SUBSTITUTED NITROGEN CONTAINING SPIRO COMPOUNDS FOR USE IN TREATING COGNITIVE DEFICITS

Abstract: There are provided novel spirocyclic compounds of formula (I), or physiologically suitable salts thereof, wherein: X and Y are taken together to form a saturated or unsaturated carbocylic or heterocyclic first ring and the shown carbon in said ring is alpha to at least one additional aromatic ring or heteroaromatic ring fused to the first ring; Z is O, S, N-NH2, 2 hydrogen atoms, or H and OH; one of Het<1> or Het<2> is 2-, 3-, or 4-pyridyl, or 2-, 4-, or 5-pyrimidinyl and the other is selected from the group including: 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3- or 4-pyrazolyl, 2- or 3-tetrahydrofuranyl, and 3-thienyl; pharmaceutical compositions containing them and method of using them in mammals to treat cognitive deficiencies and/or neurological dysfunction and/or mood disturbances as found, for example, in degenerative nervous system diseases.

Description: Substituted Nitrogen Containing Spiro Compounds for Use in Treating Cognitive Deficits FIELD OF THE INVENTION This invention relates to novel spirocyclic compounds, pharmaceutical compositions containing them and methods of using them in mammals to treat cognitive deficiencies and/or neurological dysfunction and/or mood disturbances as found, for example, in degenerative nervous system diseases . BACKGROUND OF THE INVENTION Nervous system disorders cause cognitive and neurological deficiencies and are becoming more prevalent in today's society. Many of these disorders are age related and/or the direct result of degenerative changes in the nervous system. Specific neurological systems are often directly affected in the early stages of some diseases (e.g. cholinergic systems in Alzheimer's Disease and the dopamineregic system in Parkinson's Disease), while multiple neurotransmitter system deficiencies (acetylcholine, dopamine, seretonin, norepinephrine) are generally found at later stages of diseases such as senile dementia, multi-infarct dementia, Huntington's disease, etc. This may explain the generally observed symptomology including cognitive, neurological and effective/psychotic components (see Gottfries, Psychσpharmacol. ££, 245, 1985) . Deficits in the synthesis and release of acetylcholine in the brain are generally thought to be related to cognitive impairment (see Francis et al, New England J. Med. r 313, 7, 1985) . Recent treatment strategies for neurodegenerative diseases include vasoactive drugs like vincamine and pentoxifylline; "metabolic enhancers" like ergoloid mesylates, piracetam and naftidrofuryl; neurotransmitter precursors like -DOPA, choline and 5-hydroxytryptamine; metabolizing enzyme inhibitors like physostigmine; and neuropeptides like ACTH and vasopressin-related peptides. Another strategy is to enhance the residual function of the affected systems by enhancing the stimulus-induced release of neurotransmitters. Such an enhancement might improve the signal-to-noise ratio during chemical transmission of information, thereby reducing deficits in processes related to cognition, neurological function and mood regulation. Cook, If . , et al., Drug Development Research 19:301- 314 (1990), Nickolson, V.J., et al., Drug Development Research 19:285-300 (1990), and DeNoble, V. J., et al., Pharmacology Biochemistry & Behavior, Vol. 36, pp. 957-961 (1990) , all have shown by invitro testing that the drug DuP 996, 3.3-bis (4-pyridinylmethyl)-l-phenylindolin-2-one, is useful in the treatment of cognition dysfunction. Saletu, B., et al., Br. J. Clin. Pharmac. (1989), 28, 1-16, suggested that DuP 996 may exhibit indirect action or may have an active metabolite, and that three metabolites have been identified, a mono-N-oxide, a bis-oxide and a C- dealkylated alcohol. Chem._Abstracts 111(13) :108875p suggests that the following structure is one of the above named metabolites of Dup 996: Neither reference presented chemical data to support their hypothesis. European Patent Application 311,010, published April 12 1989, discloses that α,α-disubstituted aromatics or heteroaromatics of the formula: -2- SUBSTITUTE SH T or a salt thereof which are useful as cognition enhancers. U.S. Patent no. 4,760,083, issued to Myers et al. on July 26, 1988, discloses indolines of the following formula: which are useful for treatment of Cognitive deficiencies. The above references teach the necessity of hetero aryl groups for activity. Patent WO 91/01/306, Feb. 7, 1991 discloses oxindole derivatives of formula: useful for treating senile dementia, i.e. improving brain functions and activating and protecting brain metabolism. This reference only discloses imides and does not suggest alkyl or aryl substituted amides . EP415-102-A discloses a series of 1,3-dihydro-l- (pyridinylamino)-2H-indol-2-ones of formula: -3- that have analgesic, an iconvulsant, aαd/or_ emory enhancing activity and are useful in the treatment of Alzheimer's disease. This reference disclosed hydrazides and does not suggest alkyl or arly substituted amides. SUMMARY OF THE INVENTION Presently, it has been found that certain spirocyclic compounds can enhance the stimulus-induced release of neurotransmitters, specifically acetylcholine in nervous tissue, and thus improve processes involved in learning and memorization of an active avoidance task. More particularly, according to the present invention there are provided novel compounds of formula: or physiologically suitable salts thereof wherein: X and Y are taken together to form a saturated or unsaturated carbocylic or heterocyclic first ring and the shown carbon in said ring is α to at least one additional aromatic ring or heteroaromatic ring fused to the first ring; Z ±s 0, S, N-NH- 2 , 2 hydrogen atoms, or H and OH; and one of Het 1 or Het 2 is 2, 3, or 4-pyridyl, or 2, 4, or 5- pyri idinyl and the other is selected from the group including: 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3- or 4-pyrazolyl, 2- or 3- tetrahydrofuranyl, and 3-thienyl. -4- This invention also provides pharmaceutical compositions comprising a suitable pharmaceutical carrier and an effective amount of one..or more of the above- described compounds effective to treat cognitive or neurological dysfunction. Still further, this invention relates to a a method of treating cognitive or neurological dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of one or more of the above-described compounds. Preferred Embodiments Preferred compounds of this invention are those of the formula (I) wherein: X and Y are taken together to form: Z is 0 or 2 hydrogen atoms; and Het 1 and Het 2 are independently: 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 2-pyrazinyl, 3-, or 4-pyridazinyl, 3-, or 4- pyrazolyl, 2-, or 3-tetrahydrofuranyl, and 3- thienyl. More preferred compounds of this invention are those of the- above mentioned formula wherein, together or independently: X and Y are taken together to form, ■ 5- Z is 0 or 2 hydrogen atoms; and Het 1 and Het 2 are independently: 2-,3-, or 4-pyridyl, 2-,4-, or 5-pyrimidinyl, 2- pyrazinyl, 3— or 4— yridazinyl, 3- or 4- pyrazolyl, 2- or 3-tetrahydrofuranyl, and 3-thienyl. Specifically preferred compounds of the present invention are: 1*-PHENYL-2, -BIS(4-PYRIDINYL)-SPIRO( (CYCLOHEXANE-L ,3—((3H)-INDOLE) )-2~(1Η)-ONE; 2, 6-BIS(4-PYRIDINYL)-SPIROCYCLOHEXANE-1,5'- ((5H))CYCLOPENTA((2,l -B:3,4:B') )DIPYRIDINE; 2,6-BIS(4-PYRIDINYL)-TRANS-SPIROCYCLOHEXANE-1, 9'- (9H)-INDEN0 (1,2-B)PYRAZINE; 2,6-BIS(3-PYRIDINYL)-SPIROCYCLOHEXANE-1,5 r -( (5H) )- CYCLOPENTA( (2, 1-B:3,4-B ~ ) )DIPYRIDINE; 2,6-BIS(2-PYRIDINYL)-SPIROCYCLOHEXANE-,5'-( (5H) )- CYCLOPENTA( (2,1-B:3,4-B') )DIPYRIDINE; .2,6-BIS (2-PYRIMIDYL)-SPIROCYCLOHEXANE-1,5'-( (5H) )- CYCLOPENTA((2,1 - B:3,4-B'))DIPYRIDINE 2,6-BIS(2-PYRAZINYL)-SPIROCYCLOHEXANE-1,5—( (5H) )- CYCLOPENT ( (2,1-B:3,4-B') )DIPYRIDINE; 1'-PHENYL-2, 6-BIS(3-PYRIDINYL)-SPIRO((CYCLOHEXANE-1 ,3'-((3H)-INDOLE))-2' fl'H)-ONE; 1'-PHENYL-2, 6-BIS(2-PYRIDINYL)-SPIRO( (CYCLOHEXANE-1 ,3'-((3H)-INDOLE))-2' (1 Η)-ONE; l'-PHENYL-2,6-BIS(4-PYRIMIDYL)-SPIRO( (CYCLOHEXANE-1 ,3 r -( (3H)-INDOLE) )-2' (1Η)-ONE; -6- l'-PHENYL-2, 6-BIS(2-PYRAZINYL)-SPIRO( (CYCLOHEXANE-1 ,3'-( (3H) -INDOLE) )-2 ' (l'H)-ONE; 2,6-BIS(3-PYRIDINYL)-TRANS-SPIRO(CYCLOHEXANE-l, 9'- (9H)-INDENO (1,2-B)PYRAZIN) -4-0NE; 2,6-BIS(2-PYRIDINYL)-TRANS-SPIROCYCLOHEXANE-l,9'- (9H)-INDENO (1,2-B)PYRAZINE; 2,6-BIS(4-PYRIMIDYL)-TRANS-SPIROCYCLOHEXANE-l,9'- (9H)-INDENO (1,2-B)PYRAZINE; 2, 6-BIS (4-PYRAZINYL)-TRANS-SPIROCYCLOHEXANE-1, 9'- (9H)-INDENO (1,2-B)PYRAZINE; l'-PHENYL-2, 6-BIS(4-PYRIDINYL)-SPIRO( (CYCLOHEXANE-1 ,3'-( (3H) -INDOLE) )-2~, 4 (1~H)-DIONE; l'-PHENYL-2, 6-BIS(3-PYRIDINYL)-SPIRO( (CYCLOHEXANE-1 ,3'-( (3H) -INDOLE) )-2 ' ,4 (1Η)-DIONE; 1'-PHENYL-2, 6-BIS (2-PYRIDINYL)-SPIRO( (CYCLOHEXANE-1 ,3'-( (3H) -INDOLE) )-2 ' , 4 (l'H)-DIONE; l'-PHENYL-2, 6-BIS(4-PYRIMIDYL)-SPIRO( (CYCLOHEXANE-1 ,3— ( (3H) -INDOLE) )-2 ' ,4 (1 ~H)-DIONE; 1'-PHENYL-2, 6-BIS ( -PYRAZINYL)-SPIRO( (CYCLOHEXANE-1 ,3—( (3H)-INDOLE) )-2 ', 4 (l'H)-DIONE; 2, 6-BIS(4-PYRIDINYL)-SPIRO( (CYCLOHEXANE-1 ,5 '- ( (5H) ) CYCLOPENTA( (2, 1-B:3, 4-B' ) )DIPYRIDIN) )-4-ONE; 2,6-BIS(3-PYRIDINYL)-SPIRO( (CYCLOHEXANE-1 ,5'-( (5H) )- CYCLOPENTA( (2, 1-B:3, 4-B • ) )DIPYRIDIN) )-4-ONE; 2,6-BIS(2-PYRIDINYL)-SPIRO( (CYCLOHEXANE-1 ,5'-( (5H) )- CYCLOPENTA( (2, 1-B:3, 4-B' ) )DIPYRIDIN) )-4-ONE; 2,6-BIS(3-PYRIMIDYL)-SPIRO( (CYCLOHEXANE-1,5'-( (5H) )- CYCLOPENTA( (2, 1-B:3, 4-B' ) )DIPYRIDIN) )-4-ONE; 2, 6-BIS(3-PYRAZINYL)-SPIRO( (CYCLOHEXANE-1, 5'- ( (5H) )- CYCLOPENTA( (2, 1-B:3,4-B'))DIPYRIDIN) )-4-ONE; 2, 6-BIS(4-PYRIDINYL)—TRANS-SPIRO(CYCLOHEXANE-1 , 9'- (9H)-INDENO(1,2-B)PYRAZIN) -4-0NE; 2, 6-BIS(3-PYRIDINYL)—TRANS-SPIRO(CYCLOHEXANE-1 ,9'' (9H)-INDENO(1,2-B)PYRAZIN)-4-0NE; 2,6-BIS(2-PYRIDINYL)—TRANS-SPIRO(CYCLOHEXANE-1 ,9'' (9H)-INDENO(1,2-B)PYRAZIN) -4-0NE; 2,6-BIS(4-PYRIMIDYL)—TRANS-SPIRO(CYCLOHEXANE-1 ,9'' (9H)-INDENO(1,2-B)PYRAZIN)-4-0NE; -7- 2, 6-BIS (4-PYRAZINYL)—TRANS-SPIRO(CYCLOHEXANE-1 , 9'- (9H)-INDENO(1,2-B)PYRAZIN)-4-0NE; DETAILED DESCRIPTION OF INVENTION A general procedure for preparing compounds of formula (I) wherein Z is 0 is presented in Scheme 1. The procedure involves reacting a core group represented by formula (II) with a dienone of formula (III) in an inert solvent in the presence of a suitable base. This is a variation of the well known Michael Reaction. The core groups represented by formula (II) are either commercially available or may be prepared using methods and techniques well known to those skilled in the art. For example, the preparation of the diazafluorene core was described in US Patent Application, serial number 07/827,429, which is hereby incorporated by reference. The symmetrical dienenones are either commercially available or may be prepared using methods and techniques well known to those skilled in the art. For example, see Haller et al, Archiv Pharmazie. 12, 932, 1969, which is hereby incorporated by reference. The Michael Reaction described in Scheme 1 is a classic synthetic reaction and is well known by the skilled artisan. See, for example, H. 0. House, Modern Synthetic Reactions. 595-623 (2nd Edition 1972) and E. D. Bergmann et al., Organic Reactions, 10, 179 (1959) both of which are hereby incorporated by reference, which disclose numerous examples, reaction conditions, solvents, bases, and reactants. The reaction is typically run by generating an anion at the methylene carbon of the core group represented by formula (II) with a suitable base and treating this anion with the desired dienenone. For example, treatment of diazafluorene with a suitable base generates an anion at the 9-position. The reaction can be run in an aprotic or protic solvent. Preferred aprotic solvents include: tetrahydrofuran, diethylether, dimethylsulfoxide, dimethylformamide, glyme and diglyme. Preferred protic solvents include C1-C14 alcohols. The choice of solvent -8- S U BSTITUTESHEET will also determine the character of the base. For protic solvents the ideal base is Triton B. Where this base is used and the diazafluorene core is used, the diazafluorene and the dienone are premixed before adding the base. If the dienenone is not soluble in a protic solvent then an aprotic solvent like ether or tetrahydrofuran may be used. When this base is used and diazafluorene is the core group, the diazafluorene is pretreated with base and the dienenone is then added to the resulting mixture. The preferred base with aprotic solvents is sodium hydride. The procedure of Scheme 1 is typically run over the temperature range -50 to 150 °C, under a inert atmosphere, and is usually complete within 10 minutes to 24 hours. The preferred temperature range is 0 to 25 °C. The preferred atmosphere is nitrogen or argon. The preferred reaction time is 1-60 minutes. The reaction can easily be monitored by thin layer chromatography. The work up of the reaction generally involves pouring it into a saturated ammonium chloride solution and extracting the product with either chloroform or methylene chloride. The organic phase is then washed with brine, dried with an appropriate reagent (sodium sulfate, potassium carbonate or magnesium sulfate) and the solvent removed at reduced pressure to give a compound of formula (I) wherein Z is 0. The compound of formula (I) thus obtained may be further purified using flash chromatography and recrystallization. -9- SUBSTITUTESHEET Scheme 1 Compounds of formula (I) wherein Z is 0 are capable of elaboration ' into other compounds of formula (I) . For example, a variety of reactions can be carried out at the carbonyl carbon atom of the cyclohexanone moiety. Scheme 2 shows three reaction sequences that can be used to transform compounds of formula (I) wherein Z is 0. The first reaction shown in Scheme 2 is reduction of the carbonyl carbon atom to a methylene group. There are a number of methods to effect this transformation which are well known to those skilled in the art. Two typical methods are the Clemmensen reduction in which a carbonyl compound is reduced with Zn/HCl or Pb/sulfuric acid and the Wolf-Kishner Reduction in which a carbonyl compound is reduced with hydrazine. The Wolf-Kishner Reduction is the preferred method. H. 0. House, Modern Synthetic Reactions, 228 (2nd Edition 1972) and D. Todd, Organic Reactions, 4., 378 (1948), both of which are hereby incorporated by reference, disclose numerous examples, reaction conditions, solvents, bases , and reactants employed in this reduction. For compounds of formula (I) wherein Z is 0, the reduction reaction is typically carried out in ethylene glycol using an excess of hydrazine and a suitable base. The compound of formula (I) is treated with excess hydrazine at 25 °C. Then a base (sodium hydroxide) is added and the reaction heated to 170-185 °C. The reaction is monitored by thin layer chromatography and when complete is cooled to room temperature and poured into water. Extraction with methylene chloride and work up provides a residue that is -10- subjected to flash chromatography and recrystallization to afford a purified compound of formula (I) wherein Z is 2 hydrogen atoms. The second reaction shown in Scheme 2 is the Wittig olefination reaction. This reaction involves treating a compound of formula (I) wherein Z is 0 with a phosphonium ylide or a phosphinoxy carbanion to give a compound of formula (I) wherein Z is CH2- This well known reaction has been reviewed by H. 0. House, Modern Synthetic Reactions, 682 (2nd Edition 1972) and G. Wittig and A. Hesse, Org. Syn. 5_Q_, 66 (1970) both of which are hereby incorporated by reference. The preferred method utilizes a phosphonium ylide and is run in an aprotic solvent such as tetrahydrofuran or benzene at 0 °C. The reagent is generated from methyl triphenyl phosphonium bromide and a strong base such as potassium tert-butoxide although many bases can be used. The carbonyl compound is then added to an excess of the reagent and the reaction monitored by thin layer chromatography. Reactions usually take from 5-30 in and are quenched with acetone, diluted with ether and worked up to provide a residue that can be purified by flash chromatography to afford a purified compound of formula (I) wherein Z is CH2. The third reaction shown in Scheme 2 is treatment of a compound of formula (I) wherein Z is 0 with a reducing agent to afford a compound of formula (I) wherein Z is OH. A wide variety of methods are available to effect this reduction. Typical reducing agents are LiAlH.4 and ' NaBH.4, • although others are available. This reaction has been extensively reviewed. See, for example, H. 0. House, Modern Synthetic Reactions, 45 (2nd Edition 1972), N.G. Gaylord and Reduction With Complex Metal Hydrides. (Wiley- Interscience, New York, 1956) which are both hereby incorporated by reference. The preferred method for preparation of compounds of formula (I) wherein Z is OH utilizes sodium borohydride as the reducing agent. In carrying out the reduction, the compound of formula (I) wherein Z is 0 is dissolved in methanol and cooled to 0 °C. -11- SUBSTtTUTESHEET The reducing agent is usually added in several portions and the reactions are usually fast. The reaction can be monitored by thin layer chromatography and upon completion the methanol is evaporated to facilitate isolation of the product. The residue is partitioned between aqueous dilute sodium hydroxide and ether or ethyl acetate. After usual workup, the residue can be purified by chromatography and recrystallization to afford a purified compound of formula (I) wherein Z is OH. -12- Scheme 2 (I), wherein Z is O Reducing Agent Wittig Reagent Reducing Agent (I), wherein (I), wherein (I), wherein Z is2H Zis CH 2 Zis H. OH EXAMPLES The invention can be further understood by the following examples in which parts and percentages are by weight unless otherwise indicated; all temperatures are in degrees centigrade. Tetrahydrofuran is referred to as (THF) . ■ 13- Example 1 - Method A 2, 6-BIS (4-PYRIDINYL)-SPIRO( (CYCLOHEXANE-1,5'- ( (5H) )CYCLOPENTA( (2, 1-B:3,4-B') )DI-PYRIDIN) )-4-ONE The reaction was carried out under an atmosphere of dry nitrogen. A mixture of 4,5-diazafluorene (0.78 g) and 1,5-(4-pyridyl)-1,4-pentadienone (1.1 g) in 8.5 mL methanol:tetrahydrof ran (1:1) was treated with a 40% solution of Triton B in methanol (0.2 mL) and stirred at 25 °C for 1 lir. The mixture was then poured into saturated ammonium chloride solution (50 mL) and extracted with chloroform (3 x 75 mL) . The organic layer was separated, dried (sodium sulfate) and the solvent removed at reduced pressure. The residue was subjected to flash chromatography (silica, 10% methanol in methylene chloride) to give the desired product as a white solid (1.3 g, 70%) . m.p. 260-261 °C. TLC R f = 0.35 (silica, 10% methanol in methylene chloride) . Example 1 - Method B The reaction is carried out under an atmosphere of dry nitrogen. 4,5-diazafluorene (50 mg) in 5 ml dry THF is treated with sodium hydride (10 mg, 60% suspension in oil) in three portions at 25 °C. After 5 min 1,5-(4-pyridyl)- 1,4—pentadienone (70 mg) in 2 ml THF is added dropwise over 2 min. After 15 min. the reaction is quenched with methanol and worked up using the same procedure as in method A. The residue was subjected to flash chromatography (silica, 10% methanol in methylene chloride) to give the desired product as a white solid (70 mg, 60%) . m.p. 260-261 °C. TLC R f = 0.35 (silica, 10% methanol in methylene chloride) . -14- 2, 6-BIS(3-PYRIDINYL)-SPIRO( (CYCLOHEXANE-1,5'- ( (5H) )- CYCLOPENTA( (2, 1-B:3, 4-B' ) )DIPYRIDIN) )-4-ONE Using the procedure of Example 1, the title compound was prepared from 1, 5- (3-pyridyl)-1, 4-pentadienone in a yield of 64%. m.p. 284-286 °C. 2, 6-BIS (2-PYRIDINYL)-SPIRO( (CYCLOHEXANE-1, 5'- ( (5H) )- CYCLOPENTA( (2, 1-B:3, -B' ) )DIPYRIDIN) )-4-ONE Using the procedure of Example 1, the title compound was prepared from 1, 5-(2-pyridyl)-1, 4-pentadienone in a yield of 75%. m.p. 236-237 °C. -15- SUBSTITUTESHEET Example 4 2, 6-BIS( (4-FLUOROPHENYL) )-SPIRO( (CYCLOHEXANE-1,5'- ( (5H) )CYCLOPENTA( (2, 1-B:3,4-B') )DIPYRIDIN) )-4-ONE Using the procedure of Example 1, the title compound was prepared from 1,5-(p-flurophenyl)-1,4—pentadienone in a yield of 80%. m.p. 130-140 °C (glass) . Example 5 2, 6-BIS( (4-(DIMETHYLAMINO)-PHENYL) )-SPIRO( (CYCLOHEXANE- l,5'-( (5H) )CYCLOPENTA( (2,1-B:3, -B « ) )DIPYRIDIN) )-4-ONE Using the procedure of Example 1, the title compound was prepared from 1, 5-(p-N,N-dimethylaminophenyl)-1,4- pentadienone in a yield of 85%, as an amorphous solid. -16- Example 6 4-METHYLENE-2, 6-BIS (4-PYRIDINYL)-SPIRO( (CYCLOHEXANE-1, 5'- ( (5H) )CYCLOPENTA( (2, 1-B:3, 4-B' ) )DIPYRIDINE The reaction was carried out under an atmosphere of dry nitrogen. Methyl triphenylphosphonium bromide (130 mg) suspended in 2 ml dry THF was cooled to 0 °C and treated with potassium tert-butoxide (36 mg) in three portions. The reactions turns bright yellow and is allowed to stir for 20 min. A solution of the compound of Example 1 (100 mg) in 2 ml THF was added to this mixture dropwise over 1 min. The reaction was stirred at 0 °C for 30 min. and then quenched with acetone (0.5 ml) . The reaction is poured into water (30 ml) , extracted with chloroform (2 X 40 ml) , the organic layer separated, dried (MgS0 4 ) and the solvent removed at reduced pressure. The residue was subjected to flash chromatography (silica, 10% methanol in methylene chloride) to give the desired olefin as a white solid (30 mgr, 33%) . m.p. 323-324 °C. TLC R f = 0.46 (silica, 10% methanol in methylene chloride) . -17- Example 7 2,6-BIS(4-PYRIDINYL)-SPIRO( (CYCLOHEXANE( (1,5'-( (5H) )- CYCLOPENT ( (2,1-B:3 r 4-B' ) )DIPYRIDIN) )-4-OL The reaction was carried out under an atmosphere of dry nitrogen. The compound of Example 1 (50 mg) dissolved in 2 ml methanol was cooled to 0 °C and treated with sodium borohydride (10 mg) in one portion. After 30 min. the reaction was quenched with one drop of acetic acid. The solvent was removed at reduced pressure and the residue taken up in chloroform (10 ml) , washed with 1 N sodium hydroxide (5 ml) , the organic layer separated, dried (MgSθ4) and solvent removed at reduced pressure. Residue recrystallized from ethyl acetate. The alcohol is obtained as a white solid (41 mg, 80%) . m.p. 302-304 °C, TLC R f = 0.22 (silica, 10% methanol in methylene chloride) . -18- SUBSTITUTESHEET Example 8 2,6-BIS(4-PYRIDINYL)-SPIRO( (CYCLOHEXANE-1,5 '- ( (5H) )CYCLOPENTA( (2, 1-B:3, :B') )DIPYRIDINE Reaction carried out under an atmosphere of dry nitrogen. The cyclohexanone from Example 1 (50 mg) in 2 ml diglyme was treated with hydrazine (0.2 ml) in one portion. Then sodium hydroxide was added (20 mg) and the reaction was heated to 175 °C for 2 h. The reaction is cooled to 25 °C and poured into water (15 ml) , extracted with chloroform (3 X 30 ml), the organic layer separated, dried (MgSθ4) and the solvent removed at reduced pressure. The residue was subjected to flash chromatography (silica, 10% methanol in methylene chloride) to give the desired cyclohexane as a white solid (37 mg, 80%) . m.p. 335-337 °C. TLC R f = 0.39 (silica, 10% methanol in methylene chloride) . Example 9 2, 6-BIS( (PHENYL) )-SPIRO( (CYCLOHEXANE-1, 5'- ((5H) )CYCLOPENTA( (2, 1-B:3,4-B' ) )DIPYRIDIN) )-4-ONE Using the procedure of Example 1 the title compound was prepared from 1, 5-diphenyl-l, -pentadienone in a yield of 80% as an amorphous solid. -19- SUBSTITUTESHEET The compounds of examples 1—9, and other compounds which can be prepared by the above methods, are illustrated by the structures represented in Table 1. The table is intended to illustrate the invention, but not to limit its breadth . -20- Table 1 11 ■ CO 2 Me ■ CO 2 Me o -21- SUBSTITUTE SHEET Table 1 continued Ex. m.p. °C 21 -Q 22 -9 23 N 24 N N -22- Example 27 1 '-PHENYL-2, 6-BIS (4-PYRIDINYL)-SPIRO( (CYCLOHEXANE-1,3 '- ( (3H)-INDOLE) )-2 ' ,4 (l'H)-DIONE The reaction was carried out under an atmosphere of dry nitrogen. A mixture of l-phenylindolin-2-one (150 mg.) and 1, 5- (4-pyridyl)-1, 4-pentadienone (170 mg) in 3.5 mL methanol:tetrahydrofuran (1:1) was treated with a 40% solution of Triton B in methanol (0.2 mL) and stirred at 25 °C for 1 hr. The mixture was then poured into saturated ammonium chloride solution (10 mL) and extracted with chloroform (3 x 15 mL) . The organic layer was separated, dried (sodium sulfate) and the solvent removed at reduced pressure. The residue was subjected to flash chromatography (silica, 10% methanol in methylene chloride) to give the desired product as a white solid (200 mg, 70%) . m.p. 210- 211 °C. TLC R f = 0.55 (silica, 10% methanol in methylene chloride) . Example 27, and other compounds which can be prepared by the above methods, are illustrated by the structures represented in Table 2. The table is intended to illustrate the invention, but not to limit its breadth. -23- Table 2 Ex. m.p. Q C 27 -Q -o 210-211 28 -Q \=N 29 -O N= -24- SUBSTITUTE SHEET -25- 2,6-DIPHENYL-TRANS-SPIRO(CYCLOHEXANE-1, 9'-(9H)-INDENO(1,2- B)PYRAZIN)-4-ONE The reaction was carried out under an atmosphere of dry nitrogen. A mixture of 1,4-diazafluorene (100 mg) and bisbenzylidene acetone (140 mg) in 0. mL ethanol was treated with a 40% solution of Triton B in methanol (0.2 mL) and stirred at 25 °C for 1 hr. The mixture was then poured into saturated ammonium chloride solution (10 mL) and extracted with chloroform (3 x 15 mL) . The organic layer was separated, dried (magnesium sulfate) and the solvent removed at reduced pressure. The residue was subjected to flash chromatography (silica, 30% ethyl acetate in hexanes ) to give the desired product as a white solid (210 mg, 88%) . m.p. 169.5 °C. TLC R f = 0.5 (silica, 50% ethyl acetate in hexanes ) . Example 61 and other compounds which can be prepared by the above methods, are illustrated by the structures represented in Table 3. The table is intended to illustrate the invention, but not to limit its breadth. -26- SUBSTITUTESHEET 60 169 61 ,CN ,CN 62 63 • CO 2 Mθ -CO 2 Me o -27- Table 3 continued Ex. m.p. °C 71 -o 72 - ? -28- -29- Utility Section The compounds of this invention and their pharmaceutically acceptable salts can enhance the stimulus- induced release of neurotransmitters, specifically acetylcholine in nervous tissue, and thus improve processes involved in learning and memorization of an active avoidance task. These compounds are useful for treating cognitive deficiencies and/or neurological dysfunction and/or mood disturbances as found, for example, in degenerative nervous system diseases. Biochemical Test Procedure The compounds effect on acetylcholine release (ACh) from rat cerebral cortex slices was tested using a slice superfusion technique described by Miller et al, Brain Res . , 70, 372 (1974) , as modified according to Nickolson et al, Uaunyn Schmied. Arch. Pharmacol.. 212., 48, (1982) . Male Wistar rats (Charles River) weighing 175-200 grams were used. They were housed for seven days before the experiment under a 12-12 hour light/dark cycle. They had ad lib access to standard rat chow (Purina) and deionized water. Rats were decapitated and brains were dissected immediately. Slices, 0.3 mm thick, from parietal cortex were prepared manually using a recessed Lucite guide and subsequently cut into squares (0.25 x 0.25 mm, average weight 100 mg) . Slices were incubated in 10 ml Krebs- Ringer medium containing (mM) : NaCI (116), C1 (3), CaCl2 (1.3), MgCl 2 (1.2), KH 2 P0 4 (1.2), Na 2 S0 4 (1.2), NaHC0 3 (25), glucose (11), to which 10 μCi 3 H-Choline (spec. act. approx. 35 Ci/mmol; NEN) and 10 mmoles unlabeled choline had been added to give a final concentration of 10~ 6 M. Incubation was carried out for 30 minutes at 37 °C under a steady flow of 95% 02/5%C02- Under these conditions part of the radioactive choline taken up is converted to radioactive acetylcholine by cholinergic nerve endings, stored in synaptic vesicles and released upon depolarization by high K + -containing media. After ACh stores labeling, the slices were washed 3 times with non-radioactive KR-medium and transferred to a -30- superfusion apparatus to measure the drug effects on ACh release. The superfusion apparatus consisted of 10 thermostated glass columns of 5 mm diameter provided with GF/F glass fiber filters to support the slices (approximately 10 mg tissue/column) . Superfusion was carried out with KR-medium (0.3 ml/min) containing 10 -5 M hemicholinium-3 (HC-3) . This prevents choline uptake, formed during the superfusion from phospholipids and released ACh, which would be converted into unlabeled ACh and released in preference to the preformed, labelled ACh. The medium was delivered by a 25-channel peristaltic pump and warmed to 37 °C in a thermostated stainless steel coil before entering the superfusion column. Each column had a 4-way slider valve allowing rapid change of low to high K + - KR-medium and with two 10-channel, 3-way valves used to change from drug-free to drug-containing low and high K + - KR-medium. _ After a 15 minute washout of non-specifically bound radioactivity, 4 minute fraction collection began. After three 4-minute collections, the KR medium was changed for KR-medium of which the KC1 concentration was increased to 25mM (high K + -KR-medium) (SI) . Depolarization-induced stimulation of release by high K + -KR-medium lasted 4 minutes. Drug free low and high K + -KR-medium were then substituted by drug or vehicle containing low and high K + - KR-medium and superfusion continued for three 4-min. collections with low K + -KR-medium, one 4-min. collection with high K + -KR-medium (S2) and two 4-min. collections with low K + -KR-medium. Drug was added to the medium by 100-fold dilution of appropriate concentrations (in 0.9% NaCl/H 2 0) with either low or high K + -KR-medium. All superfusion fractions were collected in liquid sintillation vials . After superfusion, slices were removed from the columns and extracted in 1 ml of 0.1 N HCl. To these fractions and extracts was added 12 ml Liquiscint counting fluid (NEN) and samples counted in a Packard Tricarb Liquid Scintillation Counter. No corrections made for quenching. -31- SUBSTITUTESHEET The S2/S1 ratio (compared to controls were no drug was present during S2)was a measure of the drug to enhance or depress stimulus-induced ACh release. The jLn vitro ACh release data is summarized in Table . Table 4 % INCREASE OF STIMULUS-INDUCED ACh RELEASE IN RAT CEREBRAL CORTEX IN VITRO Daily dosage ranges from 1 mg to 2000 mg. Dosage forms (compositions) suitable for administration ordinarily will contain 0.5-95% by weight of the active ingredient based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions; it can also be administered parenterally in sterile liquid dosage forms. Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, * starch, cellulose derivatives, magnesium stearate, stearic acid r and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for -32- SUBSTITUTESHEET continuous release of medication over a period of hours . Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol . Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field. -33- SUBSTITUTESHEET

Claims: WE CLAIM: 1. compounds of formula : (i) or physiologically suitable salts thereof, wherein: X and Y are taken together to form a saturated or unsaturated carbocylic or heterocyclic first ring and the shown carbon in said ring is α to at least one additional aromatic ring or heteroaromatic ring fused to the first ring; Z is 0, S, N-NH 2 , 2 hydrogen atoms, or H and OH; one of Het 1 or Het 2 is 2-, 3-, or 4-pyridyl, or 2-, 4—, or 5- pyrimidinyl and the other is selected from the group including: 2—, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3- or 4-pyrazolyl, 2- or 3— tetrahydrofuranyl, and 3-thienyl. -34- SUB S TITUTESHEET 2 . The compound of formula ( I ) wherein : X and Y are taken together to form : Z is O or 2 hydrogen atoms; and Het 1 and Het 2 are independently: 2-, 3-, or 4-pyridyl, 2- , 4-, or 5-pyrimidinyl, 2-pyrazinyl, 3-, or 4-pyridazinyl, 3-, or 4- pyrazolyl, 2-, or 3-tetrahydrofuranyl, and 3- thienyl. 3. The compound of formula (I) wherein: X and Y are taken together to form Z is 0 or 2 hydrogen atoms; Het 1 and Het 2 are independently : 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 2- pyrazinyl, 3- or 4-pyridazinyl, 3- or 4- pyrazolyl, 2- or 3-tetrahydrofuranyl, and 3-thieriyl . -35- SUBSTITUTE SHEET 4. The compound of Claim 1 which is l ' -PHENYL-2, 6-BIS (4- PYRIDINYL) -SPIRO ( (CYCLOHEXANE-L , 3 — ( ( 3H) -INDOLE) ) - 2- (l ' H) -ONE . 5 . The compound of Claim 1 which is 2 , 6-BIS (4- PYRIDINYL) -SPIROCYCLOHEXANE-1, 5 ' - U5H))CYCLOPENTA((2,1 -B:3,4:B'))DIPYRIDINE. 6. The compound of Claim 1 which is 2,6-BIS(4- PYRIDINYL)-TRANS-SPIROCYCLOHEXANE-1, 9'-(9H)- INDENO(1,2-B)PYRAZINE. 7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 1. 8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 2 . 9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 3. 10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim . 11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 5. -36- 12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 6. 13. A method of treating a cognitive or neurological disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Claim 1. 14 A method of treating a cognitive or neurological disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Claim 2. 15. A method of treating a cognitive or neurological disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Claim 3. 16. A method of treating a cognitive or neurological disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Claim 4. 17. A method of treating a cognitive or neurological disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Claim 5. 18. A method of treating a cognitive or neurological disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Claim 6. -37- SUBSTITUTESHEET

Inventors: ABELMAN MATTHEW MARK, BRITTELLI DAVID ROSS, NUGIEL DAVID ALAN, VOSS MATTHEW ERNST, ABELMAN, MATTHEW, MARK, BRITTELLI, DAVID, ROSS, NUGIEL, DAVID, ALAN, VOSS, MATTHEW, ERNST
Applicants: DU PONT MERCK PHARMA, THE DU PONT MERCK PHARMACEUTICAL COMPANY
Application year: 1993
Main classification: C07D471
IPC codes: A61K31, A61P25, C07D209, C07D241, C07D401, C07D403, C07D405, C07D409, C07D471