Disclosed are compounds of the formula: ##STR1## wherein Ar, R.sub.1, R.sub.2, R.sub.3, W, X, Y, and Z are substituents as defined herein, which compounds are highly selective partial agonists or antagonists at human CRF.sub.1 receptors and are useful in the diagnosis and treatment of treating stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety.

BACKGROUND OF THE INVENTION
 1. Field of the Invention
 This invention relates to pyrido[2,3-b]indolizine derivatives and aza
 analogues thereof that selectively bind to corticotropin-releasing factor
 (CRF) receptors. It also relates to pharmaceutical compositions comprising
 such compounds. It further relates to the use of such compounds in
 treating stress related disorders such as post traumatic stress disorder
 (PTSD) as well as depression, headache and anxiety.
 2. Description of the Related Art
 Posselt, K., Arzneim.-Forsch. 1978, 28, 1056-65, describe the synthesis of
 10-(4-methoxyphenyl)pyrido[2,3-b]indolizine. Volovenko et al., Khim.
 Geterotsikl. Soedin. 1991, 6, 852, describe the synthesis of 2-chloro and
 2-methylthio-10-tosylmethylpyrimido[4,5-b]indolizine.
 SUMMARY OF THE INVENTION
 This invention provides novel compounds of Formula I which interact with
 CRF receptors.
 In one aspect, the invention provides pharmaceutical compositions
 comprising compounds of Formula I. In another aspect, it provides
 compositions useful in treating stress related disorders such as post
 traumatic stress disorder (PTSD) as well as depression, headache and
 anxiety. These compositions include a compound of Formula I. Further, in a
 third aspect, the invention provides methods of treating such stress
 related disorders.
 Accordingly, a broad aspect of the invention is directed to compounds of
 Formula I:
 ##STR2##
 Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 4-
 or 5-pyrimidyl, each of which is optionally mono-, di-, or trisubstituted
 with halogen, trifluoromethyl, hydroxy, amino, mono- or di(C.sub.1
 -C.sub.6) alkyl amino, carboxamido, C.sub.1 -C.sub.6 alkyl, C.sub.3
 -C.sub.7 cycloalkyl, or C.sub.1 -C.sub.6 alkoxy, with the proviso that at
 least one of the positions ortho or para to the point of attachment of Ar
 to the tricyclic ring system is substituted;
 R.sub.1 and R.sub.2 independently represent
 C.sub.1 -C.sub.6 alkyl;
 C.sub.3 -C.sub.7 cycloalkyl;
 C.sub.3 -C.sub.7 cycloalkyl(C.sub.1 -C.sub.6)alkyl;
 C.sub.1 -C.sub.6 alkoxy(C.sub.1 -C.sub.6)alkyl; or
 aryl(C.sub.1 -C.sub.6)alkyl where aryl is phenyl, 1- or 2-naphthyl, 2-, 3-,
 or 4-pyridyl, 2- or 3-thienyl or 2-, 4 or 5-pyrimidyl, each of which is
 optionally mono- or disubstituted with halogen, hydroxy, C.sub.1 -C.sub.6
 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.6 alkoxy, or (C.sub.1
 -C.sub.6 alkylene)-A--R.sub.4, wherein A is O, S, NH, or N(C.sub.1
 -C.sub.6 alkyl) and R.sub.4 is hydrogen, C.sub.3 -C.sub.7 cycloalkyl, or
 C.sub.1 -C.sub.6 alkyl; or
 R.sub.1 and R.sub.2 taken together represent --(CH.sub.2).sub.n
 --A--(CH.sub.2).sub.m -- wherein n is 2, 3 or 4, A is methylene, oxygen,
 sulfur, or NR.sub.5, wherein R.sub.5 is hydrogen, C.sub.3 -C.sub.7
 cycloalkyl, or C.sub.1 -C.sub.6 alkyl, and m is 0, 1, or 2;
 R.sub.3 is C.sub.1 -C.sub.6 alkyl, or (C.sub.1 -C.sub.6
 alkylene)-G--R.sub.6, wherein G is O, S, NH, or N(C.sub.1 -C.sub.6 alkyl)
 and R.sub.6 is hydrogen, C.sub.3 -C.sub.7 cycloalkyl, or C.sub.1 -C.sub.6
 alkyl; and
 W, X, Y, and Z are independently N or C--R.sub.7, wherein R.sub.7 is
 hydrogen, C.sub.3 -C.sub.7 cycloalkyl, or C.sub.1 -C.sub.6 alkyl.
 These compounds are highly selective partial agonists or antagonists at CRF
 receptors and are useful in the diagnosis and treatment of stress related
 disorders such as post traumatic stress disorder (PTSD) as well as
 depression and anxiety.
 Another aspect of the invention is directed to intermediates useful in the
 preparation of the compounds of Formula I.
 In a further aspect, the invention provides methods for making the
 compounds of Formula I and the intermediates for preparing such compounds.
 DETAILED DESCRIPTION OF THE INVENTION
 Preferred compounds of Formula I are those where Ar is phenyl substituted
 in the 2, 4, and 6 positions, preferably with methyl, ethyl or propyl;
 naphthyl substituted in the 2 and 6 positions, preferably with methyl,
 ethyl or propyl; or 3-pyridyl substituted in the 2, 4, and 6 positions,
 preferably with methyl, ethyl or propyl; 5-pyrimidiyl substituted in the
 2, 4, and 6 positions, preferably with methyl, ethyl, or propyl.
 Particularly, preferred components of Formula I include those where the Ar
 group is substituted in the 2 and 6 or the 2, 4, and 6 positions with
 methyl.
 Preferred compounds of the invention have Formula II:
 ##STR3##
 wherein
 Ar, R.sub.1, R.sub.2, and R.sub.3 are as defined above for Formula I; and
 X, Y, and Z are independently N or C--R.sub.7, wherein R.sub.7 is hydrogen,
 C.sub.3 -C.sub.7 cycloalkyl, or C.sub.1 -C.sub.6 alkyl.
 Preferred compounds of Formula II are those where X and Z are both CH and Y
 is CH or nitrogen. More preferred compounds of Formula II are those where
 R.sub.3 is C.sub.1 -C.sub.4 alkyl or C.sub.3 -C.sub.6 cycloalkyl(C.sub.1
 -C.sub.3)alkyl. Other more preferred compounds of Formula II are those
 where R.sub.1 and R.sub.2 independently represent C.sub.1 -C.sub.6 alkyl,
 C.sub.3 -C.sub.7 cycloalkyl(C.sub.1 -C.sub.6)alkyl, --(CH.sub.2).sub.2
 O(CH.sub.2).sub.2 --; and Ar is phenyl trisubstituted with C.sub.1
 -C.sub.3 alkyl in the 2, 4, and 6 positions relative to the point of
 attachment of Ar to the tricyclic ring system. Particularly preferred
 compounds of the Formula II are those where Ar is phenyl trisubstituted
 with methyl in the 2, 4, and 6 positions relative to the point of
 attachment of Ar to the tricyclic ring system.
 Other particularly preferred compounds of Formula II are those where X, Y
 and Z are all CH.
 Other preferred compounds of the invention have Formula III
 ##STR4##
 wherein
 Ar, R.sub.1, R.sub.2, and R.sub.3 are as defined above for Formula I; and
 X and Z are independently N or C--R.sub.7, wherein R.sub.7 is hydrogen,
 C.sub.3 -C.sub.7 cycloalkyl, or C.sub.1 -C.sub.6 alkyl.
 More preferred compounds of Formula III are those where R.sub.3 is C.sub.1
 -C.sub.4 alkyl or C.sub.3 -C.sub.6 cycloalkyl(C.sub.1 -C.sub.3)alkyl.
 Other more preferred compounds of Formula III are those where R.sub.1 and
 R.sub.2 independently represent C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7
 cycloalkyl(C.sub.l -C.sub.6)alkyl, --(CH.sub.2).sub.2 O(CH.sub.2).sub.2
 --; and Ar is phenyl trisubstituted with C.sub.1 -C.sub.3 alkyl in the 2,
 4, and 6 positions relative to the point of attachment of Ar to the
 tricyclic ring system. Particularly preferred compounds of the Formula III
 are those where Ar is phenyl trisubstituted with methyl in the 2, 4, and 6
 positions relative to the point of attachment of Ar to the tricyclic ring
 system.
 Still other preferred compounds of the invention have formula:
 ##STR5##
 wherein
 wherein Ar, R.sub.1, R.sub.2, and R.sub.3 are as defined above for Formula
 I; and
 W, X, and Z are independently N or C--R.sub.7, wherein R.sub.7 is hydrogen,
 C.sub.3 -C.sub.7 cycloalkyl, or C.sub.1 -C.sub.6 alkyl.
 Preferred compounds of Formula IV are those where X and Z are both CH.
 More preferred compounds of Formula IV are those where R.sub.3 is C.sub.1
 -C.sub.4 alkyl or C.sub.3 -C.sub.6 cycloalkyl(C.sub.1 -C.sub.3)alkyl.
 Other more preferred compounds of Formula IV are those where R.sub.1 and
 R.sub.2 independently represent C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7
 cycloalkyl(C.sub.1 -C.sub.6)alkyl, --(CH.sub.2).sub.2 O(CH.sub.2).sub.2
 --; and Ar is phenyl trisubstituted with C.sub.1 -C.sub.3 alkyl in the 2,
 4, and 6 positions relative to the point of attachment of Ar to the
 tricyclic ring system. Particularly preferred compounds of the Formula IV
 are those where Ar is phenyl trisubstituted with methyl in the 2, 4, and 6
 positions relative to the point of attachment of Ar to the tricyclic ring
 system.
 Other particularly preferred compounds of IV are those where W is CH and X
 and Z are both CH.
 Yet other preferred compounds of the invention have formula:
 ##STR6##
 wherein Ar, R.sub.1, R.sub.2, and R.sub.3 are as defined above for Formula
 I; and
 X and Z are independently N or C--R.sub.7, wherein R.sub.7 is hydrogen,
 C.sub.3 -C.sub.7 cycloalkyl, or C.sub.1 -C.sub.6 alkyl.
 Preferred compounds of Formula V are those where R.sub.3 is C.sub.1
 -C.sub.4 alkyl or C.sub.3 -C.sub.6 cycloalkyl(C.sub.1 -C.sub.3)alkyl.
 Other more preferred compounds of Formula V are those where R.sub.1 and
 R.sub.2 independently represent C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7
 cycloalkyl(C.sub.1 -C.sub.6)alkyl, --(CH.sub.2).sub.2 O(CH.sub.2).sub.2
 --; and Ar is phenyl trisubstituted with C.sub.1 -C.sub.3 alkyl in the 2,
 4, and 6 positions relative to the point of attachment of Ar to the
 tricyclic ring system. Particularly preferred compounds of the Formula V
 are those where Ar is phenyl trisubstituted with methyl in the 2, 4, and 6
 positions relative to the point of attachment of Ar to the tricyclic ring
 system.
 The invention also provides intermediates useful in preparing compounds of
 Formula I. These intermediates have Formulae VI-X.
 ##STR7##
 where Ar, and X, Y and Z are defined as above for Formula I.
 Preferred compounds of Formula VI are those where Y is CH or N and X and Z
 are CH, and Ar is phenyl trisubstituted with C.sub.1 -C.sub.3 alkyl in the
 2, 4, and 6 positions relative to the point of attachment of Ar to the
 methylene group. Particularly preferred compounds of the Formula VII are
 those where Y is CH or N, X and Z are CH, and Ar is phenyl trisubstituted
 with methyl in the 2, 4, and 6 positions relative to the point of
 attachment of Ar to the methylene group.
 ##STR8##
 where R.sub.8 is NH.sub.2 or N.dbd.C(R.sub.3)C(R.sub.7) where R.sub.3 and
 R.sub.7 are as defined above for Formula I; and
 Ar, and X, Y and Z are defined as above for Formula I.
 Preferred compounds of Formula VII are those where Y is CH or N and X and Z
 are CH, and Ar is phenyl trisubstituted with C.sub.1 -C.sub.3 alkyl in the
 2, 4, and 6 positions relative to the point of attachment of Ar to the
 bicyclic ring system. Particularly preferred compounds of the Formula VII
 are those where Y is CH or N; X and Z are CH; and Ar is phenyl
 trisubstituted with methyl in the 2, 4, and 6 positions relative to the
 point of attachment of Ar to the bicyclic ring system.
 ##STR9##
 where R.sub.9 is halogen or hydroxy; and R.sub.3, R.sub.7, Ar, and X, Y and
 Z are defined as above for Formula I.
 Preferred compounds of Formula VIII are those where Y is CH or N; X and Z
 are CH; and Ar is phenyl trisubstituted with C.sub.1 -C.sub.3 alkyl in the
 2, 4, and 6 positions relative to the point of attachment of Ar to the
 tricyclic ring system. Particularly preferred compounds of the Formula
 VIII are those where Y is CH or N; X and Z are CH; and Ar is phenyl
 trisubstituted with methyl in the 2, 4, and 6 positions relative to the
 point of attachment of Ar to the tricyclic ring system.
 ##STR10##
 where R.sub.10 is NH.sub.2 or NHC(O)R.sub.3, where R.sub.3 is as defined
 above for Formula I; and Ar, and X, Y and Z are defined as above for
 Formula I.
 Preferred compounds of Formula IX are those where Y is CH or N; X and Z are
 CH; and Ar is phenyl trisubstituted with C.sub.1 -C.sub.3 alkyl in the 2,
 4, and 6 positions relative to the point of attachment of Ar to the
 bicyclic ring system. Particularly preferred compounds of the Formula IX
 are those where Y is CH or N; X and Z are CH; and Ar is phenyl
 trisubstituted with methyl in the 2, 4, and 6 positions relative to the
 point of attachment of Ar to the bicyclic ring system.
 ##STR11##
 where R.sub.3, Ar, X, Y and Z are defined as above for Formula I.
 Preferred compounds of Formula X are those where Y is CH or N; X and Z are
 CH; and Ar is phenyl trisubstituted with C.sub.1 -C.sub.3 alkyl in the 2,
 4, and 6 positions relative to the point of attachment of Ar to the
 tricyclic ring system. Particularly preferred compounds of the Formula X
 are those where Y is CH or N; X and Z are CH; and Ar is phenyl
 trisubstituted with methyl in the 2, 4, and 6 positions relative to the
 point of attachment of Ar to the tricyclic ring system.
 In certain situations, the compounds of Formula I may contain one or more
 asymmetric carbon atoms, so that the compounds can exist in different
 stereoisomeric forms. These compounds can be, for example, racemates or
 optically active forms. In these situations, the single enantiomers, i.e.,
 optically active forms, can be obtained by asymmetric synthesis or by
 resolution of the racemates. Resolution of the racemates can be
 accomplished, for example, by conventional methods such as crystallization
 in the presence of a resolving agent, or chromatography, using, for
 example a chiral HPLC column.
 Representative compounds of the present invention, which are encompassed by
 Formula I, include, but are not limited to the compounds in Table I and
 their pharmaceutically acceptable acid addition salts. In addition, if the
 compound of the invention is obtained as an acid addition salt, the free
 base can be obtained by basifying a solution of the acid salt. Conversely,
 if the product is a free base, an addition salt, particularly a
 pharmaceutically acceptable addition salt, may be produced by dissolving
 the free base in a suitable organic solvent and treating the solution with
 an acid, in accordance with conventional procedures for preparing acid
 addition salts from base compounds.
 Non-toxic pharmaceutical salts include salts of acids such as hydrochloric,
 phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic,
 methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic,
 alkanoic such as acetic, HOOC--(CH.sub.2)n--COOH where n is 0-4, and the
 like. Those skilled in the art will recognize a wide variety of non-toxic
 pharmaceutically acceptable addition salts.
 The present invention also encompasses the acylated prodrugs of the
 compounds of Formula I. Those skilled in the art will recognize various
 synthetic methodologies which may be employed to prepare non-toxic
 pharmaceutically acceptable addition salts and acylated prodrugs of the
 compounds encompassed by Formula I.
 Where a compound exists in various tautomeric forms, the invention is not
 limited to any one of the specific tautomers. The invention includes all
 tautomeric forms of a compound.
 By "C.sub.1 -C.sub.6 alkyl" or "lower alkyl" in the present invention is
 meant straight or branched chain alkyl groups having 1-6 carbon atoms,
 such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl,
 sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,
 2-hexyl, 3-hexyl, and 3-methylpentyl. Preferred C.sub.1 -C.sub.6 alkyl
 groups are methyl, ethyl, propyl, butyl, cyclopropyl and
 cyclopropylmethyl.
 By "C.sub.1 -C.sub.6 alkoxy" or "lower alkoxy" in the present invention is
 meant straight or branched chain alkoxy groups having 1-6 carbon atoms,
 such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,
 sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy,
 hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
 By the term "halogen" in the present invention is meant fluorine, bromine,
 chlorine, and iodine.
 Representative pyrido[2,3-b]indolizine derivatives and their aza analogues
 of the present invention are shown in Table 1. The number below each
 compound is its compound number.
 TABLE 1
 ##STR12##
 ##STR13##
 ##STR14##
 ##STR15##
 ##STR16##
 ##STR17##
 The interaction of compounds of the invention with CRF receptors is shown
 in the examples. This interaction results in the pharmacological
 activities of these compounds as illustrated in relevant animal models.
 The compounds of general formula I may be administered orally, topically,
 parenterally, by inhalation or spray or rectally in dosage unit
 formulations containing conventional non-toxic pharmaceutically acceptable
 carriers, adjuvants and vehicles. The term parenteral as used herein
 includes subcutaneous injections, intravenous, intramuscular, intrasternal
 injection or infusion techniques. In addition, there is provided a
 pharmaceutical formulation comprising a compound of general formula I and
 a pharmaceutically acceptable carrier. One or more compounds of general
 formula I may be present in association with one or more non-toxic
 pharmaceutically acceptable carriers and/or diluents and/or adjuvants and
 if desired other active ingredients. The pharmaceutical compositions
 containing compounds of general formula I may be in a form suitable for
 oral use, for example, as tablets, troches, lozenges, aqueous or oily
 suspensions, dispersible powders or granules, emulsion, hard or soft
 capsules, or syrups or elixirs.
 Compositions intended for oral use may be prepared according to any method
 known to the art for the manufacture of pharmaceutical compositions and
 such compositions may contain one or more agents selected from the group
 consisting of sweetening agents, flavoring agents, coloring agents and
 preserving agents in order to provide pharmaceutically elegant and
 palatable preparations. Tablets contain the active ingredient in admixture
 with non-toxic pharmaceutically acceptable excipients which are suitable
 for the manufacture of tablets. These excipients may be for example, inert
 diluents, such as calcium carbonate, sodium carbonate, lactose, calcium
 phosphate or sodium phosphate; granulating and disintegrating agents, for
 example, corn starch, or alginic acid; binding agents, for example starch,
 gelatin or acacia, and lubricating agents, for example magnesium stearate,
 stearic acid or talc. The tablets may be uncoated or they may be coated by
 known techniques to delay disintegration and absorption in the
 gastrointestinal tract and thereby provide a sustained action over a
 longer period. For example, a time delay material such as glyceryl
 monosterate or glyceryl distearate may be employed.
 Formulations for oral use may also be presented as hard gelatin capsules
 wherein the active ingredient is mixed with an inert solid diluent, for
 example, calcium carbonate, calcium phosphate or kaolin, or as soft
 gelatin capsules wherein the active ingredient is mixed with water or an
 oil medium, for example peanut oil, liquid paraffin or olive oil.
 Aqueous suspensions contain the active materials in admixture with
 excipients suitable for the manufacture of aqueous suspensions. Such
 excipients are suspending agents, for example sodium
 carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,
 sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;
 dispersing or wetting agents may be a naturally-occurring phosphatide, for
 example, lecithin, or condensation products of an alkylene oxide with
 fatty acids, for example polyoxyethylene stearate, or condensation
 products of ethylene oxide with long chain aliphatic alcohols, for example
 heptadecaethyleneoxycetanol, or condensation products of ethylene oxide
 with partial esters derived from fatty acids and a hexitol such as
 polyoxyethylene sorbitol monooleate, or condensation products of ethylene
 oxide with partial esters derived from fatty acids and hexitol anhydrides,
 for example polyethylene sorbitan monooleate. The aqueous suspensions may
 also contain one or more preservatives, for example ethyl, or n-propyl
 p-hydroxybenzoate, one or more coloring agents, one or more flavoring
 agents, and one or more sweetening agents, such as sucrose or saccharin.
 Oily suspensions may be formulated by suspending the active ingredients in
 a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut
 oil, or in a mineral oil such as liquid paraffin. The oily suspensions may
 contain a thickening agent, for example beeswax, hard paraffin or cetyl
 alcohol. Sweetening agents such as those set forth above, and flavoring
 agents may be added to provide palatable oral preparations. These
 compositions may be preserved by the addition of an anti-oxidant such as
 ascorbic acid.
 Dispersible powders and granules suitable for preparation of an aqueous
 suspension by the addition of water provide the active ingredient in
 admixture with a dispersing or wetting agent, suspending agent and one or
 more preservatives. Suitable dispersing or wetting agents and suspending
 agents are exemplified by those already mentioned above. Additional
 excipients, for example sweetening, flavoring and coloring agents, may
 also be present.
 Pharmaceutical compositions of the invention may also be in the form of
 oil-in-water emulsions. The oily phase may be a vegetable oil, for example
 olive oil or arachis oil, or a mineral oil, for example liquid paraffin or
 mixtures of these. Suitable emulsifying agents may be naturally-occurring
 gums, for example gum acacia or gum tragacanth, naturally-occurring
 phosphatides, for example soy bean, lecithin, and esters or partial esters
 derived from fatty acids and hexitol, anhydrides, for example sorbitan
 monoleate, and condensation products of the said partial esters with
 ethylene oxide, for example polyoxyethylene sorbitan monoleate. The
 emulsions may also contain sweetening and flavoring agents.
 Syrups and elixirs may be formulated with sweetening agents, for example
 glycerol, propylene glycol, sorbitol or sucrose. Such formulations may
 also contain a demulcent, a preservative and flavoring and coloring
 agents. The pharmaceutical compositions may be in the form of a sterile
 injectable aqueous or oleaginous suspension. This suspension may be
 formulated according to the known art using those suitable dispersing or
 wetting agents and suspending agents which have been mentioned above. The
 sterile injectable preparation may also be sterile injectable solution or
 suspension in a non-toxic parentally acceptable diluent or solvent, for
 example as a solution in 1,3-butanediol. Among the acceptable vehicles and
 solvents that may be employed are water, Ringer's solution and isotonic
 sodium chloride solution. In addition, sterile, fixed oils are
 conventionally employed as a solvent or suspending medium. For this
 purpose any bland fixed oil may be employed including synthetic mono-or
 diglycerides. In addition, fatty acids such as oleic acid find use in the
 preparation of injectables.
 The compounds of general formula I may also be administered in the form of
 suppositories for rectal administration of the drug. These compositions
 can be prepared by mixing the drug with a suitable non-irritating
 excipient which is solid at ordinary temperatures but liquid at the rectal
 temperature and will therefore melt in the rectum to release the drug.
 Such materials are cocoa butter and polyethylene glycols.
 Compounds of general formula I may be administered parenterally in a
 sterile medium. The drug, depending on the vehicle and concentration used,
 can either be suspended or dissolved in the vehicle. Advantageously,
 adjuvants such as local anesthetics, preservatives and buffering agents
 can be dissolved in the vehicle.
 Dosage levels of the order of from about 0.1 mg to about 140 mg per
 kilogram of body weight per day are useful in the treatment of the
 above-indicated conditions (about 0.5 mg to about 7 g per patient per
 day). The amount of active ingredient that may be combined with the
 carrier materials to produce a single dosage form will vary depending upon
 the host treated and the particular mode of administration. Dosage unit
 forms will generally contain between from about 1 mg to about 500 mg of an
 active ingredient.
 It will be understood, however, that the specific dose level for any
 particular patient will depend upon a variety of factors including the
 activity of the specific compound employed, the age, body weight, general
 health, sex, diet, time of administration, route of administration, and
 rate of excretion, drug combination and the severity of the particular
 disease undergoing therapy.
 The preparation of the pyrido[2,3-b]indolizines and aza analogues thereof
 of the present invention is illustrated in Schemes I and II. Those having
 skill in the art will recognize that the starting materials may be varied
 and additional steps employed to produce compounds encompassed by the
 present invention.
 ##STR18##
 In Scheme I, the variables Ar, R.sub.1, R.sub.2, R.sub.3, R.sub.7, X, Y,
 and Z are defined as above for Formula I.
 ##STR19##
 In Scheme I, the variables Ar, R.sub.1, R.sub.2, R.sub.3, X, Y, and Z are
 defined as above for Formula I.
 The disclosures of all articles and references mentioned in in this
 application, including patents, are incorporated herein by reference.
 The preparation of the compounds of the present invention is illustrated
 further by the following examples which are not to be construed as
 limiting the invention in scope or spirit to the specific procedures and
 compounds described in them.
 Commercial reagents were used without further purification. DMSO refers to
 dimethyl sulfoxide. THF refers to tetrahydrofuran. DMF refers to
 dimethylformamide. Room temperature refers to 20 to 25.degree. C.
 Concentration in vacuo implies the use of a rotary evaporator.
 Chromatography refers to flash column chromatography performed using 32-63
 mm silica gel. Proton NMR chemical shifts are reported in parts per
 million (d) relative to tetramethylsilane as an internal standard.

##STR22##
 To a solution of
 2-amino-3-ethoxycarbonyl-1-(2,4,6-trimethylphenyl)-indolizine (19.2 g;
 59.6 mmol) in 2,2-dimethoxypropane (100 mL) is added dl-camphorsulfonic
 acid (0.2 g). The mixture is stirred at reflux for 30 minutes and then
 distilled slowly to remove ca. 60 mL of volatiles over a 30-minute period.
 The solution is cooled to ambient temperature under an inert atmosphere,
 diluted with anhydrous toluene (50 mL), and concentrated in vacuo. The
 residue is dissolved in toluene (50 mL) and to the stirred solution is
 then added a 0.5M solution of potassium bis(trimethylsilyl)amide in
 toluene (250 mL; 125 mmol) dropwise over a 1-hour period. After the
 addition is complete, the mixture is further stirred for 2 hours at room
 temperature before being concentrated in vacuo to a small volume and then
 diluted with aqueous ammonium chloride. The resulting emulsion-like
 biphasic mixture is suction-filtered and washed succesively with water,
 methanol, and ethyl ether. Air- and vacuum drying provides 10.1 g of the
 title compound as a pale yellow solid (54%).
 D. 4-Chloro-2-methyl-10-(2,4,6-trimethylphenyl)pyrido[2,3-b]-indolizine

##STR23##
 A solution of
 4-hydroxy-2-methyl-10-(2,4,6-trimethylphenyl)pyrido-[2,3-b]indolizine
 (10.1 g; 32 mmol) in phosphorus oxychloride (60 mL) is heated at
 100.degree. C. for 1 hour, cooled to room temperature, and concentrated in
 vacuo. The residue is partitioned into ice water and dichloromethane. The
 aqueous phase is separated and extracted twice with dichloromethane. The
 combined organics are washed with a 1 N aqueous sodium hydroxide solution
 and then with water. The solution is dried (Na.sub.2 SO.sub.4), filtered,
 and concentrated in vacuo, and the resulting dark residue is filtered
 through a short pad of silica gel and washed with 25% ethyl acetate in
 hexane. The filtrate is concentrated in vacuo to give 10.1 g of the title
 compound as a yellow solid (94%): .sup.1 H nmr (400 MHz, CDCl.sub.3) d
 2.00 (s, 6 H), 2.37 (s, 3 H), 2.64 (s, 3 H), 6.58 (t, 1 H), 6.95 (dd, 1
 H), 7.00 (s, 2 H), 7.07 (s, 1 H), 7.08 (d, 1 H), 9.26 (d, 1 H).
 E.
 4-(N,N-Dipropyl)amino-2-methyl-10-(2,4,6-trimethylphenyl)-pyrido[2,3-b]ind
 olizine

##STR25##
 A solution of 2-amino-3-cyano-1-(2,4,6-trimethylphenyl)indolizine (220 mg)
 in an acetic anhydride (0.5 mL)--acetic acid (2 mL) mixture is heated at
 100.degree. C. for 1 hour. The mixture is cooled to room temperature and
 concentrated in vacuo. The residue is then heated in 85% phosphoric acid
 (5 mL) at 100.degree. C. for 1.5 hours, allowed to cool to room
 temperature, diluted with water, and neutralized to pH 7 by adding aqueous
 ammonium hydroxide. The resulting yellow suspension is extracted twice
 with dichloromethane and the combined extracts are dried (Na.sub.2
 SO.sub.4), filtered, concentrated, and chromatographed (50% ethyl acetate
 in hexane to 10% methanol in ethyl acetate) to give 120 mg of the title
 compound as a yellow solid.
 B. 4-Chloro-2-methyl-10-(2,4,6-trimethylphenyl)pyrimido[4,5-b]indolizine

##STR26##
 A solution of
 4-hydroxy-2-methyl-10-(2,4,6-trimethylphenyl)pyrimido-[4,5-b]indolizine
 (120 mg) in phosphorus oxychloride (2 mL) is heated at 100.degree. C. for
 2 hours, cooled to room temperature, and concentrated in vacuo. The
 residue is partitioned into ice water and dichloromethane. The aqueous
 phase is separated and extracted twice with dichloromethane. The combined
 organic extracts are washed with a saturated sodium bicarbonate solution
 and subsequently dried (Na.sub.2 SO.sub.4), filtered, and concentrated in
 vacuo. The resulting dark residue is chromatographed on silica gel (10% to
 20% ethyl acetate in hexane) to give 54 mg of the title compound as a
 greenish yellow foam: .sup.1 H nmr (400 MHz, CDCl.sub.3) d 1.99 (s, 6 H),
 2.38 (s, 3 H), 2.79 (s, 3 H), 6.80 (m, 1 H), 7.00 (s, 2 H), 7.19 (m, 2 H),
 9.27 (d, 1 H).
 C.
 4-(N-Benzylethylamino)-2-methyl-10-(2,4,6-trimethylphenyl)-pyrimido[4,5-b]
 indolizine

##STR30##
 A catalytic amount of dl-camphorsulfonic acid is added to a solution of
 ethyl
 2-amino-1-(2,4,6-trimethylphenyl)pyrrolo[1,2-a]pyrazine-2-carboxyl-ate
 (0.40 g) in 2,2-dimethoxypropane (10 mL) and the mixture is heated to
 reflux for 30 minutes. Over this period, about 5 mL of volatiles are
 removed by slow distillation; the remaining material is further refluxed
 for another 15 minutes. The mixture is cooled to room temperature and
 concentrated in vacuo. The residue is dissolved in THF (6 mL), cooled to
 0.degree. C. to the cooled solution is added dropwise a 1.0 M solution of
 sodium bis(trimethylsilyl)amide in THF (2.5 mL). After the addition, the
 deep red solution is allowed to warm to room temperature and stirred for 2
 additional hours before being diluted with aqueous ammonium chloride and
 extracted with three portions of dichloromethane. The combined organic
 extracts are dried (Na.sub.2 SO.sub.4), filtered, concentrated in vacuo,
 and triturated with hot ethyl acetate. The product, which precipitates
 upon cooling and dilution with ethyl ether, is filtered and air-dried (220
 mg). The filtrate is concentrated in vacuo and another crystallization in
 minimal ethyl acetate and ether provides an additional 100 mg crop of the
 title compound as a light yellow solid: .sup.1 H nmr (400 MHz, CDCl.sub.3)
 d 2.0 (s, 6 H), 2.38 (s, 3 H), 2.40 (s, 3 H), 6.14 (s, 1 H), 7.04 (s, 2
 H), 7.81 (d, 1 H), 8.2 (br, 1 H), 8.60 (s, 1 H), 8.43 (d, 1 H).
 D.
 4-Chloro-2-methyl-10-(2,4,6-trimethylphenyl)pyrido[2',3':
 4,5]-pyrrolo[2-a]pyrazine

##STR32##
 To a solution of
 4-Chloro-2-methyl-10-(2,4,6-trimethylphenyl)pyrido-[2',3':
 4,5]pyrrolo[1,2-a]pyrazine (23 mg) in DMSO (0.5 mL) is added dipropylamine
 (0.1 mL) and the resulting mixture is heated at 130.degree. C. for 3.5
 days. The mixture is then allowed to cool to room temperature, diluted
 with aqueous ammonium chloride, and extracted twice with ethyl -ether. The
 extracts are combined, washed with saturated brine, dried (Na.sub.2
 SO.sub.4), filtered, concentrated in vacuo, and chromatographed (10 to 20%
 ethyl acetate in hexane) to give 14.3 mg of the title compound (compound
 6, Table 1) as a yellow, glassy oil: 0.90 (t, 6 H), 1.6 (m, 4 H), 2.03 (s,
 6 H), 2.38 (s, 3 H), 2.62 (s, 3 H), 3.2 (br, 4 H), 6.81 (s, 1 H), 7.02 (s,
 2 H), 7.60 (d, 2 H), 8.6 (m, 2 H).
 The following compounds are prepared essentially according to the
 procedures set forth above in Example 8.
 EXAMPLE 9
 4-(1-Morpholino)-2-methyl-10-(2,4,6-trimethylphenyl)pyrido-[2',3':
 4,5]pyrrolo[1,2-a]pyrazine. (Compound 9)
 EXAMPLE 10
 4-(N,N-Bis-(2-methoxyethyl)amino)-2-methyl-10-(2,4,6-trimethyl-phenyl)pyrid
 o-[2',3':4,5]pyrrolo[1,2-a]pyrazine. (Compound 10)
 EXAMPLE 11
 The pharmaceutical utility of compounds of the invention is indicated by
 the following assay.
 Assay for CRF Receptor Binding Activity
 CRF receptor binding is performed using a modified version of the assay
 described by Grigoriadis and De Souza (Biochemical, Pharmacological, and
 Autoradiographic Methods to Study Corticotropin-Releasing Factor
 Receptors. Methods in Neurosciences, Vol. 5, 1991). Membrane pellets
 containing CRF receptors are resuspended in 50 mM Tris buffer pH 7.7
 containing 10 mM MgCl.sub.2 and 2 mM EDTA and centrifuged for 10 minutes
 at 48000 g. Membranes are washed again and brought to a final
 concentration of 1500 mg/ml in binding buffer (Tris buffer above with 0.1%
 BSA, 15 mM bacitracin and 0.01 mg/ml aprotinin.). For the binding assay,
 100 ml of the membrane preparation is added to 96 well microtube plates
 containing 100 ml of 125I-CRF (SA 2200 Ci/mmol, final concentration of 100
 pM) and 50 ml of drug. Binding is carried out at room temperature for 2
 hours. Plates are then harvested on a Brandel 96 well cell harvester and
 filters are counted for gamma emissions on a Wallac 1205 Betaplate liquid
 scintillation counter. Non-specific binding is defined by 1 mM cold CRF.
 IC.sub.50 values are calculated with the non-linear curve fitting program
 RS/1 (BBN Software Products Corp., Cambridge, Mass.). The binding affinity
 for the compounds of the invention, expressed as an IC.sub.50 value,
 generally ranges from about 0.5 nanomolar to about 10 micromolar.
 The invention and the manner and process of making and using it, are now
 described in such full, clear, concise and exact terms as to enable any
 person skilled in the art to which it pertains, to make and use the same.
 It is to be understood that the foregoing describes preferred embodiments
 of the present invention and that modifications may be made therein
 without departing from the spirit or scope of the present invention as set
 forth in the claims. To particularly point out and distinctly claim the
 subject matter regarded as invention, the following claims conclude this
 specification.