CA1211444A - Imidazo[2,1-c] [1,2,4] benzotriazine-2- carboxylic acid derivatives - Google Patents
Imidazo[2,1-c] [1,2,4] benzotriazine-2- carboxylic acid derivativesInfo
- Publication number
- CA1211444A CA1211444A CA000416869A CA416869A CA1211444A CA 1211444 A CA1211444 A CA 1211444A CA 000416869 A CA000416869 A CA 000416869A CA 416869 A CA416869 A CA 416869A CA 1211444 A CA1211444 A CA 1211444A
- Authority
- CA
- Canada
- Prior art keywords
- compound
- formula
- benzotriazine
- imidazo
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
ABSTRACT OF THE DISCLOSURE
This invention discloses novel imidazo[2,1-c] [1,2,4] benzotriazine-2-carboxylic acid derivatives, process for their preparation, pharmaceutical compositions thereof and methods for using the compounds. The compounds of this invention are useful in the treatment of anaphylactic reactions and aller-gic conditions in a mammal.
This invention discloses novel imidazo[2,1-c] [1,2,4] benzotriazine-2-carboxylic acid derivatives, process for their preparation, pharmaceutical compositions thereof and methods for using the compounds. The compounds of this invention are useful in the treatment of anaphylactic reactions and aller-gic conditions in a mammal.
Description
~L2~4~
IMIDAZ0~2,1-c] 11,2,4] BENZOTRIAZINE-2-CARBOXYLIC ACID DERIVATIVES
This inYention relates to novel imidazo[2,1-c] ~,2,4] benzotriazine-a-carbo~ylic acid derivatives, to therapeutically accept~ble addition salts ther~
of, to processes for their preparation~ to methods of using the derivatives and to pharmaceutical compositions of the derivatives. The compounds of this in-5 vention ~re useful in the treatment of ~naphylactic reactions and allergic con-ditions in mammals.
Although the compounds of this invention are novel compounds, somewhat related tricyclic compounds are known, for example antihypertensiYe dihydroimidazo[2,1-c~ ~,2,4] benzothiadiazines are described by R. Friary and 10 E.H. Gold, Heterocycles~ 7, 765 (1977); imidazo~5,1-c] ~,2,43 benzotriazines and pyrazolo[5,1-c~ ~,2,4] benzotriazines are described in Germ&n Ofenlegungsshrift2,348,382, April 3, 197~; and antiallergic imidazo[l,2-a] quinoxalines are des-cribed by A.C. Barnes and D.A. Rowlands, U.S. P~tent 4,333,934, issued ~une 8,1982. The compounds reported in the above references do not have the tri-15 cyclic ring system or the substituents characteristic o~ the compounds of thisinvention.
Summary of the Invention The compounds of this invention are represented by formula I
COOR
1~
Rl~ N ~N ~I) ( )n o in which Rl is hydrogen, lower ~lkyl, lower ~oxy, trifluoromethyl or halo;
and R is hydrogen or lowe~ alkyl; ~nd n is O or l, or a therapeutically accept-able salt thereof.
L9~4~L
-a- AH~8163 A preferred group of compounds of this invention is represented by formula I in which Rl is hydrogen; R2 is hydrogen or lower alkyl having one to four carbon atoms; and n is 0 or 1 or a therapeutically flcceptable salt ther~
of.
The compounds of this inven~ion are useful for preventing or treat-5 ing anaphylactic reactions or allergic conditions in a mammal by administeringto the mammal an effective anaphylactic alleviating or allergic alleviating amounl of a compound of formula I or a therapeutically acceptable addition salt thereof.
The compounds of this invention form a pharmaceutical compc6ition 10 which comprises a compound of form~da I~ or a therapeu'ffcally acceptable ad- dition salt thereof and a pharmaceuti~lly acceptable carrier.
The compounds of formlda I Qre prepared by sele~ti~ a pro~ess from the group of:
(&~ condensing a compound of formlda II
R ~ N~$~YY NH2 ~ I I) in which R is as defined herein with an ester of form~a III
X{:H2COCOOR2 (I.U) 25 in which R2 is lower alkyl and X is b~omo or chl~ro to obtain the corresponding compound of ~orm~a I in whic~ Rl is as defined herein, :R2 is lower alkyl and n is l;
(b) reducing a compound of form~a I in which Rl and R2 are as defined herein and n is 1 with sodium dithios~ite ~der aL'caline conditions to 30 obtain the corresponding compound of formula I in which Rl and R2 are as defined herein and n is 0;
L9 44~
(c) hydrolyzing a compound o~ formula I in which Rl and n are as defined herein and R is lower ~lkyl to obtain the corresponding compound of formula I in which Rl and n ~Ire as defined herein and R2 is hydrogen;
~ d) reacting a compound of formllla I in which Rl, R2 and n are as defined herein with a therapeutically acceptable acid to obtain the corres-5 ponding compound of formlda I as the salt with the therapeutically acceptableacid; and (e) reacting a compound of formula I in which Rl and n are as defined herein and R2 is hydrogen with a therapeutically acceptQble base to obtain the corresponding compound of form~la I as the salt with the therapeu-10 tically acceptable base.
The term 'lower alkyl" as used herein means straight and branchedchain alkyl radicals containing from one to si2c carbon atoms, preferably one to four carbon atoms, and includes methyl, ethyl, propyl, l-methylethyl, butyl, 15 l,l-dimethylethyl, pentyl and the like, unless stated otherwise The term "halo" as used herein means halo radicals and includes fluoro, chloro, bromo and iodo, ~less stated otherwise.
The term '~ower alkoxy" as used herein means straight chain aLco2~r radicals containing from one to six carbon atoms and branched chain aL`coxy 20 radicals containing three to six carbon atoms and includes methoxy, ethoxy, l-methylethoxy9 butoxy, hexoxy and the like.
The compounds vf this inYention are capable of forming acid ad-dition salts with ther~peutically acceptable acids. The acid addition salt~s sreprepared by reacting the base form of the appropriate compound of formula 25 I with one or more equivalents, preferably with an excess, o~ the approplqateacid in an organic solvent, for exarnple, diethyl ether or an eth~ol-diethyl ether mixture.
These salts, when administered to a mammal9 possess the same pharma-cologic actiYities as the corresp~nding bases. For many purposes it is preferable 30 to administer the salts rather than the basic compounds. Suitable acids to form these salts include the common mineral aci~s, e.g. hydrohalic9 s~furic or phos-phoric acid; the organic acids, e.g. maleic, citric or tartaric acid; and acids which are sparingly soluble in body fluids and which impart slow-release pro-., ~2~
perties to their respective salts, e.g. pamoic or tannic acid or carboxymethyl cellul~se. The acid addition s~lts thus obtained are the functional equivalent of the parent base compound in respect to their therapeuffc use. Hence, these acid addition salts are Included within the scope of this invention Qnd are limited only by the requirement that the ~cids employed in forrning the salts be thera-5 peutically acceptable.
The acidi~ compounds of formula I, in which R2 is hydrogen, forms~lts with suitable ~erapeuffcally acceptable inorganic and organic bases.
These derived salts possess the sarne activity as tile parent acid and are included within the scope of this invention. The acid is transformed in excellent yield 10 into the corresponding therapeutically acceptable salt by neutralization of said acid with the appropriate inorganic or organic base. The salts are administered in the same manner as the parent acid connpounds. Suitable inorganic bases to form these salts include, for example, the hydroxides, carb~nOates, bicarbonRtes or alkoxides of the allcali metals or allcaline earth metals, for example, sodium, 15 potassium, magnesium, calcium and the likeO Suitable organic bases include the following amines; loYlrer mono-, di- and triaL~cylamines, the alkyl radicalsof which contain up to three earbon atoms, such as methylamine, dimethylamine, trimethylamine, ethylamine, di- and triethylamine, methylethylamine, and the like; mono-, dl and triaL'canol~mines9 the alkanol radicals of which contain20 up to three carbon atoms, for example, mono-, di- and triethanolamine; alkylene-diamines which contain up to six c~rbon atoms, such as hexamethylenediamine;
~yclic saturated or Imsaturated bases containing up to six carbon atoms, such as pyrrolidine, piperidine, morpholine, piperazine and their N-aL~cyl and N-hy-droxyalkyl derivatives, such as N-methyl-morpholine ~nd N-(2-hydroxyethyl~
25 piperidine, as well as pyridine. Furthermore9 there may be mentioned the cor-responding quatern~ry salts, such as the tetraalkyl (for example tetramethyl~, alkyl-aL'canol ( for example methyltriethanol and trimethyl-monoethanol) and cyclic ammonium s~lts, for example the N-methylpyridinium, N-methyl N-(2-hydroxyethyl~morpholinium, N,N~imethylmorpholinium, N-methyl-N-(2-hy-30 droxyethyl~morpholinium, N,N-dimethylpiperidinium salts, which ~re character-ized by having good water-solubility. In principle, however, there c~n be used all the ammonium salts which are physiologically compatible.
4~
The transformations to the salts can be carried out by a variety of methods known in the art. For example, in the case of the inorganic salts, it is preferred to dissolve the acid of formula I in water containing at least one equivalent of the salt desired. Advantageously, the reaction is performed in a water miscible, inert organic solvent, for example, methanol, ethanol, 5 dioxane, and the like in the presence of water. For example~ such use of sodium hydroxide, sodium carbonate or sodium bicarbonate gives a solution of the sodiumsalt. Evaporation of the soluffon or addition of a water-miscible solvent of a more moderate polarity, for example, a lower alkanol, for instance, butanol, or a lower alkanone, for instance, ethyl methyl ketone, gives the solid inorganic 10 salt if that form is d~sired.
To produce an amine salt, the acidic compound of formula I is dis-solved in a suitable solvent of either moderate or lower polarity,.for example, ethanol, methanol, ethyl acetate, diethyl ether and benzene. At least an equiva-lent amount of the amine corresponding to the desired cation is then added 15 to that solution. If the resulting salt does not precipitate, it can usua11y be obtained in solid form by addition of a miseible diluent of low polarity, for ex-ample, benzene or petroleum ether, or by evaporation. If the amine is relativelyvolatile, any excess can easily be removed by evaporation. It is preferred to use substantially equivalent amounts of the less volatile amines.
Salts~ wherein the cation is quaternary ammonium, are produced by mLxing the acid of formula I with an equivalent amount of the correspond-ing quaternary ammonium hydroxide in water solution, followed by evaporation of the water.
The compounds of this invention of formula I or a therapeutically 25 acceptable addition salt thereof are useful in the prevention or treatment of allergic reactions in a mamm~
More specifically, the compounds of this invention are useful for the prophylactic treatment as well as for the management of ~aphylacffc re-actions and atopic allergic manifestations, for example, bronchial asthma, hay 30 fever, allergic rhinitis, allergic conj~ctivities, food allergies, urticaria and the like, in a sensitized mammal.
The prevention or treatment of allergic reactions in a mammal by administration of a compound of formula I is demonstrated by using known anti-allergic tests in sn appropri~te animal model.
In one such test for the determination of useful anti-allergic activity, the compounds of formula I are tested using the passive paw anaphylaxis (PPA) method, described by R.R. Martel and J. Klicius, Int. Archs. Allergy Appl. Immun., _, 205 (1977). In this method reaginic ~ntibody-induced hypersensitivity is 5 produced in the rat hindpaw. Increased vascular permeability is determined by measuring the increase in paw volume. An effecffve anti-allergic drug inhibits the increase in paw volume when compared to the untreated reaginic hyper-sensitive controls. In this test, the following illustr~tive cornpounds o~ formlda I are effective anti-allergic agents: imidazo[a,l-c] 11,2,4] benzotriazine-2-car-10 boxylic acid, ethyl ester 5-oxide (described in E~ample l) at an intraperitoneal dose of 30 mg/kg of body weight c~uses a 43% inhibition at 15 minutes of the increase in paw ~lolume, imidazo[2,1-c~ 11,2,4] benzotriazine-2-carboxylic aeid-5-oxide (descrlbed in Example 2) at an intraper~toneal dose of 30 mg per kg of body weight causes a 34~ inhibition at 15 minutes of the increase in paw 15 volume, imid~zo[2,1-c] ~,2,4] benzotriazin~2-carbo2ylic acid, ethyl ester (des-cribed in Example 3) at an intraperitoneal dose of 30 mg per kg of body weight causes a 38% inhibition at 15 minutes of the increase in paw volume and imidazo-[2,1-c] ~,a,4~ benzotriazin~2-carboxylic acid (described in Example 4) at an intraperitoneal dose of 30 mg per kg of body weight causes a 23% inhibition 20 at 15 minutes of the increase in paw volume.
When the compounds of form~a I of this invention are used for sup-pressing allergic manifestations of anaphylactic reactions ~d atopic hypersen-sitiv;ty in a mammal, they are used alone or in combination with pharmacolo-gically acceptaMe carriers, the proportion o~ which is determined by the solu-25 bility and the chemical nature of the compound, chosen route of administraffonand standard biological practice.
For example, they are administered orally in solid form i.e. caps~e or tablet. They can a3so be admlnistered oraUy in the form of suspensions or solutions or they may be injected parenterally~ They can be administered par-30 enterally ~y the nasal route, for inst~nce, as drops or aerosol; or by inhalationfrom an aerosol.
In addition, the compounds of this inventiorl can be administered in conjuncffon with common anti-allergie agents, for example, known compounds 12~
effecting anti-histaminic, analgesic, central nervous system depressant, anti-hypertensive, immunosupressive9 anti-bradykinin, anti-serotonin or endocrinol~
gical responses.
The tablet compositions for oral administration contain the active ingredient in admixture with non-toxic pharmaceutical excipients known to 5 be suitable in the manufacture of tablets. Suitable pharmaceutical exeipients are, for example, starch, milk sugar, certain types of clay and so forth. The tablets can be uncoated or they can be eoated by known techniques so as to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
The aqueous suspensions of the compounds of formula I for oral administration cont~in the active ingredient in admixture with one or more non-toxic pharmaceutical excipients known to be suitable in the~ manufacture of Qqueous suspensions. Suitable excipients are, for example, methylcellulose, sodium alginate, gum acacia, lecithin and so forth. The aqueous suspensions 15 can also contain one or more preservatives, cne or more coloring agents, one or more flavoring agents and one or more sweetening agents.
Non-aqueous suspensions for oral administr~tion can be formulated by suspending the active ingredient in ethanol, in a vegetable oil, for example,ar&chis oil, olive oil, sesame oil5 or coconut oil, or in a mineral oil, for example 20 liquid paraffin, and the suspension may contain a thickening agent, for example beeswax or hard paraffin. These compositions can also contain a sweetening agent, flavoring agent and antioxi~dant.
For administration of a mamm~l by parenteral injection, it is pre-ferred to use the compounds of formula I in solution in a sterile aqueous vehicle 25 which may also contnin other solutes, such as buffers or preservatives7 as well as ~ufficient quantities of pharm~ceutically acceptable salts or of glucose to make the solution isotonic.
The compounds of form-da I can also be administered as nasal powders or insufflations. For such purpose, the compounds are administered in finely 30 divided solid form together with a pharmaceutically acceptable solid carrier,îor example, a finely divided polyethylene glycol (e.g. "Carbowax 1540'1) or finely divided lactose. Such compositions may also contain other excipients in finely divided solid form.
: L2~ 4 For administering the compounds of this invention by inhalation from an aerosol, the compound of form~da I is dissolved in water or ethanol and mixed with a volatile propellant, for example, dichlorotetrafluoroethane and dichlorodifluoromethane, and placed in a pressurized container having a metering valve to release a predetermined amount of material.
S The dosage of the compounds of formula I as anti-allergic agents will vary with the form of administration Qnd the particular compound chosen.
Furthermore, it will vary with the particular host as weLI as the age, weight and condition of $he host under treatment as well as with the r~ture and extent of the symptoms. Generally, treatment is initiated with small dosages substan-10 tially le~s than the optimum dose of the compound. Thereafter, the dosage is increased by small increments ~til the optimum effect under circumst~nces is reached. In general, the compounds of this invention are most desirably ad-ministered at ~ concentration level that will generally afford effective resultswithout causing any harmful or deleterious side effects. For example, an ef-15 fective anti-allergic amount of a compound of form~da I usually ranges from about 0.1 mg to about 500 mg per kg of body weight per day in si~le or divided doses, although as aforementioned, variations will occur. However, a dosage level that is in the range from about n.s mg to about 200 mg per kg of body weight per day in single or divided dose is employed most desirably in order 20 to achieve effective resldts.
The following reaction scheme illustrates a method for prep~ring the compounds of formula I~
~5 cooR2 ~N~N t' X C~2COCool~ ~(o~
tII) I in which R is ~s Other compounds of defined herein, R2 is formula I lower alkyl and n is l With refererlce to the aboYe reaction scherne, the startin~ material of formula II in which Rl is hydrogen is described by F.J. Wolf et Rl., J. Amer.Chem. Soc., 76, 3551(1954)9 and other starting materials of formula II can be prepared in an analogous manner.
Condensation of the compound of formula II in which l;Cl is as defined 15 herein with an ester of formula III in which R2 is lower aL'cyl and X is bromo or chloro gives the corresponding compound of formula T in which Rl is as d~
fined herein, R2 is lower alkyl and n is 1. Preferred conditions for the conden-sation involve reacting the compounds of formula II with about one to ~our molarequivalents of the compound of formula III in ~ inert organic solvent, preferably 20 tetrahydrofuran, at about 40 to ~5 C for about 15 to 40 hours.
If desired~ the compound of formula I in which Rl is as defined herein, R is lower alkyl ~Id n is 1 is reduced to obtain the corresponding compound of formula I in which R is as de~ined herein, R2 is lower aL'tyl and n is 0. An efficient method of reduction involves reacting the N-oxide of formula I with 25 sodium dithionite under aL'cflline conditions. ln the preferred method of reduction, the N~xide of formlda I is reacted with about four to ten molar equivalents of sodium dithionite in an aqueous solution of a water miscible organic solvent,preferably dimethyl~ormamide, containing an excess of sodium bicarbsnate at about 90 to 140 C for about two to ten hours. If the reduction Plso reduces 30 the aromatic system of the triazine, the aromatic system of the triazine can be readily regenerated by treating the reduction product with palladium on charcoal in en inert organic solvent at about 100 to 150 C for about one to five hours.
~Z~L~4~91 If desired, the compound of formula I in which Rl and n are ~s defined herein and R is lower aL'cyl is hydrolyzed to obtain the corresponding compound of formula I in which Rl and n are as defined herein and R2 is hydrogen. Pre-ferably, the compound of form~a I is hydrolyzed with one to ten molar e~uiva-lents of a strong base, for example, ss)dium or pot~ssium hydroxide9 in solvent 5 of water and a water miscible orgflnic solvent, preferably ethanol, at about 50 to 100 C for about 5 minutes to ten hours. The compound of formula I can be isolated from the soluSon in the ~orm of a salt with the base. Alternatively,the solution can be acidified to provide the free acid o~ the compound of ~or-mldH I in which R2 is hydrogen.
If desired~ the compound of ~orm~a I in which Rl is as defined herein, R is hydrogen and n is 1 is reduced with sodium dithionite, in the sarne manner as described above, to obtain the corresponding compound of formula I in which Rl is as defined herein, R2 is hydrogen and n is 0.
The following examples illustrate further the invention:
Imidazo[2,1-c] [1,2,43 benzotriazine-2-carboxylic Acid, Ethyl Ester 5-Oxide (I:
Rl=H,R2=Etandn=l) 3-Arnino-1,234-benzotriazine-l o~de [5060 g, 34.4 mmol, described by F.J. Wolf et al.i J. Amer. Chem. Soc., 769 3551(1954)] was stirred at room 20 temperature for 2 hours as a suspension in dry tetrahydrofuran (300 mL) in the presence of ethyl bromopyruvate (6 mL). The mixture was refluxed for 24 hours.
Ethanol tl.5 L) was then added to the mixture which was refluxed for another 12 hours. A yellow solid precipitated upon cooling and filtration gave a cake of material which was washed with ethanol and then dried. This mass of crystals (5.60 g, mp 261-262 C) was recrystallized from acetonitril~diethyl ether to ~fford the title compound ~5.25 g); mp 267-268b C; IR (mineral oil) 1700 and 1265 cm 1; NMR (DMSO-d6) ~ 1.37 (t, 3EI), 4.42 (q, 2H), 7.82 (t, lH), 8.17 (t, lH), 8.60 (t, 2H) and 9.37 ~s, lH); and Anal. Calcd for C12HloN403 C, 5$.81%
H, 3.90% N, 21.70% and Found: C, 55.45% H, 3.90% N, 21.70%.
Imidaæo~2,1-c] ~,2,4] benzotriazine-2-carboxylic Aci~5-oxide (I: Rl ~nd R2 =
H andn=l~
Imldazo[2,1-c~ [1,2,41 benæotriazine-2-carboxyIic acid, ethyl ester 12~14 ~4 5-o~de (5.50 g, 21.2 mmoles, des¢ribed in Example 1) was refluxed for 1 hour in 50% aqueous ethanol (200 mL) containing 10% aqueous sodium hydro2nde (100 mL). Most of the ethanol was eYaporated and the cold solution was acidiIied with 2N hydrochloric acid. The yellow powder was collected by filtration Qnd recrystallized from dimethylformamide-diethyl ether to afford the title compound(4.03 g); mp 2~9-280 C; IR (mineral oil) 1900 and 1700 cm 1; NMR (DMSO-d6) ~ 7.9 (m, 2~I), 8.5 ~m, 2H) and s.a (s~ lH); and Anal. Calcd for CloH6N403:
C, 52.18% H, 2.63% N, 24.34% and Found: C, 51.9~% ~, 2.70% N, 24.40%.
Imidazo[2,1-c] l1,2,4] benzotriazine-2-cRrboxylic Acid, Ethyl Ester (I: Rl = H, 10 R = Et and n - 0) Sodium dithionite (20.00 g, 115 mmoles) was added to a stirred sus-pension of imidazo[2,1-c] n,2,4] benzotriuzin~2-carboxylic acid, ethyl ester 5-o~de (10.00 g, 38.7 mmoles, described in Example 1) in agueous dimethylfor-mamide (66%, 300 mL) in th~ presence of sodium bicarbonate (200 mL, saturated 15 aqueous solution). More sodium dithionite (20.00 g, 115 mmoles) was added in small portions to the reaction mixture heated under reflux conditions during 3 hours. The mixture was cooled, and the precipitate was filtered and dissolved in xylene (~0 mL)~ This solution was refluxed for 1.5 hours in the presence o~
palladium on charcoal (10%,1.0 g). Chloroform was then added to the cold mixture20 and the catalyst was removed by filtration. The filtrate was evaporated and the residue was crystallized from methylene chlorid~hexane to give the title compound (2.32 g), mp 239-~40~ C; IR (mineral oil) 1700,1601,1579 and 1260 cm 1;NMR (DMS~d6) C 1.39 (t, 3H), 4.40 (q, 2EI), 7.95 (m, 2H), 8.60 (d, 2H) snd 9.46 ~s, lH)y and Anal. ~alcd for C12~10NgLO2 C, 59.50% H, 4.16~6 N, 23.13% and 25 ~ound: C, 59.02% H, 4.18% N, 22~96%o EXAMP~E 4 Imidazo[2,1-c] ~,~,4] benzotriazine-2-r~rboxylic Acid (I: Rl and R2 = H and n =o) Imidazo[2,1-c] ~,2,4] benzotriazine-2-carboxylic acid, ethyl ester 30 (2.00 g, 8.25 mmoles, described in Example 3) was stirred ~der reflux ~nditions in ethanol (60 mL) cont~ining 10% aqueous sodium hydroxide (60 mL)~ Most of the alcohol was evaporated and the remaining solution was cooled and acidified with conc. hydrochloric acid. The yellow precipitate was coLlected and recry-~5 12~19L~4 stallized from dimethylformamid~diethyl ether to give the title compound (1.51 g); mp 264-~65 C; IR (miner~l oil) 3080, 2500,1680, 16Q0 and 1590 cm 1;
NMR (DMSO-d6) ~ 7.90 (m9 2H), 8.60 (m, 2H) and 9.40 (m, lH); and Anal. Calcd for CloH6N4O2. one mole dimethylformamide: C, 54.35% H, 4.56% N, 24.38%
5 and Found: C, 53.96% H, 4.56% N, 24.27%.
IMIDAZ0~2,1-c] 11,2,4] BENZOTRIAZINE-2-CARBOXYLIC ACID DERIVATIVES
This inYention relates to novel imidazo[2,1-c] ~,2,4] benzotriazine-a-carbo~ylic acid derivatives, to therapeutically accept~ble addition salts ther~
of, to processes for their preparation~ to methods of using the derivatives and to pharmaceutical compositions of the derivatives. The compounds of this in-5 vention ~re useful in the treatment of ~naphylactic reactions and allergic con-ditions in mammals.
Although the compounds of this invention are novel compounds, somewhat related tricyclic compounds are known, for example antihypertensiYe dihydroimidazo[2,1-c~ ~,2,4] benzothiadiazines are described by R. Friary and 10 E.H. Gold, Heterocycles~ 7, 765 (1977); imidazo~5,1-c] ~,2,43 benzotriazines and pyrazolo[5,1-c~ ~,2,4] benzotriazines are described in Germ&n Ofenlegungsshrift2,348,382, April 3, 197~; and antiallergic imidazo[l,2-a] quinoxalines are des-cribed by A.C. Barnes and D.A. Rowlands, U.S. P~tent 4,333,934, issued ~une 8,1982. The compounds reported in the above references do not have the tri-15 cyclic ring system or the substituents characteristic o~ the compounds of thisinvention.
Summary of the Invention The compounds of this invention are represented by formula I
COOR
1~
Rl~ N ~N ~I) ( )n o in which Rl is hydrogen, lower ~lkyl, lower ~oxy, trifluoromethyl or halo;
and R is hydrogen or lowe~ alkyl; ~nd n is O or l, or a therapeutically accept-able salt thereof.
L9~4~L
-a- AH~8163 A preferred group of compounds of this invention is represented by formula I in which Rl is hydrogen; R2 is hydrogen or lower alkyl having one to four carbon atoms; and n is 0 or 1 or a therapeutically flcceptable salt ther~
of.
The compounds of this inven~ion are useful for preventing or treat-5 ing anaphylactic reactions or allergic conditions in a mammal by administeringto the mammal an effective anaphylactic alleviating or allergic alleviating amounl of a compound of formula I or a therapeutically acceptable addition salt thereof.
The compounds of this invention form a pharmaceutical compc6ition 10 which comprises a compound of form~da I~ or a therapeu'ffcally acceptable ad- dition salt thereof and a pharmaceuti~lly acceptable carrier.
The compounds of formlda I Qre prepared by sele~ti~ a pro~ess from the group of:
(&~ condensing a compound of formlda II
R ~ N~$~YY NH2 ~ I I) in which R is as defined herein with an ester of form~a III
X{:H2COCOOR2 (I.U) 25 in which R2 is lower alkyl and X is b~omo or chl~ro to obtain the corresponding compound of ~orm~a I in whic~ Rl is as defined herein, :R2 is lower alkyl and n is l;
(b) reducing a compound of form~a I in which Rl and R2 are as defined herein and n is 1 with sodium dithios~ite ~der aL'caline conditions to 30 obtain the corresponding compound of formula I in which Rl and R2 are as defined herein and n is 0;
L9 44~
(c) hydrolyzing a compound o~ formula I in which Rl and n are as defined herein and R is lower ~lkyl to obtain the corresponding compound of formula I in which Rl and n ~Ire as defined herein and R2 is hydrogen;
~ d) reacting a compound of formllla I in which Rl, R2 and n are as defined herein with a therapeutically acceptable acid to obtain the corres-5 ponding compound of formlda I as the salt with the therapeutically acceptableacid; and (e) reacting a compound of formula I in which Rl and n are as defined herein and R2 is hydrogen with a therapeutically acceptQble base to obtain the corresponding compound of form~la I as the salt with the therapeu-10 tically acceptable base.
The term 'lower alkyl" as used herein means straight and branchedchain alkyl radicals containing from one to si2c carbon atoms, preferably one to four carbon atoms, and includes methyl, ethyl, propyl, l-methylethyl, butyl, 15 l,l-dimethylethyl, pentyl and the like, unless stated otherwise The term "halo" as used herein means halo radicals and includes fluoro, chloro, bromo and iodo, ~less stated otherwise.
The term '~ower alkoxy" as used herein means straight chain aLco2~r radicals containing from one to six carbon atoms and branched chain aL`coxy 20 radicals containing three to six carbon atoms and includes methoxy, ethoxy, l-methylethoxy9 butoxy, hexoxy and the like.
The compounds vf this inYention are capable of forming acid ad-dition salts with ther~peutically acceptable acids. The acid addition salt~s sreprepared by reacting the base form of the appropriate compound of formula 25 I with one or more equivalents, preferably with an excess, o~ the approplqateacid in an organic solvent, for exarnple, diethyl ether or an eth~ol-diethyl ether mixture.
These salts, when administered to a mammal9 possess the same pharma-cologic actiYities as the corresp~nding bases. For many purposes it is preferable 30 to administer the salts rather than the basic compounds. Suitable acids to form these salts include the common mineral aci~s, e.g. hydrohalic9 s~furic or phos-phoric acid; the organic acids, e.g. maleic, citric or tartaric acid; and acids which are sparingly soluble in body fluids and which impart slow-release pro-., ~2~
perties to their respective salts, e.g. pamoic or tannic acid or carboxymethyl cellul~se. The acid addition s~lts thus obtained are the functional equivalent of the parent base compound in respect to their therapeuffc use. Hence, these acid addition salts are Included within the scope of this invention Qnd are limited only by the requirement that the ~cids employed in forrning the salts be thera-5 peutically acceptable.
The acidi~ compounds of formula I, in which R2 is hydrogen, forms~lts with suitable ~erapeuffcally acceptable inorganic and organic bases.
These derived salts possess the sarne activity as tile parent acid and are included within the scope of this invention. The acid is transformed in excellent yield 10 into the corresponding therapeutically acceptable salt by neutralization of said acid with the appropriate inorganic or organic base. The salts are administered in the same manner as the parent acid connpounds. Suitable inorganic bases to form these salts include, for example, the hydroxides, carb~nOates, bicarbonRtes or alkoxides of the allcali metals or allcaline earth metals, for example, sodium, 15 potassium, magnesium, calcium and the likeO Suitable organic bases include the following amines; loYlrer mono-, di- and triaL~cylamines, the alkyl radicalsof which contain up to three earbon atoms, such as methylamine, dimethylamine, trimethylamine, ethylamine, di- and triethylamine, methylethylamine, and the like; mono-, dl and triaL'canol~mines9 the alkanol radicals of which contain20 up to three carbon atoms, for example, mono-, di- and triethanolamine; alkylene-diamines which contain up to six c~rbon atoms, such as hexamethylenediamine;
~yclic saturated or Imsaturated bases containing up to six carbon atoms, such as pyrrolidine, piperidine, morpholine, piperazine and their N-aL~cyl and N-hy-droxyalkyl derivatives, such as N-methyl-morpholine ~nd N-(2-hydroxyethyl~
25 piperidine, as well as pyridine. Furthermore9 there may be mentioned the cor-responding quatern~ry salts, such as the tetraalkyl (for example tetramethyl~, alkyl-aL'canol ( for example methyltriethanol and trimethyl-monoethanol) and cyclic ammonium s~lts, for example the N-methylpyridinium, N-methyl N-(2-hydroxyethyl~morpholinium, N,N~imethylmorpholinium, N-methyl-N-(2-hy-30 droxyethyl~morpholinium, N,N-dimethylpiperidinium salts, which ~re character-ized by having good water-solubility. In principle, however, there c~n be used all the ammonium salts which are physiologically compatible.
4~
The transformations to the salts can be carried out by a variety of methods known in the art. For example, in the case of the inorganic salts, it is preferred to dissolve the acid of formula I in water containing at least one equivalent of the salt desired. Advantageously, the reaction is performed in a water miscible, inert organic solvent, for example, methanol, ethanol, 5 dioxane, and the like in the presence of water. For example~ such use of sodium hydroxide, sodium carbonate or sodium bicarbonate gives a solution of the sodiumsalt. Evaporation of the soluffon or addition of a water-miscible solvent of a more moderate polarity, for example, a lower alkanol, for instance, butanol, or a lower alkanone, for instance, ethyl methyl ketone, gives the solid inorganic 10 salt if that form is d~sired.
To produce an amine salt, the acidic compound of formula I is dis-solved in a suitable solvent of either moderate or lower polarity,.for example, ethanol, methanol, ethyl acetate, diethyl ether and benzene. At least an equiva-lent amount of the amine corresponding to the desired cation is then added 15 to that solution. If the resulting salt does not precipitate, it can usua11y be obtained in solid form by addition of a miseible diluent of low polarity, for ex-ample, benzene or petroleum ether, or by evaporation. If the amine is relativelyvolatile, any excess can easily be removed by evaporation. It is preferred to use substantially equivalent amounts of the less volatile amines.
Salts~ wherein the cation is quaternary ammonium, are produced by mLxing the acid of formula I with an equivalent amount of the correspond-ing quaternary ammonium hydroxide in water solution, followed by evaporation of the water.
The compounds of this invention of formula I or a therapeutically 25 acceptable addition salt thereof are useful in the prevention or treatment of allergic reactions in a mamm~
More specifically, the compounds of this invention are useful for the prophylactic treatment as well as for the management of ~aphylacffc re-actions and atopic allergic manifestations, for example, bronchial asthma, hay 30 fever, allergic rhinitis, allergic conj~ctivities, food allergies, urticaria and the like, in a sensitized mammal.
The prevention or treatment of allergic reactions in a mammal by administration of a compound of formula I is demonstrated by using known anti-allergic tests in sn appropri~te animal model.
In one such test for the determination of useful anti-allergic activity, the compounds of formula I are tested using the passive paw anaphylaxis (PPA) method, described by R.R. Martel and J. Klicius, Int. Archs. Allergy Appl. Immun., _, 205 (1977). In this method reaginic ~ntibody-induced hypersensitivity is 5 produced in the rat hindpaw. Increased vascular permeability is determined by measuring the increase in paw volume. An effecffve anti-allergic drug inhibits the increase in paw volume when compared to the untreated reaginic hyper-sensitive controls. In this test, the following illustr~tive cornpounds o~ formlda I are effective anti-allergic agents: imidazo[a,l-c] 11,2,4] benzotriazine-2-car-10 boxylic acid, ethyl ester 5-oxide (described in E~ample l) at an intraperitoneal dose of 30 mg/kg of body weight c~uses a 43% inhibition at 15 minutes of the increase in paw ~lolume, imidazo[2,1-c~ 11,2,4] benzotriazine-2-carboxylic aeid-5-oxide (descrlbed in Example 2) at an intraper~toneal dose of 30 mg per kg of body weight causes a 34~ inhibition at 15 minutes of the increase in paw 15 volume, imid~zo[2,1-c] ~,2,4] benzotriazin~2-carbo2ylic acid, ethyl ester (des-cribed in Example 3) at an intraperitoneal dose of 30 mg per kg of body weight causes a 38% inhibition at 15 minutes of the increase in paw volume and imidazo-[2,1-c] ~,a,4~ benzotriazin~2-carboxylic acid (described in Example 4) at an intraperitoneal dose of 30 mg per kg of body weight causes a 23% inhibition 20 at 15 minutes of the increase in paw volume.
When the compounds of form~a I of this invention are used for sup-pressing allergic manifestations of anaphylactic reactions ~d atopic hypersen-sitiv;ty in a mammal, they are used alone or in combination with pharmacolo-gically acceptaMe carriers, the proportion o~ which is determined by the solu-25 bility and the chemical nature of the compound, chosen route of administraffonand standard biological practice.
For example, they are administered orally in solid form i.e. caps~e or tablet. They can a3so be admlnistered oraUy in the form of suspensions or solutions or they may be injected parenterally~ They can be administered par-30 enterally ~y the nasal route, for inst~nce, as drops or aerosol; or by inhalationfrom an aerosol.
In addition, the compounds of this inventiorl can be administered in conjuncffon with common anti-allergie agents, for example, known compounds 12~
effecting anti-histaminic, analgesic, central nervous system depressant, anti-hypertensive, immunosupressive9 anti-bradykinin, anti-serotonin or endocrinol~
gical responses.
The tablet compositions for oral administration contain the active ingredient in admixture with non-toxic pharmaceutical excipients known to 5 be suitable in the manufacture of tablets. Suitable pharmaceutical exeipients are, for example, starch, milk sugar, certain types of clay and so forth. The tablets can be uncoated or they can be eoated by known techniques so as to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
The aqueous suspensions of the compounds of formula I for oral administration cont~in the active ingredient in admixture with one or more non-toxic pharmaceutical excipients known to be suitable in the~ manufacture of Qqueous suspensions. Suitable excipients are, for example, methylcellulose, sodium alginate, gum acacia, lecithin and so forth. The aqueous suspensions 15 can also contain one or more preservatives, cne or more coloring agents, one or more flavoring agents and one or more sweetening agents.
Non-aqueous suspensions for oral administr~tion can be formulated by suspending the active ingredient in ethanol, in a vegetable oil, for example,ar&chis oil, olive oil, sesame oil5 or coconut oil, or in a mineral oil, for example 20 liquid paraffin, and the suspension may contain a thickening agent, for example beeswax or hard paraffin. These compositions can also contain a sweetening agent, flavoring agent and antioxi~dant.
For administration of a mamm~l by parenteral injection, it is pre-ferred to use the compounds of formula I in solution in a sterile aqueous vehicle 25 which may also contnin other solutes, such as buffers or preservatives7 as well as ~ufficient quantities of pharm~ceutically acceptable salts or of glucose to make the solution isotonic.
The compounds of form-da I can also be administered as nasal powders or insufflations. For such purpose, the compounds are administered in finely 30 divided solid form together with a pharmaceutically acceptable solid carrier,îor example, a finely divided polyethylene glycol (e.g. "Carbowax 1540'1) or finely divided lactose. Such compositions may also contain other excipients in finely divided solid form.
: L2~ 4 For administering the compounds of this invention by inhalation from an aerosol, the compound of form~da I is dissolved in water or ethanol and mixed with a volatile propellant, for example, dichlorotetrafluoroethane and dichlorodifluoromethane, and placed in a pressurized container having a metering valve to release a predetermined amount of material.
S The dosage of the compounds of formula I as anti-allergic agents will vary with the form of administration Qnd the particular compound chosen.
Furthermore, it will vary with the particular host as weLI as the age, weight and condition of $he host under treatment as well as with the r~ture and extent of the symptoms. Generally, treatment is initiated with small dosages substan-10 tially le~s than the optimum dose of the compound. Thereafter, the dosage is increased by small increments ~til the optimum effect under circumst~nces is reached. In general, the compounds of this invention are most desirably ad-ministered at ~ concentration level that will generally afford effective resultswithout causing any harmful or deleterious side effects. For example, an ef-15 fective anti-allergic amount of a compound of form~da I usually ranges from about 0.1 mg to about 500 mg per kg of body weight per day in si~le or divided doses, although as aforementioned, variations will occur. However, a dosage level that is in the range from about n.s mg to about 200 mg per kg of body weight per day in single or divided dose is employed most desirably in order 20 to achieve effective resldts.
The following reaction scheme illustrates a method for prep~ring the compounds of formula I~
~5 cooR2 ~N~N t' X C~2COCool~ ~(o~
tII) I in which R is ~s Other compounds of defined herein, R2 is formula I lower alkyl and n is l With refererlce to the aboYe reaction scherne, the startin~ material of formula II in which Rl is hydrogen is described by F.J. Wolf et Rl., J. Amer.Chem. Soc., 76, 3551(1954)9 and other starting materials of formula II can be prepared in an analogous manner.
Condensation of the compound of formula II in which l;Cl is as defined 15 herein with an ester of formula III in which R2 is lower aL'cyl and X is bromo or chloro gives the corresponding compound of formula T in which Rl is as d~
fined herein, R2 is lower alkyl and n is 1. Preferred conditions for the conden-sation involve reacting the compounds of formula II with about one to ~our molarequivalents of the compound of formula III in ~ inert organic solvent, preferably 20 tetrahydrofuran, at about 40 to ~5 C for about 15 to 40 hours.
If desired~ the compound of formula I in which Rl is as defined herein, R is lower alkyl ~Id n is 1 is reduced to obtain the corresponding compound of formula I in which R is as de~ined herein, R2 is lower aL'tyl and n is 0. An efficient method of reduction involves reacting the N-oxide of formula I with 25 sodium dithionite under aL'cflline conditions. ln the preferred method of reduction, the N~xide of formlda I is reacted with about four to ten molar equivalents of sodium dithionite in an aqueous solution of a water miscible organic solvent,preferably dimethyl~ormamide, containing an excess of sodium bicarbsnate at about 90 to 140 C for about two to ten hours. If the reduction Plso reduces 30 the aromatic system of the triazine, the aromatic system of the triazine can be readily regenerated by treating the reduction product with palladium on charcoal in en inert organic solvent at about 100 to 150 C for about one to five hours.
~Z~L~4~91 If desired, the compound of formula I in which Rl and n are ~s defined herein and R is lower aL'cyl is hydrolyzed to obtain the corresponding compound of formula I in which Rl and n are as defined herein and R2 is hydrogen. Pre-ferably, the compound of form~a I is hydrolyzed with one to ten molar e~uiva-lents of a strong base, for example, ss)dium or pot~ssium hydroxide9 in solvent 5 of water and a water miscible orgflnic solvent, preferably ethanol, at about 50 to 100 C for about 5 minutes to ten hours. The compound of formula I can be isolated from the soluSon in the ~orm of a salt with the base. Alternatively,the solution can be acidified to provide the free acid o~ the compound of ~or-mldH I in which R2 is hydrogen.
If desired~ the compound of ~orm~a I in which Rl is as defined herein, R is hydrogen and n is 1 is reduced with sodium dithionite, in the sarne manner as described above, to obtain the corresponding compound of formula I in which Rl is as defined herein, R2 is hydrogen and n is 0.
The following examples illustrate further the invention:
Imidazo[2,1-c] [1,2,43 benzotriazine-2-carboxylic Acid, Ethyl Ester 5-Oxide (I:
Rl=H,R2=Etandn=l) 3-Arnino-1,234-benzotriazine-l o~de [5060 g, 34.4 mmol, described by F.J. Wolf et al.i J. Amer. Chem. Soc., 769 3551(1954)] was stirred at room 20 temperature for 2 hours as a suspension in dry tetrahydrofuran (300 mL) in the presence of ethyl bromopyruvate (6 mL). The mixture was refluxed for 24 hours.
Ethanol tl.5 L) was then added to the mixture which was refluxed for another 12 hours. A yellow solid precipitated upon cooling and filtration gave a cake of material which was washed with ethanol and then dried. This mass of crystals (5.60 g, mp 261-262 C) was recrystallized from acetonitril~diethyl ether to ~fford the title compound ~5.25 g); mp 267-268b C; IR (mineral oil) 1700 and 1265 cm 1; NMR (DMSO-d6) ~ 1.37 (t, 3EI), 4.42 (q, 2H), 7.82 (t, lH), 8.17 (t, lH), 8.60 (t, 2H) and 9.37 ~s, lH); and Anal. Calcd for C12HloN403 C, 5$.81%
H, 3.90% N, 21.70% and Found: C, 55.45% H, 3.90% N, 21.70%.
Imidaæo~2,1-c] ~,2,4] benzotriazine-2-carboxylic Aci~5-oxide (I: Rl ~nd R2 =
H andn=l~
Imldazo[2,1-c~ [1,2,41 benæotriazine-2-carboxyIic acid, ethyl ester 12~14 ~4 5-o~de (5.50 g, 21.2 mmoles, des¢ribed in Example 1) was refluxed for 1 hour in 50% aqueous ethanol (200 mL) containing 10% aqueous sodium hydro2nde (100 mL). Most of the ethanol was eYaporated and the cold solution was acidiIied with 2N hydrochloric acid. The yellow powder was collected by filtration Qnd recrystallized from dimethylformamide-diethyl ether to afford the title compound(4.03 g); mp 2~9-280 C; IR (mineral oil) 1900 and 1700 cm 1; NMR (DMSO-d6) ~ 7.9 (m, 2~I), 8.5 ~m, 2H) and s.a (s~ lH); and Anal. Calcd for CloH6N403:
C, 52.18% H, 2.63% N, 24.34% and Found: C, 51.9~% ~, 2.70% N, 24.40%.
Imidazo[2,1-c] l1,2,4] benzotriazine-2-cRrboxylic Acid, Ethyl Ester (I: Rl = H, 10 R = Et and n - 0) Sodium dithionite (20.00 g, 115 mmoles) was added to a stirred sus-pension of imidazo[2,1-c] n,2,4] benzotriuzin~2-carboxylic acid, ethyl ester 5-o~de (10.00 g, 38.7 mmoles, described in Example 1) in agueous dimethylfor-mamide (66%, 300 mL) in th~ presence of sodium bicarbonate (200 mL, saturated 15 aqueous solution). More sodium dithionite (20.00 g, 115 mmoles) was added in small portions to the reaction mixture heated under reflux conditions during 3 hours. The mixture was cooled, and the precipitate was filtered and dissolved in xylene (~0 mL)~ This solution was refluxed for 1.5 hours in the presence o~
palladium on charcoal (10%,1.0 g). Chloroform was then added to the cold mixture20 and the catalyst was removed by filtration. The filtrate was evaporated and the residue was crystallized from methylene chlorid~hexane to give the title compound (2.32 g), mp 239-~40~ C; IR (mineral oil) 1700,1601,1579 and 1260 cm 1;NMR (DMS~d6) C 1.39 (t, 3H), 4.40 (q, 2EI), 7.95 (m, 2H), 8.60 (d, 2H) snd 9.46 ~s, lH)y and Anal. ~alcd for C12~10NgLO2 C, 59.50% H, 4.16~6 N, 23.13% and 25 ~ound: C, 59.02% H, 4.18% N, 22~96%o EXAMP~E 4 Imidazo[2,1-c] ~,~,4] benzotriazine-2-r~rboxylic Acid (I: Rl and R2 = H and n =o) Imidazo[2,1-c] ~,2,4] benzotriazine-2-carboxylic acid, ethyl ester 30 (2.00 g, 8.25 mmoles, described in Example 3) was stirred ~der reflux ~nditions in ethanol (60 mL) cont~ining 10% aqueous sodium hydroxide (60 mL)~ Most of the alcohol was evaporated and the remaining solution was cooled and acidified with conc. hydrochloric acid. The yellow precipitate was coLlected and recry-~5 12~19L~4 stallized from dimethylformamid~diethyl ether to give the title compound (1.51 g); mp 264-~65 C; IR (miner~l oil) 3080, 2500,1680, 16Q0 and 1590 cm 1;
NMR (DMSO-d6) ~ 7.90 (m9 2H), 8.60 (m, 2H) and 9.40 (m, lH); and Anal. Calcd for CloH6N4O2. one mole dimethylformamide: C, 54.35% H, 4.56% N, 24.38%
5 and Found: C, 53.96% H, 4.56% N, 24.27%.
Claims (12)
1. A process for preparing a compound of formula I
(I) in which R1 is hydrogen, lower alkyl, lower alkoxy, tri-fluoromethyl or halo; R2 is hydrogen or lower alkyl and n is 0 or 1, or a therapeutically acceptable salt there-of, which comprises selecting a process from the group of:
(a) condensing a compound of formula II
(II) in which R1 is as defined herein with an ester of formula III
X-CH2COCOOR2 (III) in which R2 is lower alkyl and X is bromo or chloro to obtain the corresponding compound of formula I
in which R1 is as defined herein, R2 is lower alkyl and n is 1;
(b) reducing a compound of formula I in which R1 and R2 are as defined herein and n is 1 with sodium dithionite under alkaline conditions to obtain the corresponding compound of formula I in which R1 and R2 are as defined herein and n is 0;
(c) hydrolyzing a compound of formula I in which R1 and n are as defined herein and R2 is lower alkyl to obtain the corresponding compound of formula I
in which R1 and n are as defined herein and R2 is hydro-gen;
(d) reacting a compound of formula I in which R1, R2 and n are as defined herein with a therapeutic-ally acceptable acid to obtain the corresponding com-pound of formula I as the salt with the therapeutically acceptable acid; and (e) reacting a compound of formula I in which R1 and n are as defined herein and R2 is hydrogen with a therapeutically acceptable base to obtain the corres-ponding compound of formula I as the salt with the therapeutically acceptable base.
(I) in which R1 is hydrogen, lower alkyl, lower alkoxy, tri-fluoromethyl or halo; R2 is hydrogen or lower alkyl and n is 0 or 1, or a therapeutically acceptable salt there-of, which comprises selecting a process from the group of:
(a) condensing a compound of formula II
(II) in which R1 is as defined herein with an ester of formula III
X-CH2COCOOR2 (III) in which R2 is lower alkyl and X is bromo or chloro to obtain the corresponding compound of formula I
in which R1 is as defined herein, R2 is lower alkyl and n is 1;
(b) reducing a compound of formula I in which R1 and R2 are as defined herein and n is 1 with sodium dithionite under alkaline conditions to obtain the corresponding compound of formula I in which R1 and R2 are as defined herein and n is 0;
(c) hydrolyzing a compound of formula I in which R1 and n are as defined herein and R2 is lower alkyl to obtain the corresponding compound of formula I
in which R1 and n are as defined herein and R2 is hydro-gen;
(d) reacting a compound of formula I in which R1, R2 and n are as defined herein with a therapeutic-ally acceptable acid to obtain the corresponding com-pound of formula I as the salt with the therapeutically acceptable acid; and (e) reacting a compound of formula I in which R1 and n are as defined herein and R2 is hydrogen with a therapeutically acceptable base to obtain the corres-ponding compound of formula I as the salt with the therapeutically acceptable base.
2. A process for preparing a compound of formula I
(I) in which R1 is hydrogen; R2 is hydrogen or lower alkyl having one to four carbon atoms and n is 0 or 1, or a therapeutically acceptable salt thereof, which comprises selecting a process form the group of:
(a) reducing a compound of formula I in which R1 and R2 are as defined herein and n is 1 with sodium dithionite under alkaline conditions to obtain the corresponding compound of formula I in which R1 and R2 are as defined herein and n is 0;
(b) hydrolyzing a compound of formula I in which R1 and n are as defined herein and R2 is lower alkyl to obtain the corresponding compound of formula I
in which R1 and n are as defined herein and R2 is hydro-gen;
(c) reacting a compound of formula I in which R1 and R2 and n are as defined herein with a therapeu-tically acceptable acid to obtain the corresponding compound of formula I as the salt with the therapeutic-ally acceptable acid; and (d) reacting a compound of formula I in which R1 and n are as defined herein and R2 is hydrogen with a therapeutically acceptable base to obtain the corres-ponding compound of formula I as the salt with the therapeutically acceptable base.
(I) in which R1 is hydrogen; R2 is hydrogen or lower alkyl having one to four carbon atoms and n is 0 or 1, or a therapeutically acceptable salt thereof, which comprises selecting a process form the group of:
(a) reducing a compound of formula I in which R1 and R2 are as defined herein and n is 1 with sodium dithionite under alkaline conditions to obtain the corresponding compound of formula I in which R1 and R2 are as defined herein and n is 0;
(b) hydrolyzing a compound of formula I in which R1 and n are as defined herein and R2 is lower alkyl to obtain the corresponding compound of formula I
in which R1 and n are as defined herein and R2 is hydro-gen;
(c) reacting a compound of formula I in which R1 and R2 and n are as defined herein with a therapeu-tically acceptable acid to obtain the corresponding compound of formula I as the salt with the therapeutic-ally acceptable acid; and (d) reacting a compound of formula I in which R1 and n are as defined herein and R2 is hydrogen with a therapeutically acceptable base to obtain the corres-ponding compound of formula I as the salt with the therapeutically acceptable base.
3. A process for preparing imidazo[2,1-c][1,2,4]
benzotriazine-2-carboxylic acid, ethyl ester 5-oxide which comprises condensing 3-amino-1,2,4-benzotriazine-1-oxide with ethyl bromopyruvate to give the required compound.
benzotriazine-2-carboxylic acid, ethyl ester 5-oxide which comprises condensing 3-amino-1,2,4-benzotriazine-1-oxide with ethyl bromopyruvate to give the required compound.
4. A process for preparing imidazo[2,1-c][1,2,4]
benzotriazine-2-carboxylic acid-5-oxide which comprises hydrolyzing imidazo[2,1-c][1,2,4]benzotriazine-2-carb-oxylic acid, ethyl ester, 5-oxide to give the required compound.
benzotriazine-2-carboxylic acid-5-oxide which comprises hydrolyzing imidazo[2,1-c][1,2,4]benzotriazine-2-carb-oxylic acid, ethyl ester, 5-oxide to give the required compound.
5. A process for preparing imidazo[2,1-c][1,2,4]
benzotriazine-2-carboxylic adid, ethyl ester which comprises reducing imidazo[2,1-c][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester 5-oxide to give the required compound.
benzotriazine-2-carboxylic adid, ethyl ester which comprises reducing imidazo[2,1-c][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester 5-oxide to give the required compound.
6. A process for preparing imidazo[2,1-c][1,2,4]
benzotriazine-2-carboxylic acid which comprises hydro-lyzing imidazo[2,1-c][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester to give the required compound.
benzotriazine-2-carboxylic acid which comprises hydro-lyzing imidazo[2,1-c][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester to give the required compound.
7. A compound of the formula in which R1 is hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or halo; R2 is hydrogen or lower alkyl, and n is 0 or 1, or a therapeutically acceptable salt thereof, whenever prepared by the process of claim 1 or its obvious chemical equivalents.
8. A compound of claim 7 wherein R1 is hydrogen;
R2 is hydrogen or lower alkyl having one to four carbon atoms' and n is 0 or 1, or a therapeutically acceptable salt thereof, whenever prepared by the process of claim 2 or its obvious chemical equivalents.
R2 is hydrogen or lower alkyl having one to four carbon atoms' and n is 0 or 1, or a therapeutically acceptable salt thereof, whenever prepared by the process of claim 2 or its obvious chemical equivalents.
9. The compound of claim 7, which is imidazo [2,1-c][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester 5-oxide, whenever prepared by the process of claim 3 or its obvious chemical equivalents.
10. The compound of claim 7, which is imidazo [2,1-c][1,2,4]benzotriazine-2-carboxylic acid-5-oxide, whenever prepared by the process of claim 4 or its obvious chemical equivalents.
11. The compound of claim 7, which is imidazo [2,1-c][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester, whenever prepared by the process of claim 5 or its obvious chemical equivalents.
12. The compound of claim 7, which is imidazo [2,1-c][1,2,4]benzotriazine-2-carboxylic acid, whenever prepared by the process of claim 6 or its obvious chemical equivalents.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000416869A CA1211444A (en) | 1982-12-02 | 1982-12-02 | Imidazo[2,1-c] [1,2,4] benzotriazine-2- carboxylic acid derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000416869A CA1211444A (en) | 1982-12-02 | 1982-12-02 | Imidazo[2,1-c] [1,2,4] benzotriazine-2- carboxylic acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1211444A true CA1211444A (en) | 1986-09-16 |
Family
ID=4124067
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000416869A Expired CA1211444A (en) | 1982-12-02 | 1982-12-02 | Imidazo[2,1-c] [1,2,4] benzotriazine-2- carboxylic acid derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1211444A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005014595A1 (en) | 2003-07-31 | 2005-02-17 | Bayer Cropscience Gmbh | The use of fused ring-1,2,4-benzotriazine derivatives as herbicides or plant growth regulators for the control of undesired plants or vegetation, compounds and compositions thereof, and processes for their preparation |
-
1982
- 1982-12-02 CA CA000416869A patent/CA1211444A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005014595A1 (en) | 2003-07-31 | 2005-02-17 | Bayer Cropscience Gmbh | The use of fused ring-1,2,4-benzotriazine derivatives as herbicides or plant growth regulators for the control of undesired plants or vegetation, compounds and compositions thereof, and processes for their preparation |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI73433C (en) | FRUIT PROCESSING FOR PHARMACOLOGICAL PROPERTIES OF IMMEDIATE / 1,2-A / PYRAZINER. | |
| CA1147338A (en) | 4-amino-3-quinolinecarboxylic acids and esters-antisecretory, anti-ulcer compounds | |
| DE1695556B2 (en) | 3-alkyl-1,2,3,4,4a, 9-hexahydropyrazino [1,2-f] morphanthridine derivatives | |
| US4808594A (en) | Imidopyridines useful in therapy | |
| FI81340C (en) | Process for the preparation of novel therapeutically useful oxindolka rboxamide derivatives | |
| PL119520B1 (en) | Process for preparing novel,condensed pyrimidine derivatives pirimidina | |
| US3932416A (en) | N-tetrazolyl quinaldamides | |
| US4232024A (en) | 1-Oxo-1H-pyrimido[6,1-b]benzthiazole derivatives | |
| US4628055A (en) | Method for treating allergic reactions and compositions therefore | |
| CA1211444A (en) | Imidazo[2,1-c] [1,2,4] benzotriazine-2- carboxylic acid derivatives | |
| JPS60156676A (en) | Novel benzimidazole | |
| WO2001009129A2 (en) | 1h-pirido[3, 4-b]indol-1-one derivatives | |
| KR880001719B1 (en) | Process for preparing 1,4,9,10-tetra hydro pyrazolo(4,3-e)pyrido(3,2-b)(1,4)diazepino-10-ones | |
| CA1171083A (en) | Tricyclic pyrroles, a process for their preparation, their use, and medicaments containing them | |
| US4254118A (en) | 1-Oxo-5H-pyrimido[2,1-c][1,4]benzthiazine-2-carboxylic acid esters | |
| US4024255A (en) | Tetrazole containing naphthyridine-3-carboxamides | |
| US4254121A (en) | 3-Oxo-5H-pyrimido[2,1-c][1,4 ]benzoxazines | |
| CA1197242A (en) | Pyrimido¬1,2-a|pyrrolo¬2,1-c|¬1, 4|benzodiazepine-3-carboxylic acid derivatives | |
| SU1015828A3 (en) | Process for preparing derivatives of pyrazolo (1,5-c) quinazoline or their salts | |
| CA1060441A (en) | Anti-allergic n-(5-tetrazolyl)-1-oxo-1h-6-alkox-ypyrimido (1,2-a)-quinoline-2-carboxamides and intermediates therefor | |
| NZ200218A (en) | Imidazo(1,2-a)quinoline derivatives | |
| NO155056B (en) | EXPLOSIVES. | |
| US4521534A (en) | Imidazo[2,1-a]pyrrolo[2,1-c][1,4]benzodiazepine derivatives, methods of preparation and use | |
| US4034075A (en) | Quinaldic acid derivatives | |
| US4492697A (en) | 4H-Imidazo[2,3-c]pyrido[2,3-e][1,4]oxazine derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |