (1966).
The present invention provides for a series of 2-phenylimidazo[4,5-c]pyridines, their formulations, and their use as orally effective positive inotropic agents which have minimal effects on blood pressure and heart rate. The compounds also possess vasodilitation, bronchodilation, and anticoagulant activities.
This invention provides for pharmaceutically useful imidazopyridine compounds having the formula ##STR1## and their pharmaceutically acceptable salts, wherein R.sub.1 is hydrogen, C.sub.1 -C.sub.4 alkyl, or chloro;
(a) if R.sub.1 and two of R.sub.2, R.sub.3, and R.sub.4 are all hydrogen, the other of R.sub.2, R.sub.3, and R.sub.4 is not hydrogen, halo, hydroxy, nitro, amino, di-(C.sub.1 -C.sub.2 alkyl)amino, or C.sub.1 -C.sub.2 alkoxy;
(b) if R.sub.1 and one of R.sub.2, R.sub.3, and R.sub.4 are both hydrogen, and another of R.sub.2, R.sub.3, and R.sub.4 is C.sub.1 -C.sub.2 alkoxy, the other of R.sub.2, R.sub.3, and R.sub.4 is not hydroxy or C.sub.1 -C.sub.2 alkoxy;
(c) if R.sub.1 is chloro and two of R.sub.2, R.sub.3, and R.sub.4 are both hydrogen, the other of R.sub.2, R.sub.3, and R.sub.4 is not hydrogen, halo, C.sub.1 -C.sub.2 alkyl, or nitro; and
(d) if R.sub.1 is chloro and R.sub.4 is hydrogen, R.sub.2 and R.sub.3 may not both be nitro.
In addition to the compounds of formula I and Ia, this invention also provides a method of treating a mammal, including a human, suffering from or susceptible to the conditions of asthma, thrombosis, hypertension, or heart failure, which comprises administering to said mammal a therapeutically effective amount of a compound of formula ##STR2## and their pharmaceutically acceptable salts, wherein R.sub.1 is hydrogen, C.sub.1 -C.sub.4 alkyl, or chloro;
According to a further aspect of the present invention there is provided a pharmaceutical formulation which comprises as active ingredient a compound of Formula II or IIa as defined above associated with a pharmaceutically acceptable carrier therefor.
The Formulae I and Ia, and II and IIa are recognized as being tautomeric structures of one another. The imidazopyridines having the hydrogen atom on the N-1 nitrogen atom and having the pyridine nitrogen atom at the 5-position (Formulas I and II, properly named 2-phenyl-1H-imidazo[4,5-c]pyridines) have corresponding tautomeric forms wherein the hydrogen atom is on the N-3 nitrogen atom (Formulas Ia and IIa, 2-phenyl-3H-imidazo[4,5-c]pyridines). As N-unsubstituted compounds, each tautomeric form exists in equilibrium with the other and cannot be prepared or isolated without the presence of the other. For this application, both forms will be considered together and will be referred to as 2-phenyl-1(3)H-imidazo[4,5-c]pyridines, 2-phenyl-imidazo[4,5-c]pyridines, or compounds of Formula I (Ia) and II (IIa).
A preferred group of compounds for treating mammals are the compounds of Formula II (IIa) wherein
Preferred groups of compounds are those compounds wherein R.sub.5 and R.sub.6 are substituted at the 3'- and 4'-positions, or especially the 2'- and 4'-positions of the phenyl ring.
Especially preferred compounds as defined above are those where "C.sub.1 -C.sub.4 alkyl" is methyl, "C.sub.1 -C.sub.4 alkylsulfinyl" is methylsulfinyl, "C.sub.1 -C.sub.4 alkylsulfonyl" is methylsulfonyl, and "C.sub.1 -C.sub.4 alkoxy" is methoxy. Preferred Z-Q-substituted C.sub.1 -C.sub.4 alkoxy compounds are those wherein C.sub.1 -C.sub.4 alkoxy is ethoxy or n-propoxy, Q is oxygen, sulfur, sulfinyl, or sulfonyl, and Z is C.sub.1 -C.sub.4 alkyl, phenyl, or phenyl substituted with halo, C.sub.1 -C.sub.4 alkoxy, or hydroxy. Compounds substituted at the 2'-position of the phenyl ring with C.sub.1 -C.sub.4 alkoxy, especially methoxy, or with the preferred Z-Q-substituted C.sub.1 -C.sub.4 alkoxy substituents, and at the 4'-position of the phenyl ring with trifluoromethyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylsulfinyl, or C.sub.1 -C.sub.4 alkylsulfonyl are particularly preferred, with 2-(2,4-dimethoxyphenyl)imidazo[4,5-c]pyridine, 2-(2-methoxy- 4-methylsulfinylphenyl)imidazo[4,5-c]pyridine, 2-(2-methoxy-4-methylsulfonylphenyl)imidazo[4,5-c]pyridine, and 2-(2-methoxy-4-trifluoromethylphenyl)imidazo[4,5-c]pyridine being the most preferred compounds.
In addition to the inotropic and other activities possessed by the compounds of this invention, we have discovered that certain of the compounds of Formula II (IIa) lower blood pressure but do not cause the expected reflex tachycardia, i.e., they appear to possess bradycardic activity. This pharmacological profile can be desirable for a compound used in the treatment of hypertension or heart failure. These compounds are those generally defined as compounds of Formula II (IIa) wherein R.sub.1 and R.sub.4 are both hydrogen, R.sub.5 is Z-Q-substituted C.sub.1 -C.sub.4 alkoxy at the 2'-position of the phenyl ring, and R.sub.6 is C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, or C.sub.1 -C.sub.4 alkylsulfonyl at the 4'-position. The preferred compounds are those containing the preferred functionalities as previously defined.
The following definitions refer to the various terms used throughout this disclosure.
The term "halo" refers to fluoro, chloro, bromo, and iodo.
The term "C.sub.1 -C.sub.4 alkyl" refers to the straight and branched aliphatic radicals of one to four carbon atoms including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. The term "C.sub.1 -C.sub.2 alkyl" refers to methyl and ethyl.
The term "C.sub.1 -C.sub.4 alkoxy" includes the straight and branched aliphatic ether radicals of one to four carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tertbutoxy. The term "C.sub.1 -C.sub.2 alkoxy" refers to methoxy and ethoxy.
The compounds of this invention as represented by Formulas II and IIa may be prepared by any of several methods known in the art.
A preferred method of preparation consists of the reaction of a pyridine of the formula ##STR3## wherein A is amino and R.sub.1 is as defined above, with a compound of the formula ##STR4## wherein B is --COOH, and R.sub.4, R.sub.5, R.sub.6 are as defined above. The reaction may be performed in the absence of a solvent, but is generally carried out in a suitable non-reactive solvent, such as benzene, toluene, xylene, ethylene glycol, pyridine, acetone, phosphorous oxychloride, polyphosphoric acid, and the like, optionally in the presence of a base, such as pyridine or triethylamine, or optionally in the presence of a catalytic amount of an acid, such as p-toluenesulfonic acid, or optionally in the presence of a dehydrating agent, such as phosphorous oxychloride, phosphorous pentoxide, or thionyl chloride. Temperatures in the range of -20.degree. C. to 250.degree. C. may be employed with a preferred range of 50.degree.-200.degree. C.
Other similar methods of preparing the compounds are likewise known. Carboxylic acid derivatives IV may be employed in the above sequence with appropriate modifications in the reaction conditions. For example, an amide derivative of IV may be substituted for the benzoic acid when condensing with the diaminopyridine III, preferably in the presence of a dehydrating agent or base at elevated temperatures, especially in the temperature range of 100.degree.-150.degree. C. If B of Formula IV is cyano, the reaction with the pyridinediamine is typically performed in the presence of a catalytic quantity of an acid, such as p-toluenesulfonic acid, usually at temperatures of 120.degree.-180.degree. C. If B is a thioamide derivative, the condensation with the diaminopyridine is best effected in a solvent, such as ethylene glycol, at temperatures of 100.degree.-150.degree. C. If, in Formula III, A is a halogen, the reaction is performed with the respective amidine derivative of IV. The intermediate thus formed may be first isolated or generated in situ, followed by cyclization at elevated temperatures, preferably in the range of 100.degree.-200.degree. C.
In the preferred scheme above, when the benzoic acid IV (B is --COOH) is unsubstituted or is substituted with unreactive functionalities (e.g., alkyl, halogen, etc.), heating with the diaminopyridine in polyphosphoric acid (PPA) is the most convenient and preferred method of preparing the respective imidazopyridine. This method was described by Middleton and Wibberley, J. Het. Chem., 17, 1757 (1980), for the preparation of imidazo[4,5-b]- and [4,5-c]pyridines.
When the benzoic acids of Formula IV are substituted with groups such as alkoxy, PPA treatment can lead to dealkylation and the preferred conditions for the reaction are by refluxing the reactants in phosphorous oxychloride or xylene with the azeotropic removal of water.
Especially when the benzoic acids (IV) contain phenolic or amino substituents, an alternate method of preparation may be employed. A substituted benzaldehyde (IV, B is --CHO) may be treated with sulfur and morpholine to produce the respective substituted-thiobenzoic acid morpholide which on further treatment with methyl iodide gives the S-methyl-substituted-thiobenzoic acid morpholide iodide derivative. Treatment of this intermediate with the appropriate diaminopyridine (III, A is amino) in a solvent such as ethylene glycol with heating produces the desired product II (IIa). By this scheme, 2-methoxybenzaldehyde was converted first to 2-methoxy-thiobenzoic acid morpholide, then to S-methyl-2-methoxy-thiobenzoic acid morpholide iodide, which on heating in ethylene glycol with 3,4-diaminopyridine gave II (IIa) (R.sub.1 , R.sub.5, and R.sub.6 are each hydrogen; R.sub.4 is 2'-methoxy).
The starting material 3,4-diaminopyridine is commercially available. Other required pyridines of Formula III are either commercially available, or may be prepared in the usual manner from available starting materials by the proper sequence of nitrations, reductions, acylations, hydrolyses, halogenations, and aminations. The required benzoic acids and derivatives of Formula IV are either commercially available, are known in the literature, or are prepared by methods known in the art.
In addition, some of the compounds of Formula II (IIa) may be prepared by subsequent derivatizations of other compounds of Formula II (IIa) by methods known in the art. Thus, amine derivatives may be prepared from intermediate halo derivatives, phenol substituents may be selectively alkylated, and the like. The sulfinyl and sulfonyl derivatives of this invention may be prepared directly by the reaction of the corresponding intermediates III with IV, or by oxidation of the corresponding mercapto compounds of Formula II (IIa) by methods known in the art. One or two equivalents, respectively, of hydrogen peroxide in an alcohol, a peracid, such as meta-chloroperbenzoic acid in methylene chloride, or similar oxidants may be used to effect these transformations.
Illustrative of the compounds of this invention are the following:
The pharmaceutically acceptable acid addition salts of this invention include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, phosphorous acid and the like, as well as salts derived from nontoxic organic acids such as aliphatic mono and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic and alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, .beta.-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and the like salts. The preferred salts of this invention are those derived from inorganic acids, especially hydrochloric acid.
The compounds may be administered by various routes including the oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes, being usually employed in the form of a pharmaceutical composition. It is a special feature of these compounds that they are effective positive inotropic agents, vasodilators, or bronchodilators following oral administration. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Accordingly, the invention includes a pharmaceutical composition comprising as active ingredient a compound of Formula II (IIa) or an acid addition salt thereof associated with a pharmaceutically acceptable carrier.
In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl- and propyl-hydroxybenzoates, talc, magnesium stearate or mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The compositions of the invention may, as is well known in the art, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to 500 mg., more usually about 25 to 300 mg., of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
The active compounds are effective over a wide dosage range. For example, dosages per day will normally fall within the range of about 0.5 to 300 mg./kg. In the treatment of adult humans, the range of about 1 to 50 mg./kg., in single or divided doses, is preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, the chosen route of administration, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
US Referenced Citations (8)
Foreign Referenced Citations (1)
| Number |
Date |
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| 820316 |
Aug 1969 |
CAX |
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| Entry |
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| Derwent E/26 52573, abstracting German Patent DE No. 3,044,497. |
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| Ber., 71B, 2347 (1938, abstracted in CA 33:984(6). |
| J. Het. Chem., 17, 1757 (1980). |
| Mutation Research, 78, 323 (1980). |
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| J. Med. Chem., 13 (4), 697 (1970). |
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Continuations (1)
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569364 |
Jan 1984 |
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Continuation in Parts (2)
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469883 |
Feb 1983 |
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373932 |
May 1982 |
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Patent Grant
4758574
