BACKGROUND OF THE INVENTION
 This invention relates to thiophenopyrimidines which possess CRF receptor
 antagonistic properties, to pharmaceutical compositions containing these
 compounds as active ingredient, and the use thereof in the treatment of
 endocrine, psychiatric and neurologic conditions or illnesses, including
 stress-related disorders in general.
 The first corticotropin-releasing factor (CRF) was isolated from ovine
 hypothalmi and identified as a 41-amino acid peptide (Vale et al., Science
 213:1394-1397, 1981). Subsequently, sequences of human and rat CRF were
 isolated and determined to be identical, but different from ovine CRF in 7
 of the 41 amino acid residues (Rivier et al., Proc. Natl. Acad. Sci. USA
 80:4851, 1983; Shibahara et al., EMBO J. 2:775, 1983). CRF has been found
 to produce profound alterations in endocrine, nervous and immune system
 functions. CRF is believed to be the major physiological regulator of the
 basal and stress-release of adrenocorticotropic hormone ("ACTH"),
 .beta.-endorphin, and other pro-opiomelanocortin ("POMC")-derived peptides
 from the anterior pituitary (Vale et al., Science 213:1394-1397, 1981).
 Briefly, CRF is believed to initiate its biological effects by binding to
 a plasma membrane receptor which has been found to be distributed
 throughout the brain (DeSouza et al., Science 221:1449-1451, 1984),
 pituitary (DeSouza et al., Methods Enzymol. 124:560, 1986; Wynn et al.,
 Biochem. Biophys. Res. Comm. 110:602-608, 1983), adrenals (Udelsman et
 al., Nature 319:147-150, 1986) and spleen (Webster, E. L., and E. B.
 DeSouza, Endocrinology 122:609-617, 1988). The CRF receptor is coupled to
 a GTP-binding protein (Perrin et al., Endocrinology 118: 1171-1179, 1986)
 which mediates CRF-stimulated increase in intracellular production of cAMP
 (Bilezikjian, L. M., and W. W. Vale, Endocrinology 113:657-662, 1983).
 In addition to its role in stimulating the production of ACTH and POMC, CRF
 is also believed to coordinate many of the endocrine autonomic, and
 behavioral responses to stress, and may be involved in the pathophysiology
 of affective disorders. Moreover, CRF is believed to be a key intermediary
 in communication between the immune, central nervous, endocrine and
 cardiovascular systems (Crofford et al., J. Clin. Invest. 90:2555-2564,
 1992; Sapolsky et al., Science 238:522-524, 1987; Tilders et al., Regul.
 Peptides 5:77-84, 1982). Overall, CRF appears to be one of the pivotal
 central nervous system neurotransmitters and plays a crucial role in
 integrating the body's overall response to stress.
 Administration of CRF directly to the brain elicits behavioral,
 physiological, and endocrine responses identical to those observed for an
 animal exposed to a stressful environment. For example,
 intracerebroventricular injection of CRF results in behavioral activation
 (Sutton et al., Nature 297:331, 1982), persistent activation of the
 electroencephalogram (Ehlers et al., Brain Res. 2/8332, 1983), stimulation
 of the sympathoadrenomedullary pathway (Brown et al., Endocrinology
 110:928, 1982), an increase of heart rate and blood pressure (Fisher et
 al., Endocrinology 110:2222, 1982), an increase in oxygen consumption
 (Brown et al., Life Sciences 30:207, 1982), alteration of gastrointestinal
 activity (Williams et al., Am. J. Physiol. 253:G582, 1987), suppression of
 food consumption (Levine et al., Neuropharmacology 22:337, 1983),
 modification of sexual behavior (Sirinathsinghji et al., Nature 305:232,
 1983), and immune function compromise (Irwin et al., Am. J. Physiol.
 255:R744, 1988). Furthermore, clinical data suggest that CRF may be
 hypersecreted in the brain in depression, anxiety-related disorders, and
 anorexia nervosa. (DeSouza, Ann. Reports in Med. Chem. 25:215-223, 1990).
 Accordingly, clinical data suggest that CRF receptor antagonists may
 represent novel antidepressant and/or anxiolytic drugs that may be useful
 in the treatment of the neuropsychiatric disorders manifesting
 hypersecretion of CRF. CRF receptor antagonists have been reported in for
 example, U.S. Pat. No. 5,063,245 disclosing substituted
 4-thio-5-oxo-3-pyrazoline derivatives and Australian Patent No.
 AU-A-41399/93, disclosing substituted 2-aminothiazole derivatives. Also,
 WO-94/13676, WO-94/13677 and WO-95/33750 disclose pyrrolopyrimidines,
 pyrazolo[3,4-d]pyrimidines and substituted purines as CRF receptor
 antagonists. EP-0,452,002 discloses thienopyrimidines as pesticides.
 Due to the physiological significance of CRF, the development of further
 biologically active small molecules having significant CRF receptor
 binding activity and which are capable of antagonizing the CRF receptor
 remains a desirable goal. Such CRF receptor antagonists would be useful in
 the treatment of endocrine, psychiatric and neurologic conditions or
 illnesses, including stress-related disorders in general.
 DESCRIPTION OF THE INVENTION
 This invention concerns compounds of formula
 ##STR2##
 including the stereoisomers and the pharmaceutically acceptable acid
 addition salt forms thereof, wherein
 X is S, SO or SO.sub.2 ;
 R.sup.1 is NR.sup.4 R.sup.5 or OR.sup.5 ;
 R.sup.2 is C.sub.1-6 alkyl, C.sub.1-6 alkyloxy or C.sub.1-6 alkylthio;
 R.sup.3 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkylsulfonyl, C.sub.1-6
 alkylsulfoxy or C.sub.1-6 alkylthio;
 R.sup.4 is hydrogen, C.sub.1-6 alkyl, mono- or di(C.sub.3-6
 cycloalkyl)methyl, C.sub.3-6 cycloalkyl, C.sub.3-6 alkenyl,
 hydroxyC.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyloxyC.sub.1-6 alkyl or
 C.sub.1-6 alkyloxyC.sub.1-6 alkyl;
 R.sup.5 is C.sub.1-8 alkyl, mono- or di(C.sub.3-6 cycloalkyl)methyl,
 Ar.sup.1 CH.sub.2, C.sub.1-6 alkyloxyC.sub.1-6 alkyl, hydroxyC.sub.1-6
 alkyl, C.sub.3-6 alkenyl, thienylmethyl, furanylmethyl, C.sub.1-6
 alkylthioC.sub.1-6 alkyl, morpholinyl, mono- or di(C.sub.1-6
 alkyl)aminoC.sub.1-6 alkyl, di(C.sub.1-6 alkyl)amino, C.sub.1-6
 alkylcarbonylC.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with imidazolyl;
 or a radical of formula --Alk--O--CO--Ar.sup.1 ;
 or R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they
 are attached may form a pyrrolidinyl, piperidinyl, homopiperidinyl or
 morpholinyl group, optionally substituted with C.sub.1-6 alkyl or
 C.sub.1-6 alkyloxyC.sub.1-6 alkyl;
 Ar is phenyl; phenyl substituted with 1, 2 or 3 substituents independently
 selected from halo, C.sub.1-6 alkyl, trifluoromethyl, hydroxy, cyano,
 C.sub.1-6 alkyloxy, benzyloxy, C.sub.1-6 alkylthio, nitro, amino and mono-
 or di(C.sub.1-6 alkyl)amino; pyridinyl; pyridinyl substituted with 1, 2 or
 3 substituents independently selected from halo, C.sub.1-6 alkyl,
 trifluoromethyl, hydroxy, cyano, C.sub.1-6 alkyloxy, benzyloxy, C.sub.1-6
 alkylthio, nitro, amino, mono- or di(C.sub.1-6 alkyl)amino and
 piperidinyl; and wherein said substituted phenyl may optionally be further
 substituted with one or more halogens;
 Ar.sup.1 is phenyl; phenyl substituted with 1, 2 or 3 substituents each
 independently selected from halo, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy,
 di(C.sub.1-6 alkyl)aminoC.sub.1-6 alkyl, trifluoromethyl and C.sub.1-6
 alkyl substituted with morpholinyl; or pyridinyl; and
 Alk is C.sub.1-6 alkanediyl.
 As used in the foregoing definitions and hereinafter, halo is generic to
 fluoro, chloro, bromo and iodo; C.sub.1-6 alkanediyl defines bivalent
 straight and branched chained saturated hydrocarbon radicals having from 1
 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl,
 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the
 branched isomers thereof; C.sub.1-2 alkyl defines straight saturated
 hydrocarbon radicals having from 1 to 2 carbon atoms such as methyl and
 ethyl; C.sub.2-4 alkyl defines straight and branched chain saturated
 hydrocarbon radicals having from 2 to 4 carbon atoms such as ethyl,
 propyl, butyl, 1-methylethyl and the like; C.sub.3-4 alkyl defines
 straight and branched chain saturated hydrocarbon radicals having from 3
 to 4 carbon atoms such as propyl, butyl, 1-methylethyl and the like;
 C.sub.1-6 alkyl includes C.sub.1-2 alkyl and C.sub.3-4 alkyl radicals as
 defined hereinbefore and the higher homologs thereof having from 5 to 6
 carbon atoms such as, pentyl, the pentyl isomers, hexyl and the hexyl
 isomers; C.sub.1-8 alkyl includes C.sub.1-6 alkyl and the higher
 homologues thereof having from 7 to 8 carbon atoms such as, for example,
 heptyl, octyl and the like; C.sub.3-6 alkenyl defines straight and
 branched chain hydrocarbon radicals containing one double bond and having
 from 3 to 6 carbon atoms such as, for example, 2-propenyl, 3-butenyl,
 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like; and where said
 C.sub.3-6 alkenyl is linked to a nitrogen or oxygen, the carbon atom
 making the link preferably is saturated. C.sub.3-6 cycloalkyl comprises
 cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. HydroxyC.sub.1-6
 alkyl refers to C.sub.1-6 alkyl substituted with a hydroxylgroup.
 Homopiperidinyl refers to a 7 membered saturated ring containing one
 nitrogen atom.
 Depending on the nature of some of the substituents, the compounds of
 formula (I) may contain one or more asymmetric centers which may be
 designated with the generally used R and S nomenclature.
 The compounds of the present invention contain basic nitrogen atoms and, as
 such, can be present as the free base or in the form of acid addition
 salts, both being part of this invention. Acid addition salts may be
 prepared by methods well known in the art, and may be formed from organic
 and inorganic acids. Suitable organic acids include maleic, fumaric,
 benzoic, ascorbic, succinic, methanesulfonic, acetic, oxalic, propionic,
 tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic,
 aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic
 acids. Suitable inorganic acids include hydrochloric, hydrobromic,
 sulfuric, phosphoric, and nitric acids.
 Particular groups of compounds within the invention are those compounds of
 formula
 (I) wherein one or more of the following restrictions apply:
 a) R.sup.1 is NR.sup.4 R.sup.5 wherein R.sup.4 is C.sub.1-6 alkyl or
 C.sub.1-6 alkyloxyC.sub.1-6 alkyl, and R.sup.5 is C.sub.1-6 alkyl,
 C.sub.3-6 alkenyl, C.sub.3-6 cycloalkylmethyl or hydroxyC.sub.1-6 alkyl;
 in particular R.sup.4 is C.sub.2-4 alkyl or methoxyC.sub.1-2 alkyl, and
 R.sup.5 is C.sub.2-4 alkyl, cyclopropylmethyl or hydroxyC.sub.2-4 alkyl;
 b) or, R.sup.1 is OR.sup.5 wherein R.sup.5 is C.sub.1-6 alkyl; in
 particular C.sub.2-4 alkyl;
 c) R.sup.2 is C.sub.1-6 alkyl, in particular C.sub.1-2 alkyl;
 d) R.sup.3 is hydrogen or C.sub.1-6 alkyl, in particular hydrogen or
 C.sub.1-2 alkyl;
 e) Ar is a phenyl substituted with 1, 2 or 3 substituents each
 independently selected from C.sub.1-6 alkyl, C.sub.1-6 alkyloxy or halo
 and one of the further hydrogens on said substituted phenyl may be a halo;
 in particular Ar is phenyl substituted on the 4-, 2,4- or 2,4,6-positions
 each independently with halo, C.sub.1-2 alkyl or C.sub.1-2 alkyloxy; or Ar
 is a pyridinyl substituted with 1, 2 or 3 substituents each independently
 selected from di(C.sub.1-6 alkyl)amino or C.sub.1-6 alkyl; in particular
 Ar is pyridinyl substituted on the 2,4-, 2,6- or 2,4,6-positions each
 independently with di(C.sub.1-2 alkyl)amino or C.sub.1-2 alkyl.
 Another particular group of compounds are those compounds of formula (I)
 wherein R.sup.1 is NR.sup.4 R.sup.5 and R.sup.4 and R.sup.5 are taken
 together with the nitrogen atom to which they are attached to form a
 pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl group;
 optionally substituted with C.sub.1-6 alkyl or C.sub.1-6 alkyloxyC.sub.1-6
 alkyl.
 Preferred compounds are those compounds of formula (I) wherein R.sup.1 is
 NR.sup.4 R.sup.5 wherein R.sup.4 is C.sub.3-4 alkyl or C.sub.1-2
 alkyloxyC.sub.3-4 alkyl, preferably propyl; and R.sup.5 is C.sub.3-4 alkyl
 or cyclopropylmethyl, preferably propyl; or R.sup.1 is OR.sup.5 wherein
 R.sup.5 is C.sub.3-4 alkyl; R.sup.2 is methyl; R.sup.3 is hydrogen or
 methyl; and Ar is substituted in the 2-, 4- and 6-positions with halo or
 C.sub.1-4 alkyl and optionally further substituted with a 3-halo; more
 preferably Ar is 2,4,6-trimethyl-phenyl, 3-bromo-2,4,6-trimethylphenyl,
 6-(dimethylamino)-4-methyl-pyridinyl or 2,4-dimethylpyridinyl.
 More preferably Ar is 3-pyridinyl substituted in the 4- and/or 6-position
 with methyl or dimethylamino.
 Most preferred are those compounds selected from
 2-methyl-6-(N-propyl-N-cyclopropylamino)-8-(2,4,6-trimethylphenyl)thiophen
 o[3,2-d]pyrimidine; or
 2-methyl-6-(N,N-dipropylamino)-8-(2,4,6-trimethylphenyl)-thiopheno[3,2-d]p
 yrimidine; the stereoisomeric forms and the pharmaceutically acceptable
 acid addition salts thereof.
 The compounds of the present invention can generally be prepared by
 alkylating a thiazolopyrimidine of formula (II) with an intermediate of
 formula (III).
 ##STR3##
 In intermediate (II), W is an appropriate leaving group such as halo, e.g.
 chloro, bromo, or a sulfonyloxy group, e.g. a mesyloxy or a tosyloxy
 group. The above reaction is typically conducted in a suitable solvent,
 e.g. an aprotic solvent such as DMF or acetonitrile, an ether, e.g.
 tetrahydrofuran, preferably at an elevated temperature and, when
 intermediates of formula (III) are volatile amines, in a sealed reaction
 vial.
 Also, compounds of formula (I) wherein R.sup.1 is OR.sup.5, said compounds
 being represented by formula (I-a), may be prepared by O-alkylating an
 intermediate of formula (IX) with an intermediate of formula (X), wherein
 W is as defined above. Said reaction can be performed in a reaction-inert
 solvent such as, for example, N,N-dimethylformamide, and in the presence
 of a suitable base such as, for example, sodium hydride, preferably at a
 temperature ranging between room temperature and reflux temperature.
 ##STR4##
 The compounds of formula (I) wherein R.sup.1 is NR.sup.4 R.sup.5,
 represented by formula (I-c), can be prepared from either compounds of
 formula (XI) or (XII) by suitable N-alkylation reactions as depicted
 herebelow, wherein W is as previously defined. These N-alkylations are
 conducted in a reaction-inert solvent such as, for example, an ether e.g.
 tetrahydofuran and preferably in the presence of a strong base, e.g. NaH.
 ##STR5##
 In certain instances, this reaction can give rise to side products wherein
 R.sup.2 is alkylated by (R.sup.4 or R.sup.5)--W, in particular where
 R.sup.2 is methyl and R.sup.4 or R.sup.5 is lower alkyl.
 As outlined below, compounds of formula (I) may be converted into each
 other following art-known transformation procedures.
 For instance, compounds of formula (I) wherein X is S can be converted into
 compounds of formula (I) wherein X is SO or SO.sub.2 by an oxidation
 reaction, e.g. treatment with a peroxide such as 3-chloroperbenzoic acid
 in a reaction-inert solvent, e.g. dichloromethane. By controlling the
 amount of oxidant and other reaction parameters, either compounds of
 formula (I) wherein X is SO or X is SO.sub.2 can be obtained, or a mixture
 of both, which subsequently can be separated by conventional methods, e.g.
 column chromatography. Also, the compounds of formula (I) wherein R.sup.3
 is C.sub.1-6 alkylthio can be converted into compounds of formula (I)
 wherein R.sup.3 is C.sub.1-6 alkylsulfonyl or C.sub.1-6 alkylsulfoxy by an
 oxidation reaction similar as above described. By controlling the amount
 of oxidant and other reaction parameters, and by separating the end
 products, the various oxidated products can be separately obtained.
 Further, the Ar group of compounds of formula (I) can be halogenated using
 a halogenating agent such as, e.g. chlorine or bromine, in a suitable
 solvent, e.g. acetic acid, and optionally the reaction may be performed at
 a temperature ranging between room temperature and the reflux temperature
 of the reaction mixture.
 Stereoisomers may be prepared by separation of the end products of formula
 (I) following art-known procedures, e.g. by treatment with an optically
 active acid and separating the thus-formed diastereoisomeric salts by
 selective crystallization or column chromatography. Or, stereoisomers may
 be prepared by using stereoisomeric starting materials in any of the above
 reaction schemes or in the preparation of intermediates described
 hereinafter.
 Intermediates of formula (II) wherein X is S, said intermediates being
 represented by compounds of formula (II-a), can be prepared as outlined
 herebelow. Intermediates of formula (VI) are prepared by treating
 intermediates of formula (IV) with an ester of formula (V) in a
 reaction-inert solvent such as an alcohol, e.g. ethanol, preferably in the
 presence of a strong base such as, e.g. sodium ethoxide or sodium hydride.
 The intermediates (VI) are reacted with methanesulphonyl chloride and
 subsequently with 2-(acetylthio)-acetonitrile, yielding aminothiophene
 derivatives of formula (VII). These are converted into intermediates
 (VIII) using conventional acylation methods such as, e.g. the use of an
 acid anhydride (R.sup.2 CO).sub.2 O. Intermediates of formula (VIII) are
 cyclized to intermediates (II'-b), in which the hydroxy group is converted
 into leaving group W, e.g. by treating intermediate (II'-b) with
 methanesulfonyloxy chloride or a halogenating reagent such as, e.g.
 POCl.sub.3, thus yielding intermediates (II-a).
 ##STR6##
 Intermediates of formula (XI) are prepared by treating intermediates of
 formula (II) with ammonia.
 In an embodiment, this invention also provides for compounds of formula
 (II'-a), defined as compounds of formula (II-a) wherein W' represents
 hydroxy, halo, mesyloxy or tosyloxy; provided that
 2-methyl-7-phenyl-thieno[3,2-d]pyrimidin-4(1H)-one is excluded.
 ##STR7##
 Said intermediates of formula (II'-a) may be prepared according to
 procedures used to prepare intermediates of formula (II-a), thereby
 thereby yielding compounds of formula (II'-b), defined as compounds of
 formula (II'-a) wherein W' is hydroxy; and optionally converting compounds
 of formula (II'-b) into compounds of formula (II-a), defined as compounds
 of formula (II'-a) wherein W' is other than hydroxy.
 The effectiveness of a compound as a CRF receptor antagonist may be
 determined by various assay methods. Suitable CRF antagonists of this
 invention are capable of inhibiting the specific binding of CRF to its
 receptor and antagonizing activities associated with CRF. A compound of
 structure (I) may be assessed for activity as a CRF antagonist by one or
 more generally accepted assays for this purpose, including (but not
 limited to) the assays disclosed by DeSouza et al. (J. Neuroscience 7:88,
 1987) and Battaglia et al. (Synapse I:572, 1987). As mentioned above,
 suitable CRF antagonists include compounds which demonstrate CRF receptor
 affinity. CRF receptor affinity may be determined by binding studies that
 measure the ability of a compound to inhibit the binding of a radiolabeled
 CRF (e.g. [.sup.125 I]tyrosine CFR) to receptor (e.g., receptors prepared
 from rat cerebral cortex membranes). The radioligand binding assay
 described by DeSouza et al. (supra, 1987) provides an assay for
 determining a compound's affinity for the CRF receptor. Such activity is
 typically calculated from the, IC.sub.50 as the concentration of a
 compound necessary to displace 50% of the radiolabeled ligand from the
 receptor, and is reported as a "K.sub.i " value calculated by the
 following equation:
 ##EQU1##
 where L=radioligand and K.sub.D =affinity of radioligand for receptor
 (Cheng and Prusoff, Biochem. Pharmacol. 22:3099, 1973).
 In addition to inhibiting CRF receptor binding, a compound's CRF receptor
 antagonist activity may be established by the ability of the compound to
 antagonize an activity associated with CRF. For example, CRF is known to
 stimulate various biochemical processes, including adenylate cyclase
 activity. Therefore, compounds may be evaluated as CRF antagonists by
 their ability to antagonize CRF-stimulated adenylate cyclase activity by,
 for example, measuring cAMP levels. The CRF-stimulated adenylate cyclase
 activity assay described by Battaglia et al. (supra, 1987) provides an
 assay for determining a compound's ability to antagonize CRF activity.
 Accordingly, CRF receptor antagonist activity may be determined by assay
 techniques which generally include an initial binding assay (such as
 disclosed by DeSouza (supra, 1987)) followed by a cAMP screening protocol
 (such as disclosed by Battaglia (supra, 1987)).
 With reference to CRF receptor binding affinities, CRF receptor antagonists
 of this invention have a K.sub.i of less than 10 .mu.M. In a preferred
 embodiment of this invention, a CRF receptor antagonist has a K.sub.i of
 less than 1 .mu.M, and more preferably less than 0.25 .mu.M (i.e., 250
 nM).
 The CRF receptor antagonists of the present invention demonstrate activity
 at the CRF receptor site, and may be used as therapeutic agents for the
 treatment of a wide range of disorders or illnesses including endocrine,
 psychiatric, and neurologic disorders or illnesses. More specifically, the
 CRF receptor antagonists of the present invention may be useful in
 treating physiological conditions or disorders arising from the
 hypersecretion of CRF. Because CRF is believed to be a pivotal
 neurotransmitter that activates and coordinates the endocrine, behavioral
 and automatic responses to stress, the CRF receptor antagonists of the
 present invention can be used to treat neuropsychiatric disorders.
 Neuropsychiatric disorders which may be treatable by the CRF receptor
 antagonists of this invention include affective disorders such as
 depression; anxiety-related disorders such as generalized anxiety
 disorder, panic disorder, obsessive-compulsive disorder, abnormal
 aggression, cardiovascular abnormalities such as unstable angina and
 reactive hypertension; and feeding disorders such as anorexia nervosa,
 bulimia, and irritable bowel syndrome. CRF antagonists may also be useful
 in treating stress-induced immune suppression associated with various
 diseases states, as well as stroke. Other uses of the CRF antagonists of
 this invention include treatment of inflammatory conditions (such as
 rheumatoid arthritis, uveitis, asthma, inflammatory bowel disease and G.I.
 motility), Cushing's disease, infantile spasms, epilepsy and other
 seizures in both infants and adults, and various substance abuse and
 withdrawal (including alcoholism).
 In another embodiment of the invention, pharmaceutical compositions
 containing one or more CRF receptor antagonists are disclosed. For the
 purposes of administration, the compounds of the present invention may be
 formulated as pharmaceutical compositions. Pharmaceutical compositions of
 the present invention comprise a CRF receptor antagonist of the present
 invention (i.e., a compound of structure (I)) and a pharmaceutically
 acceptable carrier and/or diluent. The CRF receptor antagonist is present
 in the composition in an amount which is effective to treat a particular
 disorder, that is, in an amount sufficient to achieve CRF receptor
 antagonist activity, and preferably with acceptable toxicity to the
 patient. Preferably, the pharmaceutical compositions of the present
 invention may include a CRF receptor antagonist in an amount from 0.1 mg
 to 250 mg per dosage depending upon the route of administration, and more
 preferably from 1 mg to 60 mg. Appropriate concentrations and dosages can
 be readily determined by one skilled in the art.
 Pharmaceutically acceptable carrier and/or diluents are familiar to those
 skilled in the art. For compositions formulated as liquid solutions,
 acceptable carriers and/or diluents include saline and sterile water, and
 may optionally include antioxidants, buffers, bacteriostats and other
 common additives. The compositions can also be formulated as pills,
 capsules, granules, or tablets which contain, in addition to a CRF
 receptor antagonist, diluents, dispersing and surface active agents,
 binders, and lubricants. One skilled in this art may further formulate the
 CRF receptor antagonist in an appropriate manner, and in accordance with
 accepted practices, such as those disclosed in Remington's Pharmaceutical
 Sciences, Gennaro, Ed., Mack Publishing Co., Easton, USA, 1990.
 In another embodiment, the present invention provides a method for treating
 a variety of disorders or illnesses, including endocrine, psychiatric and
 neurologic disorders or illnesses. Such methods include administering of a
 compound of the present invention to a warm-blooded animal in an amount
 sufficient to treat the disorder or illness. Such methods include systemic
 administration of a CRF receptor antagonist of this invention, preferably
 in the form of a pharmaceutical composition. As used herein, systemic
 administration includes oral and parenteral methods of administration. For
 oral administration, suitable pharmaceutical compositions of CRF receptor
 antagonists include powders, granules, pills, tablets, and capsules as
 well as liquids, syrups, suspensions, and emulsions. These compositions
 may also include flavorants, preservatives, suspending, thickening and
 emulsifying agents, and other pharmaceutically acceptable additives. For
 parental administration, the compounds of the present invention can be
 prepared in aqueous injection solutions which may contain, in addition to
 the CRF receptor antagonist, buffers, antioxidants, bacteriostats, and
 other additives commonly employed in such solutions.
 As mentioned above, administration of a compound of the present invention
 can be used to treat a wide variety of disorders or illnesses. In
 particular, the compounds of the present invention may be administered to
 a warm-blooded animal for the treatment of depression, anxiety disorder,
 panic disorder, obsessive-compulsive disorder, abnormal aggression,
 unstable angina, reactive hypertension, anorexia nervosa, bulimia,
 irritable bowel syndrome, stress-induced immune suppression, stroke,
 inflammation, Cushing's disease, infantile spasms, epilepsy, and substance
 abuse or withdrawal.
 Hence, the use of a compound of formula (I) as a medicine is provided

The following examples are provided for purposes of illustration, not
 limition.
 Experimental Part
 Hereinafter "THF" means tetrahydrofuran, "DCM" means dichloromethane,
 "DMSO" means dimethylsulfoxide and "ACN" means acetonitrile.
 A. Preparation of the Intermediates
 EXAMPLE A.1
 a) A solution of 2,4,6-trimethylphenylacetonitrile (75 g) and ethyl formate
 (67 g) in 225 ml absolute ethanol was treated with solid sodium ethoxide
 (36 g) in small portions over 10 minutes, with good stirring. The mixture
 was heated to 60.degree. C. under nitrogen for 16 hours and allowed to
 cool to room temperature. The reaction mixture was poured into 1.2 liters
 of water, extracted with diethyl ether (3.times.200 ml). The aqueous phase
 was acidified with 6M HCl to pH=1 and extracted with ethyl acetate. The
 ethyl acetate extract was washed with brine, dried over MgSO.sub.4 and
 concentrated, yielding 46 g (98%) of
 3-hydroxy-2-(2,4,6-trimethylphenyl)acrylonitrile (intermediate 1).
 b) A solution of intermediate 1 (1 g) in 10 ml pyridine was cooled to
 0.degree. C. under nitrogen and then treated with methanesulfonyl chloride
 (0.67 g) with good stirring. The solution was allowed to come to room
 temperature and stirred for 1 hour. The reaction mixture was poured into
 water and extracted with ethyl acetate. The organic phase was washed with
 1M HCl, water and brine, dried (MgSO.sub.4) and concentrated to give
 3-methanesulfonyl-2-(2,4,6-trimethylphenyl)acrylonitrile (intermediate 2)
 as a brown solid (1.4 g).
 c) To a suspension of NaOEt (3.7 g) in 40 ml of DMSO was added
 2-(acetylthio)acetonitrile. After 30 minutes, a solution of intermediate 2
 (13.2 g) in THF (80 ml) was added. LiN(TMS).sub.2 (1.0M in THF, 100 ml)
 was added via a syringe. The reaction was quenched with approximately 1
 equivalent of acetic acid, after 1 hour at room temperature. After
 removing most of the THF by evaporation, the residue was dissolved in 500
 ml of ethyl acetate and extracted twice with 500 ml water. The crude
 2-cyano-3-amino-4-(2,4,6-trimethylphenyl)-thiophene (intermediate 3) (6.0
 g) was carried on to the next step without further purification.
 d) To a solution of intermediate 3 (6.0 g) in acetic acid (6 ml) was added
 acetic anhydride (5 g). The reaction mixture was stirred for 1 hour at
 110.degree. C. After cooling, the crude mixture was poured into a mixture
 of ethyl acetate (400 ml), water (600 ml) and saturated NaHCO.sub.3 (200
 ml). The organic layer was rinsed with water and concentrated. The residue
 was purified by column chromatography on SiO.sub.2 (gradient;
 hexane:diethyl ether=2:1 to hexane:ethyl acetate=1:1) to give
 N-[2-cyano-4-(2,4,6-trimethylphenyl)-thiophen-3-yl]-acetamide
 (intermediate 4).
 e) A suspension of intermediate 4 (2.8 g) in 85% of H.sub.3 PO.sub.4 (2 ml)
 was stirred under nitrogen with an oil bath temperature of 130.degree. C.
 for 30 minutes. After cooling, 20 ml of water was poured into this
 mixture. After mixing to induce precipitation, the resulting solid was
 filtered and dried in a vacuum oven to give 2.7 g of
 3-methyl-6-hydroxy-8-(2,4,6,-trimethylphenyl)-thiopheno[3,2-d]pyrimidine
 (intermediate 5).
 f) A suspension of intermediate 5 (2.6 g) in POCl.sub.3 (8.0 g) was stirred
 for 2 hours at 100.degree. C. After cooling, the mixture was poured into a
 mixture of saturated NaHCO.sub.3 and DCM (100 ml). The organic phase was
 removed, concentrated in vacuo and the residue was purified by column
 chromatography on SiO.sub.2 (gradient; ethyl acetate:hexane=1:4 to ethyl
 acetate:methanol=4:1) to give 0.3 g of
 2-methyl-6-chloro-8-(2,4,6-trimethyl-phenyl)-thiopheno[3,2-d]pyrimidine
 (intermediate 6).
 Table 1 lists the intermediates that were prepared according to example
 A.1.
 TABLE 1
 ##STR8##
 Interm.
 No. R.sup.3 Ar
 6 CH.sub.3 2,4,6-trimethylphenyl
 7 CH.sub.3 2,6-dimethyl-3-pyridinyl
 8 CH.sub.3 4-chlorophenyl
 9 CH.sub.3 6-(dimethylamino)-4-methyl-3-pyridinyl
 10 CH.sub.3 6-(diethylamino)-4-methyl-3-pyridinyl
 11 CH.sub.3 4,6-dimethyl-3-pyridinyl
 12 H 2,4,6-trimethyl-3-pyridinyl
 13 H 6-(dimethylamino)-2,4-dimethyl-3-pyridinyl
 14 H 2,4,6-trimethylphenyl
 15 CH.sub.3 4-methoxyphenyl
 16 CH.sub.3 2,4-dimethoxyphenyl
 B. Preparation of the Final Products
 EXAMPLE B.1
 A solution of intermediate 6 (20 mg) with N,N-dipropylamine in a 3 ml
 reaction vial was stirred at 120.degree. C. After 1 hour the reaction
 mixture was cooled, 0.5 ml of acetonitrile was added and refluxed for
 another 30 minutes. The resulting suspension was allowed to cool to room
 temperature and diluted with additional acetonitrile. The residue was
 purified using SiO.sub.2 column chromatography (diethyl ether/hexanes) to
 give
 2-methyl-6-(N,N-dipropylamino)-8-(2,4,6-trimethylphenyl)-thiopheno[3,2-d]p
 yrimidine (compound 1).
 EXAMPLE B.2
 Treatment of intermediate 6 with sodium hydride and 2-propanol in THF and
 purification using SiO.sub.2 column chromatography gave
 2-methyl-6-(isopropoxy)-8-(2,4,6-trimethyl-phenyl)-thiopheno[3,2-d]pyrimid
 ine (compound 6).
 EXAMPLE B.3
 A solution of compound 1 (5 mg) in 1 ml DCM was treated with
 meta-chloro-perbenzoic acid (20 mg). This solution was stirred for 24
 hours, then poured into a mixture of ethyl acetate and water. The organic
 phase was washed with 5% aqueous NaHCO.sub.3 solution and brine, dried
 (MgSO.sub.4) and concentrated. The residue was purified by preparative TLC
 (diethyl ether/hexane: 1/9) to give
 2-methyl-6-(N,N-dipropylamino)-8-(2,4,6-trimethylphenyl)-thiopheno[3,2-d]p
 yrimidine-S,S-dioxide (compound 7).
 EXAMPLE B.4
 Compound 2 (0.05 mmol) was stirred with excess bromine in 1 ml of acetic
 acid at room temperature for 30 minutes. The mixture was poured into a
 mixture of DCM and saturated aqueous NaHCO.sub.3 and the organic layer was
 evaporated. The residue was purified by SiO.sub.2 chromatography (diethyl
 ether/hexane), yielding
 2-methyl-6-N-propyl-N-cyclopropylamino)-8-(3-bromo-2,4,6-trimethylphenyl)t
 hiopheno[3,2-d]pyrimidine (compound 5).
 Tables 2, 3 and 4 list the compounds that were prepared according to one of
 the above Examples and table 5 and 6 list the analytical data for these
 compounds.
 TABLE 2
 ##STR9##
 Co. Ex.
 No. No. R.sup.3 R.sup.4 R.sup.5
 1 B.1 H n-propyl n-propyl
 2 B.1 H n-propyl cyclopropylmethyl
 3 B.1 H hydrogen 3-pentyl
 4 B.1 H n-propyl 2-methoxyethyl
 9 B.1 H hydrogen (CH.sub.3).sub.2 N(CH.sub.2).sub.3
 10 B.1 H CH.sub.3 O(CH.sub.2).sub.2 CH.sub.3 O(CH.sub.2).sub.2
 11 B.1 H hydrogen 4-methoxyphenylmethyl
 12 B.1 H hydrogen CH.sub.3 O(CH.sub.2).sub.2
 13 B.1 H n-propyl 2-hydroxyethyl
 14 B.1 H hydrogen 4-trifluoromethylphenylmethyl
 15 B.1 H hydrogen 3-hydroxypropyl
 16 B.1 H hydrogen 1-hydroxy-2-hexyl
 17 B.1 H hydrogen 1-hydroxy-2-pentyl
 18 B.1 H hydrogen ##STR10##
 19 B.1 H hydrogen CH.sub.3 CH.sub.2 --S--(CH.sub.2).sub.2
 20 B.1 H hydrogen CH.sub.3 --S--(CH.sub.2).sub.2
 21 B.1 H hydrogen (CH.sub.3).sub.2 N
 22 B.1 H hydrogen 2-ethoxyphenylmethyl
 23 B.1 H n-propyl CH.sub.3 CH.sub.2 --CO--(CH.sub.2).sub.2
 24 B.1 H hydrogen n-propyl
 25 B.1 H hydrogen butyl
 26 B.1 H ethyl 3-hydroxypentyl
 27 B.1 H n-propyl 3-hydroxypentyl
 28 B.1 H n-butyl 3-hydroxypentyl
 29 B.1 H n-propyl 3-hydroxybutyl
 30 B.1 H n-butyl 3-hydroxybutyl
 31 B.1 H n-propyl ##STR11##
 32 B.1 H n-propyl ##STR12##
 33 B.1 H n-propyl ##STR13##
 34 B.1 H n-propyl ##STR14##
 35 B.1 H hydrogen 4-morpholinyl
 Co. Ex.
 No. No. R.sup.3 R.sup.4 and R.sup.5 taken together
 36 B.1 H ##STR15##
 37 B.1 H ##STR16##
 38 B.1 H ##STR17##
 39 B.1 H ##STR18##
 40 B.1 H ##STR19##
 TABLE 3
 ##STR20##
 Co. Ex.
 No. No. R.sup.3 R.sup.4 R.sup.5 Ar
 5 B.4 H n-propyl cyclopropylmethyl
 3-bromo-2,4,6-trimethylphenyl
 8 B.1 CH.sub.3 n-propyl n-propyl
 2,6-dimethyl-3-pyridinyl
 41 B.1 CH.sub.3 n-propyl n-propyl 4-chlorophenyl
 42 B.1 CH.sub.3 n-propyl 2-hydroxyethyl 4-chlorophenyl
 43 B.1 CH.sub.3 n-propyl n-propyl
 6-(dimethylamino)-4-methyl-
 3-pyridinyl
 44 B.1 CH.sub.3 n-propyl n-propyl
 6-(diethylamino)-4-methyl-
 3-pyridinyl
 45 B.1 CH.sub.3 n-propyl n-propyl 4-methoxyphenyl
 46 B.1 CH.sub.3 n-propyl 2-methoxyethyl 4-methoxyphenyl
 47 B.1 CH.sub.3 2-methoxyethyl 2-methoxyethyl 4-methoxyphenyl
 48 B.1 CH.sub.3 n-propyl n-propyl 2,4-dimethoxyphenyl
 49 B.1 CH.sub.3 2-methoxyethyl 2-methoxyethyl 2,4-dimethoxyphenyl
 50 B.1 CH.sub.3 n-propyl n-propyl
 4,6-dimethyl-3-pyridinyl
 51 B.1 CH.sub.3 ethyl n-butyl
 4,6-dimethyl-3-pyridinyl
 52 B.1 CH.sub.3 n-propyl cyclopropylmethyl
 4,6-dimethyl-3-pyridinyl
 53 B.1 H n-propyl cyclopropylmethyl 6-(dimethylamino)-2,4-
 dimethyl-3-pyridinyl
 54 B.1 H n-propyl n-propyl 6-(dimethylamino)-
 2,4-dimethyl-3-pyridinyl
 55 B.1 H n-propyl 2-hydroxyethyl 2,4,6-trimethylphenyl
 56 B.1 H n-propyl CH.sub.3 COO(CH.sub.2).sub.2
 2,4,6-trimethylphenyl
 57 B.1 H n-propyl 2-hydroxypropyl 2,4,6-trimethylphenyl
 58 B.1 H n-propyl n-propyl 2,4,6-trimethylphenyl
 Co. Ex.
 No. No. R.sup.3 R.sup.4 and R.sup.5 taken together Ar
 59 B.1 H ##STR21## 2,4,6-trimethylphenyl
 60 B.1 CH.sub.3 ##STR22## 4-chlorophenyl
 TABLE 4
 ##STR23##
 Co. No. Ex. No. X R.sup.1 Ar
 6 B.2 S (CH.sub.3).sub.2 CH--O-- 2,4,6-trimethylphenyl
 7 B.3 SO.sub.2 (CH.sub.3 CH.sub.2 CH.sub.2).sub.2 N--
 2,4,6-trimethylphenyl
 TABLE 4
 ##STR24##
 Co. No. Ex. No. X R.sup.1 Ar
 6 B.2 S (CH.sub.3).sub.2 CH--O-- 2,4,6-trimethylphenyl
 7 B.3 SO.sub.2 (CH.sub.3 CH.sub.2 CH.sub.2).sub.2 N--
 2,4,6-trimethylphenyl
 TABLE 6
 Analytical data
 Co. No. Mass spectra data
 9 368 (M.sup.+)
 10 399 (M.sup.+)
 11 403 (M.sup.+)
 12 341 (M.sup.+)
 13 370 (MH.sup.+)
 14 441 (M.sup.+)
 15 342 (MH.sup.+)
 16 384 (MH.sup.+)
 17 370 (MH.sup.+)
 18 392 (MH.sup.+)
 19 371 (M.sup.+)
 20 357 (M.sup.+)
 21 327 (MH.sup.+)
 22 417 (M.sup.+)
 23 410 (MH.sup.+)
 24 326 (MH.sup.+)
 25 340 (MH.sup.+)
 26 398 (MH.sup.+)
 27 412 (MH.sup.+)
 28 426 (MH.sup.+)
 29 398 (MH.sup.+)
 30 412 (MH.sup.+)
 31 531 (MH.sup.+)
 32 559 (MH.sup.+)
 33 573 (MH.sup.+)
 34 475 (MH.sup.+)
 35 368 (MH.sup.+)
 36 337 (M.sup.+)
 37 382 (MH.sup.+)
 38 351 (M.sup.+)
 39 379 (M.sup.+)
 40 365 (M.sup.+)
 41 373 (M.sup.+)
 42 376 (MH.sup.+)
 43 397 (M.sup.+)
 44 425 (M.sup.+)
 45 369 (M.sup.+)
 46 385 (M.sup.+)
 47 410 (M.sup.+)
 48 --
 49 --
 50 368 (M.sup.+)
 51 368 (M.sup.+)
 52 380 (M.sup.+)
 53 409 (M.sup.+)
 54 397 (M.sup.+)
 55 372 (M.sup.+)
 56 --
 57 372 (M.sup.+)
 58 368 (M.sup.+)
 59 353 (M.sup.+)
 60 385 (M.sup.+)
 C. Pharmacological Examples
 EXAMPLE C.1
 Representative Compounds Having CRF Receptor Binding Activity
 Compounds were evaluated for binding activity to the CRF receptor by a
 standard radioligand binding assay as generally described by DeSouza et
 al. (J. Neurosci. 7:88-1000, 1987) by utilizing various radiolabeled CRF
 ligands, the assay may be used to evaluate the binding activity of the
 compounds of the present invention with any CRF receptor subtype. Briefly,
 the binding assay involves the displacement of a radiolabeled CRF ligand
 from the CRF receptor. More specifically, the binding assay was performed
 in 1.5 ml Eppendorf tubes using approximately 1.times.10.sup.6 cells per
 tube stably transfected with human CRF receptors. Each tube received about
 0.1 ml of assay buffer (e.g., Dulbecco's phosphate buffered saline, 10 mM
 magnesium chloride, 20 .mu.M bacitracin) with or without unlabeled
 sauvagine, urotensin I or CRF (final concentration, 1 .mu.M) to determine
 nonspecific binding, 0.1 ml of [.sup.125 I] tyrosine--ovine CRF (final
 concentration .about.200 pM or approximately the K.sub.D as determined by
 Scatchard analysis) and 0.1 ml of a membrane suspension of cells
 containing the CRF receptor. The mixture was incubated for 2 hours at
 22.degree. C. followed by the separation of the bound and free radioligand
 by centrifugation. Following two washes of the pellets, the tubes were cut
 just above the pellet and monitored in a gamma counter for radioactivity
 at approximately 80% efficiency. All radioligand binding data were
 analyzed using a non-linear least-square curve-fitting program. Binding
 activity corresponds to the concentration (nM) of the compound necessary
 to displace 50% of the radiolabeled ligand from the receptor. All
 compounds as listed in Tables 2-4 have a K.sub.i.ltoreq.250 nM. Compounds
 1, 2, 8, 10, 12-18, 20, 23, 34, 35, 37-41, 43, 48-56 were found to show
 the best score in this test.
 EXAMPLE C.2
 CRF Stimulated Adenylate Cyclase Activity
 The compounds of the present invention may also be evaluated by various
 functional testing. For example, the compounds of the present invention
 may be screened for CRF-stimulated adenylate cyclase activity. An assay
 for the determination of CRF-stimulated adenylate cyclase activity may be
 performed as generally described by Battaglia et al. (Synapse 1:572,
 1987), with modifications to adapt the assay to whole cell preparations.
 More specifically, the standard assay mixture may contain the following in
 a final volume of 0.5 ml: 2 mM L-glutamine, 20 mM HEPES, and 1 mM IMBX in
 DMEM buffer. In stimulation studies, whole cells with the transfected CRF
 receptors are plated in 24-well plates and incubated for 1 hour at
 37.degree. C. with various concentrations of CRF-related and unrelated
 peptides in order to establish the pharmacological rank-order profile of
 the particular receptor subtype. Following the incubation, the medium is
 aspirated, the wells rinsed once gently with fresh medium, and the medium
 aspirated. To determine the amount of intracellular cAMP, 300 .mu.l of a
 solution of 95% ethanol and 20 mM aqueous hydrochloric acid is added to
 each well and the resulting suspensions are incubated at -20.degree. C.
 for 16 to 18 hours. The solution is removed into 1.5 ml Eppendorf tubes
 and the wells washed with an additional 200 .mu.l of ethanol/aqueous
 hydrochloric acid and pooled with the first fraction. The samples are
 lyophilized and then resuspended with 500 .mu.l sodium acetate buffer. The
 measurement of cAMP in the samples is performed using a single antibody
 kit. For the functional assessment of the compounds, a single
 concentration of CRF or related peptides causing 80% stimulation of cAMP
 production is incubated along with various concentrations of competing
 compounds (10.sup.-12 to 10.sup.-6 M).
 D. Composition Examples
 The following formulations exemplify typical pharmaceutical compositions in
 dosage unit form suitable for systemic or topical administration to
 warm-blooded animals in accordance with the present invention. "Active
 ingredient" (A.I.) as used throughout these examples relates to a compound
 of formula (I), a N-oxide form, a pharmaceutically acceptable acid or base
 addition salt or a stereochemically isomeric form thereof.
 EXAMPLE D. 1
 Oral Solutions
 9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate are
 dissolved in 4 l of boiling purified water. In 3 l of this solution are
 dissolved first 10 g of 2,3-dihydroxybutanedioic acid and thereafter 20 g
 of the A.I. The latter solution is combined with the remaining part of the
 former solution and 12 l of 1,2,3-propanetriol and 3 l of sorbitol 70%
 solution are added thereto. 40 g of sodium saccharin are dissolved in 0.5
 l of water and 2 ml of raspberry and 2 ml of gooseberry essence are added.
 The latter solution is combined with the former, water is added q.s. to a
 volume of 20 l providing an oral solution comprising 5 mg of the A.I. per
 teaspoonful (5 ml). The resulting solution is filled in suitable
 containers.
 EXAMPLE D.2
 Capsules
 20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose, 0.8
 g colloidal silicon dioxide, and 1.2 g magnesium stearate are vigorously
 stirred together. The resulting mixture is subsequently filled into 1000
 suitable hardened gelatin capsules, each comprising 20 mg of the A.I.
 Example D.3
 Film-coated Tablets
 Preparation of Tablet Core
 A mixture of 100 g of the A.I., 570 g lactose and 200 g starch is mixed
 well and thereafter humidified with a solution of 5 g sodium dodecyl
 sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. The wet
 powder mixture is sieved, dried and sieved again. Then there are added 100
 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. The
 whole is mixed well and compressed into tablets, giving 10.000 tablets,
 each comprising 10 mg of the active ingredient.
 Coating
 To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanol
 there is added a solution of 5 g of ethyl cellulose in 150 ml of
 dichloromethane. Then there are added 75 ml of dichloromethane and 2.5 ml
 1,2,3-propanetriol. 10 g of polyethylene glycol is molten and dissolved in
 75 ml of dichloromethane. The latter solution is added to the former and
 then there are added 2.5 g of magnesium octadecanoate, 5 g of
 polyvinylpyrrolidone and 30 ml of concentrated colour suspension and the
 whole is homogenated. The tablet cores are coated with the thus obtained
 mixture in a coating apparatus.
 EXAMPLE D.4
 Injectable Solution
 1.8 g methyl 4-hydroxybenzoate and 0.2 g propyl 4-hydroxybenzoate were
 dissolved in about 0.5 l of boiling water for injection. After cooling to
 about 50.degree. C. there were added while stirring 4 g lactic acid, 0.05
 g propylene glycol and 4 g of the A.I. The solution was cooled to room
 temperature and supplemented with water for injection q.s. ad 1 l volume,
 giving a solution of 4 mg/ml of A.I. The solution was sterilized by
 filtration and filled in sterile containers.
 EXAMPLE D.5
 Suppositories
 3 Grams A.I. was dissolved in a solution of 3 grams
 2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400. 12 Grams
 surfactant and 300 grams triglycerides were molten together. The latter
 mixture was mixed well with the former solution. The thus obtained mixture
 was poured into moulds at a temperature of 37 to 38.degree. C. to form 100
 suppositories each containing 30 mg/ml of the A.I.