The invention discloses novel 4H-imidazo[2,3-c]pyrido[2,3-e][1,4]oxazine derivatives, processes 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 allergic conditions in a mammal.

BACKGROUND OF THE INVENTION 
This invention relates to novel 4H-imidazo[2,3-c]pyrido[2,3-e][1,4]oxazine 
derivatives to processes for their preparation, to methods of using the 
derivatives and to pharmaceutical compositions of the derivatives. The 
compounds of this invention are useful in the treatment of anaphylactic 
reactions and allergic conditions in mammals. 
The compounds of this invention have a novel 
4H-imidazo[2,3-c]pyrido[2,3-e][1,4]oxazine ring system. The closest 
related and known ring system is illustrated by the imidazobenzoxazine 
derivatives described by D. A. Rowlands et al., U.S. Pat. No. 4,145,419, 
Mar. 20, 1979. The compounds of this invention are distinguished from the 
known compounds by having a different ring system and different 
substituents on the ring system. 
SUMMARY OF THE INVENTION 
The compounds of this invention are represented by formula I 
##STR1## 
in which R.sup.1 and R.sup.2 are hydrogen, or R.sup.1 is amino and R.sup.2 
is COR.sup.3 wherein R.sup.3 is lower alkoxy, lower alkylamino, di(lower 
alkyl)amino, 1-pyrrolidinyl or 1-piperidinyl, or a therapeutically 
acceptable acid addition salt thereof. 
A preferred group of compounds is represented by formula I in which R.sup.1 
and R.sup.2 are hydrogen, or R.sup.1 is amino and R.sup.2 is lower 
alkoxycarbonyl or 1-pyrrolidinylcarbonyl, or a therapeutically acceptable 
acid addition salt thereof. 
The compounds of this invention are useful for preventing or treating 
anaphylactic reactions or allergic conditions in a mammal by administering 
to the mammal an effective anaphylaxis alleviating or allergy alleviating 
amount of a compound of formula I. 
The compounds of this invention form a pharmaceutical composition which 
comprises a compound of formula I and a pharmaceutically acceptable 
carrier. 
DETAILED DESCRIPTION OF THE INVENTION 
The term "lower alkyl" as used herein means straight and branched chain 
alkyl radicals containing from one to six carbon atoms, preferably one to 
three carbon atoms, and includes methyl, ethyl, propyl, 1-methylethyl, 
butyl, 1,1-dimethylethyl, pentyl and the like, unless stated otherwise. 
The term "lower alkoxy" as used herein means straight chain alkoxy radicals 
containing from one to six carbon atoms and branched chain alkoxy radicals 
containing three to six carbon atoms and includes methoxy, ethoxy, 
1-methylethoxy, butoxy, hexoxy and the like. 
The term "lower alkanol" as used herein means both straight and branched 
chain alkanols containing from one to four carbon atoms and includes 
methanol, ethanol, 1-methylethanol, butanol and the like. 
The compounds of formula I are capable of forming acid addition salts with 
therapeutically acceptable acids. The acid addition salts are prepared by 
reacting the base form of the appropriate compound of formula I with one 
or more equivalents, preferably with an excess, of the appropriate acid in 
an organic solvent, for example, diethyl ether or an ethanol-diethyl ether 
mixture. These salts, when administered to a mammal, possess the same 
pharmacologic activities as the corresponding bases. For many purposes it 
is preferable to administer the salts rather than the base compounds. 
Examples of suitable acids to form these salts include: the common mineral 
acids, e.g., hydrohalic, sulfuric or phosphoric acids; the organic acids, 
e.g., formic, acetic, maleic, methanesulfonic, malic, citric, or tartaric 
acid; and acids which are sparingly soluble in body fluids and which 
impart slow-release properties to their respective salts, e.g., pamoic 
acid, tannic acid or carboxymethyl cellulose. The addition salts thus 
obtained are the functional equivalent of the parent base compound in 
respect to their therapeutic use. Hence, these addition salts are included 
within the scope of this invention and are limited only by the requirement 
that the acids employed in forming the salts be therapeutically 
acceptable. 
The compounds of this invention of formula I are useful in the prevention 
or treatment of allergic reactions in a mammal. 
More specifically, the compounds of this invention are useful for the 
prophylactic treatment as well as for the management of anaphylactic 
reactions and atopic allergic manifestations, for example, bronchial 
asthma, hay fever, allergic rhinitis, allergic conjunctivities, 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 an appropriate 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., 54, 205 (1977). In this method, reaginic 
antibody-induced hypersensitivity is produced in the rat hindpaw. 
Increased vascular permeability is determined by measuring the increase in 
paw volume. An effective anti-allergic drug inhibits the increase in paw 
volume when compared to the untreated reaginic hypersensitive controls. In 
this test, the following illustrative compounds of formula I are effective 
anti-allergic agents when administered at an intraperitoneal dose of 30 
mg/kg of body weight: 4H-imidazo[2,3-c]pyrido[2,3-e][1,4]oxazine 
hydrochloride causes a 23% inhibition at 15 minutes of the increase in paw 
volume; 
2-[1-(pyrrolidinyl)carbonyl]-4H-imidazo[2,3-c]pyrido[2,3-e][1,4]oxazine-1- 
amine causes a 20% inhibition at 15 minutes of the increase in paw volume; 
and 1-amino-4H-imidazo[2,3-c]pyrido[ 2,3-e][1,4]oxazine-2-carboxylic acid, 
ethyl ester causes a 30% inhibition at 15 minutes of the increase in paw 
volume. 
When the compounds of formula I of this invention are used for suppressing 
allergic manifestations of anaphylactic reactions and atopic 
hypersensitivity in a mammal, they are used alone or in combination with 
pharmacologically acceptable carriers, the proportion of which is 
determined by the solubility and the chemical nature of the compound, 
chosen route of administration and standard biological practice. 
For example, they are administered orally in solid form i.e. capsule or 
tablet. They can also be administered orally in the form of suspensions or 
solutions or they may be injected parenterally. They can be administered 
parenterally by the nasal route, for instance, as drops or aerosol; or by 
inhalation from an aerosol. 
In addition, the compounds of this invention can be administered in 
conjunction with common anti-allergic agents, for example, known compounds 
effecting anti-histaminic, analgesic, central nervous system depressant, 
anti-hypertensive, immunosupressive, anti-bradykinin, anti-serotonin or 
endocrinological responses. 
The tablet compositions for oral administration contain the active 
ingredient in admixture with non-toxic pharmaceutical excipients known to 
be suitable in the manufacture of tablets. Suitable pharmaceutical 
excipients are, for example, starch, milk sugar, certain types of clay and 
so forth. The tablets can be uncoated or they can be coated 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 contain the active ingredient in admixture with one or more 
non-toxic pharmaceutical excipients known to be suitable in the 
manufacture of aqueous suspensions. Suitable excipients are, for example, 
methylcellulose, sodium alginate, gum acacia, lecithin and so forth. The 
aqueous suspensions can also contain one or more preservatives, one or 
more coloring agents, one or more flavoring agents and one or more 
sweetening agents. 
Non-aqueous suspensions for oral administration can be formulated by 
suspending the active ingredient in ethyl alcohol, in a vegetable oil, for 
example, arachis oil, olive oil, sesame oil, or coconut oil, or in a 
mineral oil, for example 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 antioxidant. 
For administration to a mammal by parenteral injection, it is preferred to 
use the compounds of formula I in solution in a sterile aqueous vehicle 
which may also contain other solutes, such as buffers or preservatives, as 
well as sufficient quantities of pharmaceutically acceptable salts or of 
glucose to make the solution isotonic. 
The compounds of formula I can also be administered as nasal powders or 
insufflations. For such purpose, the compounds are administered in finely 
divided solid form together with a pharmaceutically acceptable solid 
carrier, for example, a finely divided polyethylene glycol (e.g. "Carbowax 
1540") or finely divided lactose. Such compositions may also contain other 
excipients in finely divided solid form. 
For administering the compounds of this invention by inhalation from an 
aerosol, the compound of formula 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. 
The dosage of the compounds of formula I as anti-allergic agents will vary 
with the form of administration and the particular compound chosen. 
Furthermore, it will vary with the particular host as well as the age, 
weight and condition of the host under treatment as well as with the 
nature and extent of the symptoms. Generally, treatment is initiated with 
small dosages substantially less than the optimum dose of the compound. 
Thereafter, the dosage is increased by small increments until the optimum 
effect under circumstances is reached. In general, the compounds of this 
invention are most desirably administered at a concentration level that 
will generally afford effective results without causing any harmful or 
deleterious side effects. For example, an effective anti-allergic amount 
of a compound of formula I usually ranges from about 0.1 mg to about 500 
mg per kg of body weight per day in single or divided doses, although as 
aforementioned, variations will occur. However, a dosage level that is in 
the range from about 0.5 mg to about 200 mg per kg of body weight per day 
in single or divided dose is employed most desirably in order to achieve 
effective results. 
The following reaction scheme illustrates a method for preparing the 
compounds of formula I: 
##STR2## 
With reference to the above reaction scheme, the compounds of formula I are 
prepared by: 
(a) condensing the compound of formula II with a compound of formula III in 
which R.sup.3 is as defined herein to obtain the corresponding compound of 
formula I in which R.sup.1 is amino and R.sup.2 is COR.sup.3 wherein 
R.sup.3 is as defined herein; or 
(b) condensing the compound of formula II with NH.sub.2 --CH.sub.2 
CH(OCH.sub.3).sub.2 to obtain the corresponding compound of formula IV and 
cyclizing the compound of formula IV to obtain the compound of formula I 
in which R.sup.1 and R.sup.2 are hydrogen. 
More specifically, the compound of formula I in which R.sup.1 is amino and 
R.sup.2 is COR.sup.3 is prepared by condensing the compound of formula II 
with about one to two molar equivalents of the compound of formula III at 
about 50.degree. to 100.degree. C. for about four to ten hours in a lower 
alkanol, preferably methanol, ethanol or propanol. 
The compound of formula I in which R.sup.1 and R.sup.2 are hydrogen is 
prepared by condensing the compound of formula II with about 1.5 to 2.0 
molar equivalents of NH.sub.2 --CH.sub.2 CH(OCH.sub.3).sub.2 at about 
70.degree. to 80.degree. C. for about three to six hours in a lower 
alkanol, preferably ethanol, to obtain the compound of formula IV. 
Cyclization of the compound of formula IV with about 2.0 to 2.5 molar 
equivalents of titanium tetrachloride at about 90.degree. to 130.degree. 
C. for about two to four hours in an inert organic solvent, preferably 
toluene, gives the compound of formula I in which R.sup.1 and R.sup.2 are 
hydrogen.