TRICYCLIC VASOPRESSIN ANTAGONISTS

Abstract: Tricyclic diazepines of Formula (I) wherein A, B, D, E, F, Y, and Z are defined in the specification which compounds have vasopressin and oxytocin antagonist activity.

Description: . tie: TRICYCLIC VASOPRESSIN ANTAGONISTS 1. Field cf the Inven xcr. This invention relates tc new tricyclic non- peptide vasopresεin antagonists which are useful in treating conditions where decreased vascpreεsin levels are desired, such as in congestive heart failure, in disease conditions with excess renal water reabscrpcicπ and in conditions with increased vascular resistance and coronary vasoconstriction. 2. Background of the Invention Vasopresεin is released from the posterior pituitary either in response to increased plasma osmolarity detected by brain os creceptors cr decreased blood volume and blood pressure sensed by low-pressure volume receptors and arterial baroreceptors . The hormone exerts its action through two well defined receptor subtypes: vascular V " ι and renal epithelial V " 2 receptors. Vasopresεin-induced ar.tidiuresis, mediated by renal epithelial V2 receptors, helps to maintain normal plasma osmolarity, blood volume and blood pressure. Vasopressin is involved in some cases of congestive heart failure where peripheral resistance is λ increased. V " ι antagonists may decrease systemic vascular resistance, increase cardiac output and prevent vaεopressin induced coronary vasoconεtriction. Thus, in conditions with vasopressin induce increases in total peripheral resistance and altered local blood flow, V-_- antagoniεts may be therapeutic agents. V " ι antagonists may decrease blood pressure, induced hypotensive effects and thus be therapeutically uεeful in treatment of seme types of hypertension. The blockage of V " 2 receptors is useful in treating diseases characterized by excess renal reabsorption of free water. Ar.cidiuresis is regulated by the hypoth iamic release cf vascpreεεin (antidiuretic hormone) which binds tc specific receptors cn renal collecting tubule cells. This binding stimulates adenylyl cyclaεe and promotes the cAMP-mediate incorporation of water pores into the luminal surface cf these cells. V " 2 antagonists may correct the fluid retention in congestive heart failure, liver cirrhosis, nephritic syndrome, central nervous system injuries, lung disease and hyponatremia. Elevated vaεopressin levels occur in congestive heart failure which is more common in cider patients with chronic heart failure. In patients with hyponatremic congestive heart failure and elevated vasopresεin levels, a \ * 2 antagonist may be beneficial in promoting free water excretion by antagonizing the action of antidiuretic hormone, On the basis cf biochemical and pharmacological effects of the hormone, antagonists of vasopresεin are expected to be therapeutically uεeful in the treatment and/or prevention of hypertension, cardiac insufficiency, coronary vascspasm, cardiac ischemia, renal vasospaεm, liver cirrhoεis, congestive heart failure, nephritic syndrome, brain edema, cerebral ischemia r~ c* _-* c*=^r*.1v-<_"._ hemorrhage-stroke, thrombosis-bleeding and abnormal states of water retention. The following prior art references describe peptide vasopreεεin antagonists: M. Manning et al . , J_. Mgd. Chem.. 3.5, 382(1992) ; M. Manning et al . , J. Med. Che .. 2 i 3895(1992) ; H. Gavras and E. Lammek, U.S. Patent 5,070,187 (1991) ; _ ■■ :. Manning and W.H. Sawyer, U.S. Patent 5,055,448(1991) F.E. Ali, U.S. Patent 4,766,108(1988); R.R. Ruffolo et al . . Druσ News and Perspective, 4(4), 217, (May) (1991) . P.D. Williams et al . , have reported cn potent hexapeptide oxytocin antagonists [J . Med. Chem. , 35 , 3905(1992)] which also exhibit weak vascpreεsin antagonist activity in binding to V ' ι and ' 2 receptors. Peptide vaεcpressin antagonists suffer from a lack cf oral activity and many of these peptides are not selective antagonists since they alεo exhibit partial agcnist activity. Non-peptide vascpreεεin antagonists have recently been diεcloεed, Y. Yamamura et al . , Science, 252. 579(1991); Y. Yamamura et al . , ≡r. J. Pharmacol. 105 , 787(1992); Ogawa et al . , (Ctsuka Pharm Co., LTD.) E? 0514667-Al; EPO 382IS5-A2; W091C554S and U.S.5, 258, 510; WO 9404525 Ya ancuchi Pharm.Cc ., td. , WO 9420473; WO 9412476; WO 9414795; Fujisawa Cc. Ltd., EP 620216-A1 Ogawa et al, (Otεuka Pharm.. Cc . ) E? 470514A disclose carbostyril derivatives and pharmaceutical co poεitionε containing the same. Non-peptide oxytccm and vaεopressin antagonist have been discloεed by Merck and Co.; M.G. Bock and P.D. Williams, EP 0533242A; M.C-. Bock et al., EP 0533244A; J.M. Erb, E.F. Verber, P.D. Williams, EP 0533240A; K. Gilbert et al. , EP 0533243A. Premature birth can cause infant health problems and mortality and a key mediator in the mechanism of labor iε the peptide hormone cxycccin. Cn the baεiε of the pharmacological action cf cxyccci , antaσonistε of thiε normone of preterm labor, B.E. Evans et al. , J. Med. Chem. 35, 3919(1992), J. Med- Chem.. 3_6, 3993(1993) and references therein. The compoundε of this invention are antagonistε of the peptide hormone oxytocin and are useful in the control of premature birth. The present invention relates to novel tricyclic derivatives which exhibit antagonist activity at Vi and/or V2 receptors and exhibit in vivo vasopressin antagonist activity. The compoundε alεo exhibit antagoniεt activity at oxytocin receptorε. SUMMARY OF THE INVENTION This invention relates to new compoundε selected from those of the ceneral fcrmula I: FORMULA I wherein Y " is a moiety selected rcr.; -(CH2)n~ wherein n is an integer 0 cr 1, and A-Ξ is a oiety selected from «>y-N- and —N N ~ -"(CK j )m '3 R wherein m is an integer from 1 to 2; and the moiety: 3 represents: (1) phenyl or substituted phenyl optionally substituted by one or two substitutents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3) lower alkoxy or (C1-C3) lower alkylamino; (2) a 5-membered aromatic (unsaturated) heterocvclic ring having one heteroatom εelected from 0, N or S, * (3) a 6-membered aromatic (unεaturated) heterocvclic ring having one nitrogen; (4) a 5 or 6-membered aromatic (unsaturated) heterocvclic ring having two nitrogen atoms; (5) a 5-membered aromatic (unεaturated! heterocvclic ring having cne nitrogen atom together with either one oxygen cr one sulfur atom; wherein the 5 cr 6-membered heterocvclic ringε are optionally substituted by (C1-C3)lower alkyl, halogen or (C1-C3) lower alkoxy; the moiety: iε a five membered aromatic(unεaturated) nitrogen containing heterocyclic ring wherein D, E and F are εelected from carbon cr nitrogen and wherein the carbor atomε may be optionally substituted by a substituent εelected from halogen, {C 3. -C3) lower alkyl, hydroxy, -COCI3, -COCF3, ■ C-O — lower alkyKO.-C 8 ) t — (C^) q -0- lower a!kyl(C C 3 ) , -(CH,) — OH O C — lower alky l(C 1 - -CHO, amino, (C1-C3) lower alkox-y and (C1 . -C3) lower alkylaminc, -CONH- (C1 . -C3) lower alkyl (C1-C3 ) , -COK.iowe: alkyl (C1-C3 ) ] 2; Q is one or twc; Rb iε independently εelected from hydrogen, -CH3 and -C2H5; R3 iε a moiety of the formula: -C-Ar wherein Ar iε wherein R^ iε εelected from wherein L iε 0, S, SO, Sθ2, -CQ- -CH2-, K' is CH or N; X iε 0, Ξ, N-lowεr alkyl (C1-C3) and w ' iε εelected from 0, S, NH, N-lower alkyl (C1-C3) and N-benzyl,- R 4 is selected from hydrogen, lower alkyl (C1-C3) , -C0- lower alkyl (C1-C3) ; R 1 and R2 are selected from hydrogen, (C1-C3) lower alkyl, (C1-C3) lower alkoxy and halogen; R5 is selected from hydrogen, lower alkyl (C1-C ) , lower alkoxy(C1-C3) -0-CH2*-CK=CH2 and halogen; R 7 iε selected from hydrogen, lower alkyl . (C1 . -C ) , halogen, 0-iower alkyl (C1-C3) and CF3; R s and R 5 are independently εelected from hydrogen, lower alkyl (C1-C3 ) , -Ξ-iower alkyl (C1-C3 ) , halogen, -NH-lower alkyl (C1-C3 ) , -N- [lower alkyl (Ci-C3)]2- -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, 0_ lower alkyl (C1-C3) , CO-lower alkyl(C1-C3) and CF3,* and the pharmaceutically acceptable salts thereof. n.-.TAILED DESCRIPTION OF THE INVENTION Within the group of compounds defined by Formula I certain subgroups of compounds are broadly preferred. Broadly preferred are those compounds wherein R**- is the moiety: —C-Ar ■nd Ar iε εelected from the moiety wherein R-, ? and ' .'' are as hereinbefore defined, Especially pr; .erred are compounds wherein R- the moiety —C-Ar and Ar iε εelected from the moiety R b is wherein K\ X, L, R 5 , R 7 - R ε and R- ε hereinbefore defined. Alεo especially preferred are compounds where Y in Formula I is -(CH2)π~ r -i n s ze- or one; A-Ξ iε -<αy n - -rf or rf—N N——(CH,)m and K', X, L, R 3 , R 5 , R β , R ~ , R δ , and R 9 are as hereinbefore defined and m iε an integer from 1-2. The most preferred cf the compoundε of Formula I are thoεe wherein Y iε -(CH2)rr and n iε one; A-B is R- .ε a mo etv —C-Ar and Ar is εelected from the moiety lb wherein K' , X, L, R- , F.', P. 3 and R- are as hereinbef- defined. The most highly broadly preferred cf the compcundε cf Formula I are those wherein Y " is -(CI--2-: and n is one cr zero; wherein the moietv iε a phenyl, εubεtituted phenyl, thiophene, furan, pyrrole or pyridine ring; t t m iε one when n is one and m iε two when n iε zero; D, E, F, K\ L, X, R 3 , R 5 , R β , R 7 , R 8 , and R 5 are aε previously defined; Eεpecially preferred are compoundε wherein P. 3 is the moiety —C-Ar and Ar is selected from the moietv p.σ τ_ £ wherein K', L, X, R*^, R 7 , R^ and ? are aε hereinbefore defined. The especially preferred of the compounds cf Formula I are those wherein Y is -(CH2)n _ *=* r ^ n iε one; A-B is —CH—N-rf or rf-N—CH^ 1 % R- 5 is a moiety —C-Ar and A.r is selected from the moiety wherein K' , X, L, ? , R 7 , R^ and P.- are as hereinbefore defined. More particularly preferred are compoundε of the formulae: /3 wherein the moiety: is selected from a phenyl, thiophene, furan, pyrrole o: pyridine ring; wherein R 3 iε the moietv o II —C-Ar and Ar is selected from the moietv R 6 is IH wherein K', 1, X, R-, R', R fc and R- are aε hereinbefore defined. Aiεo particularly preferred are ccmpoundε cf the ormulae*. wherein m is two; and the moiety is selected from a phenyl, thiophene, furan, pyrrcle o: pyridine ring; /5 wherein R 3 is the moietv —C-Ar and Ar is selected from the moiety P." is wherein K', L, X, R-" 1 , R 7 , R*- 5 and F.9 are aε hereinbefore defined. More particularly preferred are compoundε of the formulae: and U, wherein R 3 iε the moiety —C-Ar and Ar iε εelected from the moiety R D i< wherein K', L, X, X, R 7 , R° and P.-' are aε hereinbefore defined. Alεo particularly preferred are compoundε of the formulae: /7 wherein R 3 is the moiety —C-Ar and Ar is selected from the moiety R b is m is two; wherein K',L, X, P.-* 1 , R 7 , R^ and P 9 are as hereinbefore defined. More particularly preferred are compounds of the formulae: 1% w τ herein the moiety : is selected from a phenyl, thiophene, furan, pyrrole c: pyridine ring; wherein P.* 3 iε the moiety o II —C-Ar ana r selected from the moietv P. b is J < f wherein K' , L, X, R 5 , R' , R 8 and R 5 are as hereinbefore defined. More particularly preferred are compoundε of the formulae: wherein R 3 is the moietv —C-Ar and A.r is εelected from the moiety R° is 10 wherein K', L, X, R 5 , P. 7 , R ε and R- are aε hereinbefore defined. Compoundε cf thiε invention may be prepared aε εhown in Scheme I by reaction of tricyclic derivativeε cf Formula la. and 3b wherein Z, Y, D, E, F and m are hereinbefore defined, with a substituted cr unsub¬ stituted 4-iodobenzoyl chloride 4a cr a substituted or unεubstituted-6-ioάopyridine-3-carbcnyi chloride b wherein R- and P.' are hereinbefore defined to give intermediates 5a. and _b. Reaction cf iε and .5b with tributvltin derivativeε J__a, 6b or 8c where P.- , R 7 , P. ε , ? , K', and X are hereinbefore defined affcrdε 7a. and 7b. 1/ 7a 7b Ϊ2. SCHEME I (CONT) Compounds of structural type .8a, .8b, and 8_c are prepared as εhown in Scheme II from the ccrreεponding bromo starting materials 6_a, .6b, and 6_c wherein R-- 1 , R 7 , R ε , P.- 5 and K' and X are hereinbefore defined, by first reacting with butyl lithium followed by reaction with tri-n-butyltin chloride to give the desired tin compound 8a, 8b and 8c . A3 SCHEME 6a 8a 6b 8b £c 8_c Alternatively, aε εhown in Scheme III, the bromo derivateε a and J9b wherein A' , Z, Y", D, E, F, P.-, R 7 and m are hereinbefore defined (prepared by reaction of 3a. snd 2 with acid chloride 8d wherein R * --, R 7 and A' are hereinbefore defined) are reacted with tetra iε (tri- phenylphoεphine)palladium (C) and bis (tributvltin) in the presence of lithium chloride to give tin interme¬ diate 11a and lib. Further reaction cf the tributyl t n derivativeε 11a and lib with bromo derivatives 10a, 10b or 10c, wherein M' is bromo or iodo and K', X, R-- 1 , R 7 - F.8 and R° are hereinbefore defined, in the presence of tetrakistriphenylphoεphine palladium (0) giveε 12a and 12b. 2.5 SCHEME 2(r> SCHEME III (CONT) 11a 11b 12a 12b .2 " 7 As shown in Scheme IV, coupling of bromo derivative £a and ^b wherein Z, Y, D, E, F, A', R 5 , R 7 and m are hereinbefore defined, with tributyltin derivativeε 13a, 13b and 13c wherein R 5 , R 7 • R 8 , R- , K' and X are hereinbefore defined affords derivativeε 14a and 14b where the linking unit between the two aromatic ringε iε a methylene (-CH2-) group. The tributyltin derivativeε 13a, 13b and 13c are prepared by εtandard procedures described in the literature. *tf SCHEME IV A' is N 9a 9b 14a 14b SCHEME IV (CONT) 1 4a 14b Alterna ively, derivatives of structural type 14a and 14b may be prepared by coupling tributyltin derivatives of formulae 11a and lib with either bromomethyl or iodomethyl derivativeε cf formulae 15a, 15b and 15_c wherein R 5 , R 7 - P. 8 , R 9 , X and ' are 3i> hereinbefore defined and M' iε I or Br, as εhown in Scheme V. SCHEME V 11a 11b 3 Tributyltin compounds 13a. 13b and 13c wherein L i* -CH2- and K', X, R 5 , R 7 , R 8 and R 9 are hereinbefore defined are prepared by reaction cf tributyltin hydride with butyl lithium followed by reaction with bromomethyl derivativeε 15a, 15b or 15c wherein M' is bromine as shown in Scheme VI. SCHEMEVI 13a 13b 13c 3% Compoundε 17a and 17b of thiε invention wherein iε 0, S, SO, Sθ2* CO or -CK2- are preferrably prepared by reaction of the tricyclic diazepineε la. or 3b with preformed carboxylic acid units of formula 16a preferrably activated by formation of the acid chlorides 16b (Scheme VII) . SCHEME VII 17a 17b 3 Preformed carboxvlic acid units of formula 18a preferrably activated by formation of the acid chloride 18b and having the formula A' is CH or N wnere: d A' are hereinbefore defined and wherein Y. X X, R- , F. ■ , F. 8 and R- * - are hereinbefore defined are synthesized aε εhown in Scheme VIII by reaction cf U? where P.---* iε an appropriate removeabie carboxvlic acid blocking group (alkyl and benzyl) with tributyl tin compoundε 8_a, £b, and 8_c in the presence c: Pd(0) tc cive intermediate 20. 8a 8b 8 c SCHEME VIII 19 20 A' is CH or N SCHEMEIX 23 Bromination of 21 wherein F,~ , R 7 and P.**-**- 1 are hereinbefore defined, with N-bromoεuccinimide in the preεence of ultraviolet light giveε bromo intermediate 22 which is coupled with δa . , 8b_ and £c_ in the preεence of Pd(O) to give intermediates 22. wherein A' is CH cr N aε previously defined. Additional intermediates necessary fcr coupling to tricyclic derivativeε 3a. and 2_b wherein Z, Y, E, E, F, and m hereinbefore defined and having the 31 formula 25 . wherein R 5 , R°, R 7 < R8 R9 anc ^ R 12 are hereinbefore defined and iε are synthesized as shown in Scheme X. SCHEME X A' is CH or N 26a 26b 26c A.cetylene intermediates 26 , 26b and 26c wherein F.5, R 7 , R 8 and P.9 are hereinbefore defined, prepared from the corresponding aldehyde by reaction with carbon tetrabromide, and triphenyiphosphine in methylene chloride followed by butyl lithium are reacted with iodo intermediate 2i wherein R*-\ P. 7 and P.-*-* are hereinbefore defined in the preεence cf palladium (C) tc give 26a, 26b, 26c, where L iε 3% c≡c— - Further intermediates for coupling to tricyclic derivatives a and 2h where L iε 0 or S and wherein Z, Y, D, E, F, and are hereinbefore defined and having the formula 22, 21/ and 22 wherein R 5 , R 6 , R 7 and R 12 are hereinbefore defined are εynthesized aε εhown in Scheme XI. 3β SCHEME XI Reaction of 22. wherein A.', F.5 , p. 7 and R**- 2 are hereinbefore defined with εcdiu εalt 22 cr 2 in a suitable solvent such aε DMF giveε intermediates 22 and 31. Further reaction of derivative 22 v. * tn one mole cf 3-chloroperbenzoic acid giveε sulfoxide intermediate 32a and reaction with two moles of 3-chloroperbenzoic acid affords the sulfone intermediate 32b. Other useful intermediates fcr the preparation of compcundε of thiε invention wherein the connecting atom L iε an oxygen atom between aryl-L-heteroaryl, heteroaryl-L-aryl or heteroaryl-1-heteroaryl units aε exemplified in formulae 34a, 34b and 22 are prepared aε εhown in Schemes XII and XIII. The reactions are carried out in inert solvents such as N, -dimethyl- formamide, N,N-dimethylacetamide, l-methyl-2-pyrroli- dinone and the like where MK is a metal hydride εuch aε lithium, pctaεεiurr., and sodium, hydride. The reaction in Schemes XII and XIII may also be carried out by first forming the anionε of 33a. 33b and 22 hy reaction with an apprcpriate alkoxide such as potassium t-butoxide. i SCHEME XII A' is CH or N MH R 1 y;z SCHEME XIII 2 or 4 substituted (Cl, Br, F) MH 37 2 or 4 substituted 3 40a 40b Ht SCHEMEXIV.CONT) 40a 40b Compounds of thiε invention may be prepared aε shown in Scheme XIV by reaction of tricyclic derivativeε cf Formula 2___ and 2_b wherein Z, Y, D, E, F and m are hereinbefore defined, with acid chloride 22 wherein F- and W are hereinbefore defined to give intermediates 39a and 39b. Reaction cf 39a and 39b with tributyltin derivatives 2a, 8b cr c where 5 , R , R s , R s , K' and X are hereinbefore defined affordε 40a and 40b. SCHEME XV 42a 42b & SCHEME XV (CQNTi 42a 42b Alternatively, aε εhown in Scheme XV, the bromo derivateε 39a and 39b wherein W, Y, D, E, F, R-- , and m are hereinbefore defined are reacted with tetra- kiε (triphenylphoεphine)palladium (0) and biε (tributyl¬ tin) in the preεence of lithium chloride tc give tin intermediate 41a and 41b. Further reaction of the tributyl tin derivativeε 41a and 41b with bromo derivativeε 10a, 10b or 10c wherein M' iε bromo cr iodo and K' , X, P.5, P.8 and P.--* are hereinbefore defined, in Y the presence of tetrakistriphenylphosphine palladium (0) gives 42a and 42b. SCHEME XVI 39b 43a 43b SCHEME XVI (CONT) Aε εhown in Scheme XV_, coupling of bromo derivative 39a and 39b with tributyltin derivatives 13 , 13b and 13c affordε derivatives 4 a and 43b where the linking unit between the two aromatic ringε iε a methylene (-CH2-) group. The tributyltin derivatives 13a, 13b and 13c are prepared by standard procedures described in the literature. 4 SCHEME XVII Compounds of thiε invention may be prepared aε εhown i: Schemes XVII and XVI11 by reaction of wherein W, P.* and P. 1 *-- are hereinbefore defined by reaction with tributyltin derivatives 8a,, 2b/ or £c where R-** ' R', R-, R- , K' and X are hereinbefore defined affordε 2 where; p iε hereinbefore defined. Reaction cf 4_5 with tricyclic derivativeε of Formula ≥ and 2b wherein Z, ': D, E, F and m are hereinbefore defined affords 46a and 46b. SCHEME XVIII 46b SJ SCHEME XIX ^2 SCHEME XX S3 Compounds of this invention may be prepared as shown in Schemes XIX and XX. Reaction of wherein W, R 5 are hereinbefore defined and R 1 ^ i s hereinbefore defined with butyl lithium and tributyltin chloride affordε H which is reacted with derivatives 15a, 15b, or 15c where R 5 ' R 7 , R s , R-, K', X and M' are hereinbefore defined affords i_δ wherein R^ is defined. Reaction of £ 8_ with tricyclic derivatives of Formula a and 2h wherein Z, Y, D, E, F and are hereinbefore defined affords 49a and 49b. Reference Example 1 10, ll-Dihvdro-10- (4-iodober.zoyl -5H-oyrrolcf2,l-c' '1,4 ' benzodiazeoine Tc a stirred solution of 1.8 g cf 10,11- dihydro-5H-pyrrolo[2, i-c] [1,4]benzodiazeoine and 3 ml cf triethylamine in 100 ml of methylene chloride at C°C iε added a εolution of 2.8 g of 4-iodobenzoyl chloride in 25 ml of methylene chloride. The reaction mixture iε εtirred at room temperature for 4 hourε and evaporated i vacuo to a reεidue which iε partitioned between water and chloroform. The organic layer is dried over K ? 4, filtered and evaporated in vacuo to a brown residue which iε crystallized from ether-hexane to give 3.0 g cf the desired product. Maεs spectrum: M+K:323. Reference Example 2 10. ll-Dihvdro-10-r4- (tributylstannyl .benzoyl1 -5H- nvrrolor2.1-c1 f1.41benzodiazeoine A mixture of 4.1 g of 10, ll-dihydro-10- (4- iodobenzoyl) -5H-pyrrolo[2,1-c] [1,4] benzodiazeoine, 200 mg of tetrakis(triphenylphoεphine)palladium!(0) , 11.β g of biε (tributyl)tin and 4.0 g of lithium chloride in 100 ml of anhydrous dioxane ' iε refluxed for 24 hourε. The reaction mixture is filtered and the reεidue is washed with dioxane. The combined filtrates are evaporated rn vacuo to a reεidue which is purified by column chromatography on εilica gel by elution with 30% ethyl acetate-hexane to give 5.0 g of the desired product as a solid. Masε spectrum: M+H:583. Reference Example 3 2- (Tributylεtannyl)toluene To a stirred solution of 3.4 g of 2- bromotoluene in 100 ml of dry tetrahydrofuran at -78°C is slowly added 8 ml of 2.5 M butyl lithium in hexane. The reaction mixture is stirred for 30 minuteε and 6.5 g of tri-n-butyl tin chloride in 25 ml of tetrahydrofuran added. The reaction mixture is stirred an additional 1 hour, quenched with water and extracted with ether. The ether extract is dried over Na2S0 , filtered and the filtrate evaporated in vacuo tc give 7.0 g cf a residue. Mass spectrum: M+K:381. Reference Example 4 1- f2-Mitrcohenyl . -lH-pyrrole-2-carbcxaldehvde Tc a solution of 3.76 g of l-(2-nitro- phenyl)pyrrole in 20 ml of N,N-dimethylforma * τ.ice at C°C iε added drcpwiεe with εtirring 3 ml of phoεphor ε oxychloride. Stirring iε continued for 30 minuteε and the reaction mixture iε heated at 90°C for 1 hour. After cooling to room temperature the mixture iε treated with crushed ice and the pK adjusted to 12 with 2N sodium hydroxide. The resulting εuspenεion is filtered, washed with water and dried to give 5.81 g of the desired product as a light yellow solid m.p. 11S-122°C. Reference Example 5 4.5-Dihvdro-pyrrolo- 1, 2-al -σuinoxaline To a solution of 1.0 g cf 1- (2-nitrophenyl ■ - lH-pyrrole-2-carboxaldehyde in 40 ml of ethyl alcohol and 40 ml cf ethyl acetate, under argon, iε added 40 mg of 10% Pd/C. The mixture is ' hydrogenated at 40 psi for 2 hours and filtered through diatomaceous earth. The filtrate iε concentrated in vacuo to a reεidue which iε diεεoived in ether and treated with hexaneε to give C.3Ξ 5 g cf the desired product as a beige solid m.p. 108- 110°C. Reference Example 6 N- (2-Nitrobenzoyl)oyrrole-2-carboxaldehvde To an ice bath cooled solution of 5.6 g cf 2- pyrrolecarboxaldehyde in 40 ml of tetrahydrofuran is added 2.4 g of 60% sodium hydride in mineral oil. The temperature elevates- to 40°C. After stirring for 20 minutes a solution of 11.0 g of 2-nitrobenzoyl chloride in 20 ml of tetrahydrofuran is added dropwise for 20 minutes. A.fter stirring in the cold for 45 minutes, the reaction mixture is poured into ice water and ether then filtered. The cake iε washed with additional ether. The twc phase filtrate is separated and the ether layer dried and concentrated in vacuo to give 10 g of a reεidue aε a dark εyrup which iε scratched with ethanol to give crystals which are collected by filtration, washed with ether and then dried to afford 3.2 g of solid, m.p. 95-99°C. Reference Example 7 10 , ll-Dihvdro-5H-pyrrolor2 , 1-c1 fl , 4lbenzodiazecin-5-one A mixture of 1.5 g of N- (2-nitrobenzovl) - pyrrole-2-carboxaldehvde in 50 ml of ethyl acetate, 2 dropε cf concentrated KCl and 0.3 g of 10% Pd/C iε shaken in a Parr apparatus under hydrogen presεure for 2 hourε. The reaction mixture iε filtered through diatomaceous earth and the filtrate concentrated in vacuo to give 1.0 g of a yellow oil. The residue is purified on thick layer chromatography plates by elution with 4:1 ethyl acetate:hexane to give 107 mg of the desired product aε an oily εolid. Reference Example 8 1- (2-Nitrobenzyl) -2-pyrrolecarboxaldehvde To 5.56 g of 60% εodium hydride in mineral oil, waεhed three times with hexane, iε added 300 ml of N,N-dimethylformamide under argon. The reaction mixture iε cooled in an ice-bath and 13.2 g of pyrrole-2- carboxaldehyde iε added slowly. The reaction mixture becomes a complete solution and is stirred for an additional 10 minutes. While stirring, 30.0 g of 2- nitrobenzyl bromide is added slowly. After complete addition, the reaction mixture is stirred fcr 30 minutes, the ice bath is removed and the reaction mixture εtirred at room temperature for 24 hourε. The N, -dimethyiformamide iε concentrated in vacuo to give a reεidue which iε εtirred with ice water for 1 hour. The reεulting εolid iε collected, air dried, then vacuum dried tc give 30.64 g of the deεired product aε a tan eciid, m.p. 12S-132°C. Reference Example 9 10 , ll-Dihvάro-5H-pyrrolof2 , 1-c 1 r1 , 41benzodiazeoine A mixture of 30.6 g of 1- (2-nitrobenzyi) -2- pyrrolecarboxaldehyde and 3.06 g of 10% Pd/C in 400 ml of ethyl acetate and 400 ml cf ethyl alcohol iε hydrogenated over 18 hourε. The reaction mixture iε filtered through diatomaceouε earth and the filtrate iε treated with activated carbon and filtered through diatcmaceouε earth. The filtrate iε concentrated i vacuo to give a reεidue which iε dissolved in methylene chlcride containing ethyl alcohol. The solution is passed through a pad of εilica gel and the pad washed with a 7:1 hexane-ethyl acetate solution to give 16.31 g of the desired product as εolid, m.p. 145-148°C. Reference Example 10 1- fo-Nitrobenzyl ■ -imidazole-2-carboxaldehvde A 2.0 g portion of sodium hydride (60% in oil) iε waεhed with pentane two timeε. To the reεidue ie added 110 ml of , -dimethyIformamide under argon. With εtirring and external cooling, 4.80 g of 2-imidazole- carboxaldehyde is added and the cooling bath removed. Sliσht external heating results in a yellow solution. The reaction mixture iε chilled in ice and 1C.8 g cf 2- S7 nitrobenzyl bromide iε added. The reaction mixture iε stirred at 0°C for 18 hourε. The volatileε are remove in vacuo to a residue which is εtirred with ice water, filtered and the cake waεhed well with water and suction dried to give 10.9 g of the desired product aε a εolid, • m.p. 141-144°C. MH+ 232. Reference Example 11 10. ll-Dihvdro-5H-imidazo 2 , 1-cl fl , 41benzodiazeoine A 5.0 g sample of 1- (o-nitrobenzyl) -imidazoie- 2-carboxaldehyde is disεolved in 150 ml of hot ethyl alcohol, cooled to room temperature and filtered. To the filtrate iε added 0.5 g cf 10% Pd/C and the mixture hydrogenated at 48 pεi for 4 hourε. An additional C.Ξ g of 10% Pd/C iε added and hydrogenation continued fcr 21 hourε at 65 psi. The mixture is filtered through diatomaceous earth and the cake waεhed with ethyl acetate. The filtrate iε evaporated in vacuo to a reεidue which iε diεεolved in methylene chloride, treated with activated carbon, filtered through diatomaceouε earth and hexaneε added to the filtrate at the boil to give 1.86 g of the deεired product aε a crystalling solid, m.p. 164-170°C. Reference Example 12 10 , ll-Pihvdro-5H-imidazor2.1-cl Q.41benzodiazeoine To a suεpenεion of 4 mmol of lithium aluminum hydride in 20 ml of anhydrouε tetrahydrofuran iε added a 1 mmol εolution of 10, ll-dihydro-ll-oxo-5H-imidazo[2, 1- c] [1, 4]benzodiazepine and the mixture iε refluxed fcr 24 hourε and cooled at 0°C. To the mixture iε added dropwiεe 0.12 ml of water and 6 ml of IN sodium hydroxide. The mixture iε extracted with ethyl acetate and the solvent removed to give the desired product as a solid. Recrystallization from methylene chloride-hexane gives crystals, m.p. 164-170°C. -5-.? Reference Example 13 10- r f6-Bromo-3-pyridinyl) carbonyll -10, ll-άihvdro-5H- pyrrolo \ 2 , 1-cl f1 , 41benzodiazeoine To a solution of 1.0 g of 10, ll-dihydro-5ϋ- pyrrolo[2, 1-c] [1, 4]benzodiazepine and 10 ml cf triethyl¬ amine in 50 ml of dichloromethane under argon iε added 3 g of 6-bromopyridine-3-carbonyl bromide. The mixture iε εtirred at room temperature for 16 hourε and then poured into 100 ml of water. The organic layer iε separated and washed with 2% HCl, water, saturated NaHCCβ and dried ( a2S04), the solvent removed under vacuum, and the reεidue chromatographed on silica gel with ethyl acetate-hexane aε solvent to give the product as a εolid. Reference Example 14 9 , 10-Dihvdro-4H-furoT2 , 3-eloyrrolo i, 2-al r , 4 " diazecir.e Tc a suspension of 4 mmol of lithium aluminum hydride in 25 ml of anhydrous tetrahydrofuran is added 1 mmol of , 10-dihydro-4H-furo[2, 3-e]pyrrclc [1, 2- a] [1, 4]diazepin-9-one. The mixture iε refluxed fcr 12 hourε and allowed to stand overnight. Tc the mixture is added dropwise 0.12 mi of water and then 6 ml cf IK sodium hydroxide. The mixture iε extracted with ethyl acetate and the extract dried (Na2S04) . he vclatiieε are removed in vacuo to give the desired product aε a εolid. Reference Example 15 9.10-Dihvdro-4H-furor2.3-eloyrrolori .2-ai r l. 1 iazeoine A εolution of 1 mmol of 4K-furo [2, 3-e]pyrrolo- [1,2-a] [l,4]diazepine and 0.2 g if 10% Pd/C in 10 ml cf ethanol is hydrogenated fcr 18 hours. The reaction mixture iε filtered through diatomaceouε earth and the filtrate iε evaporated in vacuo to give the desired product as a εolid. Reference Example 16 10- r (6-Iodo-3-oyriάinyl) carbonyll -10, ll-dihvdro-5H- pyrrolo \ 2 , 1-cl fl , 41benzodiazeoine To a solution of 1.0 g of 10, ll-dihydro-5H- pyrrolc [2, 1-c] [1, 4]benzodiazepine and 10 ml cf triethyl¬ amine in 50 ml of dichloromethane under argon is added 3.2 g of 6-iodopyridine-3-carbonyl chloride. The mixture is εtirred at room temperature fcr 16 hourε and then poured into 100 ml of water. The organic layer iε separated and waεhed with 2% HCl, water, saturated NaKC03 and dried (Na2S04) . The solvent is re cved under vacuum and the reεidue chromatographed on εilica gel with ethyl acεtate-hexane aε solvent to give the product as a εolid. Reference Example 17 9 , 10-Dihvdro-4H-pyrrolori , 2-al thier.cr2.3- e1 r1 , 41diazeoine To a mixture cf 7.0 g of 9-cxo- , 10-dihydro- 4r.-pyrrclo[1, 2-a] thieno[2, 3-e] [1, 4]diazepin n 25 mi cf anhydrous tetrahydrofuran is added 9 ml cf 1 molar bcror.-dimechylεulfide in tetrahydrofuran. The mixture iε refluxed for 6 hourε. The solution is cccled to room, temperature and 25 ml of methanol added dropwise. The vciatileε are removed under vacuum. To the reεidue is added 100 ml of 2N NaOH. The mixture iε refluxed 5 hours and filtered. The εolid is extracted with dichloromethane and the extract is waεhed with 2N citric acid, water and dried (Na2S04) . The scivent iε removed in vacuo to give the deεired product aε a εolid. Reference Example 18 , 10-Dihvdro-5H-pyrrolo \ 1 , 2-al thieno r 3.2- el f1 , 41diazeoine To a εuεpenεicn of 7.0 g cf 5-cxc-4,Ξ- dihydropyrrclc[l,2-a] thieno [3 , 2-e] [1, 4;dιazecir.e in 25 r.l cf anhvdrouε tetrahydrofuran iε adds borane-dimethylsulfide in tetrahydrofuran. The mixture iε refluxed for 6 hours. The εolution is cooled to room temperature and 25 ml of methanol added dropwiεe. The volatileε are removed under vacuum. To the reεidue iε added 100 ml of 2N NaOH. The mixture iε refluxed Ξ hourε and filtered. The solid is extracted with dichloromethane and the extract is washed with 2N citric acid, water and dried (Na2S04) . The solvent iε removed to give a εolid. Reference Example 19 . -Dihvάro-4H- f1.2.4 triazolor4.3-al r1 , Ξ ' enzodiazeoine A mixture of 7.0 g of 5, 6-dihydrc-4H- [1, 2 , 4] - triazolo- [4, 3-a] [1, 5]benzodiazepin-5-cne in 2Ξ ml cf tetrahydrofuran iε added 9 ml of 10 M borane- dimethylsulfide in tetrahydrofuran. The mixture iε refluxed for 6 hours, cooled to room temperature and 2Ξ ml of methanol added dropwiεe. The vciatiieε are removed under vacuum and to the reεidue is added IOC ml cf 2N εodiu . hydroxide. The mixture s refluxed fcr Ξ hcurε, chilled and extracted with dichiorc ethane . T e extract is washed with 2K citric acid, water and dried (Na2S04) . The εolvent iε removed under vacuum tc give a εolid. The εolid iε purified by chromatography c εilica gel tc give the deεired product. Reference Example 20 1 - (2-Nitroohenyl) -lH-pyrrole-2-carbcxaldehvde A εample of 4.7 g of sodium hydride (60% in oil) iε waεhed with hexane (under argon) . Tc the εodium hydride iε added 200 ml of dry N,N-cirr.ethylformamide and the mixture iε chilled to 0°C. To the mixture iε added 10.11 g of pyrrole-2-carboxaldehvde in small portions. The mixture iε εtirred 10 minutes and 15.0 g of 1- fluoro-2-nitrobenzene added dropwise. After the addition, the mixture iε stirred at room temperature 16 hours and the mixture concentrated (65°C) under nigh vacuum. To the residue iε added 400 ml cf U dichloromethane and the mixture washed with 150 ml each of H2O, brine and dried (Na2S04) . The solvent is removed in vacuo to give a yellow solid. Crystallization from ethyl acetate-hexane (9:1) giveε 17.0 g of light yellow cryεtals, m.p. 119-122°C. Reference Example 21 4.10-Dihvdro-5H-pyrrolofl.2-althienoT .7- el [1 , 41diazepjne To an ice cooled mixture of 2.1 g cf pyrrole- 2-carboxylic acid and 3.2 g of methyl 3-amino-thiophene- 2-carboxylate in 40 ml of dry dichloromethane iε added 4 g of N,N-dicyclohexylcarbodiimide. The mixture iε εtirred at room temperature for 3 hours and filtered. The filter cake iε waεhed with dichloromethane and then extracted twice with 60 ml of acetone. The acetone extract iε concentrated tdo dryneεε to give 0.8 g cf εolid, m.p. 214-218°C. To a suspension of the preceding compound (1.19 g) in 20 ml of dry tetrahydrofuran is added 0.2 g of εodium hydride (60% in oil) . After the hydrogen evolution, the mixture iε εtirred and refluxed for 4.5 hours, cooled and poured into ice-water. The precipitated solid is filtered and the solid triturated with petroleum ether (bp 30-60°C) to give 0.75 g of 4, 10-dihydro-4, 10-dioxo-5H-pyrrolo[1, 2-a] thieno[3,2- e] [1, 4]diazepine as a εolid, m.p. 280-290°C. The preceding compound (0.362 g) iε added to an ice-water cooled εolution of 1 M diborane in tetrahydrofuran. The mixture is stirred at room temperature for 65 hourε. The solution is concentrated to dryneεε and ice-water added tc the reεidue. The mixture iε acidified with dilute HCl, εtirred and then baεified with εolid NaHCCs . The mixture iε filtered to give 0.223 g of a εclid (foam) m.p. 80-85°C. Reference Example 22 10, ll-Dihvdro-5H-l, 2 , 4-triazolo r , 4-ci ri .41 - benzodiazeoine A mixture of 2.2 g of 2-cyanoaniiine, 2.0 g cf methyl bromoacetate and 1.3 g of potaεεium carbonate in 12 ml of dry N,N-dimethyIformamide iε heated at 150- 155°C for 40 minutes. The cooled mixture is poured into ice-water and the mixture filtered to give 2 g of methyl [N- (2-cyanophenyl)amino]acetate aε a yellow εolid, m.p. 70-78°C. The preceding compound (2.0 g) iε added to a solution of 0.5 g of εodium methoxide in 50 ml of methanol. The mixture iε shaken under an atmosphere of hydrogen with the catalyst Raney-Ni for 19 hours. The mixture iε filtered through diatomaceouε earth and the filtrate evaporated. Water iε added to the reεidue and the mixture filtered to give 2, 3, 4, 5-tetrahydrc-iH-l, - benzodiazepin-3-one aε a yellow εolid, m.p. 167-170°C. A mixture of the preceding compound (1.6 g) and 0.84 g of phosphorus pentasulfide in 10 ml cf dry (dried over KOH) pyridine iε εtirred and heated at 80- 85°C fcr 15 minuteε. The mixture iε poured into water and εtirred for 30 minuteε. Filtration giveε 1.0 g cf 1,2,4, 5-tetrahyάro-3K-l, 4-benzodiazepin-3-th cne aε yellow εolid, m.p. 150-153°C. The preceding compound (0.5 g) and 0.5 g cf !.- fcrmylhydrazine in 6 ml of dry n-butanci iε refluxed fcr 16 hourε and the εolvent removed. The gummy * reεidue is triturated with cold water and the mixture filtered. The solid iε triturated with acetone to give 0.15 g of yellow εolid, m.p. 232-237°C. Reference Example 23 4.5-Dihvdro-6H-ri.2.41triazolor4.3-c- ri, 5 ■ - benzodiazeoine A mixture of 2, 3 , 4, 5-tetrahydrc-lH-l, 5- benzodiazepin-2-thione (0.8 g) and 0.80 g cf K- formylhydrazine in 8 ml of n-butanol is εtirred and refluxed for 18 hourε and the εolvent removed under vacuum. Ice water iε added to tdhe residual solid and (o3 the mixture filtered to give 0.312 g of a gray solid, m.p. 162-165°C. Reference Example 24 4 , 5-Dihvdro-6H-imidazofl , 2-al fl , 51benzodiazeoine A mixture of 30 g of acrylic acid, 33 g cf o- phenylenediamine is heated on a steam bath for 1.5 hours and the cooled black mixture triturated with ice-water. The aqueous phase is decanted and ice and aqueous ammonium hydroxide added to the reεidue. The mixture iε extracted with dichloromethane and the extract concentrated to drynesε. The residue is triturated with carbon tetrachloride and filtered. The oily solid iε triturated with a εmall amount of ethanol to give 9.7 g of a εolid. Trituration cf the εciid with ethyl acetate giveε 2, 3 , 4, 5-tetrahydro-lH-l, 5-benzodiazepine-2-one as an impure solid, m.p. 75-107°C. A mixture of the preceding compound (11.3 g) and 5.9 g cf phosphorus pentasulfide in 70 ml cf dry pyridine iε εtirred and heated at approximately 8C°C fcr 20 minuteε. The mixture iε poured into water and the mixture εtirred for 30 minuteε. Filtration giveε 8.6 g of 2, 3 , 4 , 5-tetrahydro-lH-l, 5-benzodiazepin-2-thione as a solid, m.p. 154-157°C. A mixture of the preceding compound (0.70 g> , 1.0 g of aminoacetaldehyde dimethyl acetal and 15 mg of 4-methylbenzenesulfonic acid monohydrate in 6 ml of dry n-butanol iε refluxed for 4 hours and the solvent removed under vacuum. The residue is heated (refluxed) with 10 ml of 3N hydrochloric acid fcr 55 minuteε. Ice is added to the cooled mixture and the mixture made basic with εolid NaHCθ3. The mixture iε extracted with dichloromethane and the extract dried ( a2Sθ4) . The εolvent iε removed to give an orange syrup which solidified on standing. The oily εolid iε triturated with acetone to give a light yellow εclid (0.185 g) m.p. 119-122°C. (o H Reference Example 25 ι - f2-Nitroohenyl) -2-pyrroleacetic acid, ethyl eεter To a εtirred mixture of 1.88 g of l-(2- nitrophenyl)pyrrole, 4.80 g of ethyl iodoacetate and 2.22 g of FeSθ4.7H2θ in 40 ml of dimethyl εulfoxide iε added dropwiεe 10 ml of 30% hydrogen peroxide while keeping the reaction mixture at room temperature with a cold water bath. The mixture iε εtirred at room temperature for one day. An additional 2.4 g cf ethyl iodoacetate, 1.1 g of FeSθ4.7H2θ and 5 ml of 30% hydrogen peroxide is added and the mixture εtirred at room temperature for 1 day. The mixture iε diluted with water and extracted with diethyl ether. The organic extract iε washed with water, brine and dried (Na2Sθ ) . The solvent iε removed and the reεidue (2.12 σ) chromatographed cn εiiica gel with ethyl acetate-hexane (1:4) aε εolvent to give 0.30 g of product aε a brown gum. Reference Example 26 6. " ~ -Dihvάro-5H-oyrrolofl .2- l f1 , E 1benzcdiazeoin-6-cne To a εolution of 0.8 mmol of i-(2-nitrc- phenyl) -2-pyrroleacetic acid, ethyl ester in 3 mi cf ethanol is added εtannus chloride dihvdrate (Sr.Cl2.H2O. in 2 ml of concentrated hydrochloric acid (with coding in water bath) . The mixture is stirred at room temperature for 5 hourε and chilled in an ice bath. To the mixture iε added εlowly εaturated εodium carbonate εolution. The solid which precipitateε iε filtered and the solid washed with water and then extracted with ethvl acetate. The ethyl acetate extract iε dried (Na2Sθ4) and the solvent removed to give 0.16 g of sciid which iε triturated with ether to give 0.11 g cf product aε an off-white εolid. Reference Example 27 6, 7-Dihvdro-5H-Dyrrolori.2-al fl.51benzodiazeoine To a εolution of 0.070 g of 6, 7-dihydro-5H- pyrrolo[l, 2-a] [1, 5]benzodiazepin-6-one in 2 mi of tetrahydrofuran is added 0.45 ml of a 2.0 M solution of diborane-dimethylsulfide in tetrahydrofuran. The mixture iε refluxed for 3 hours, poured into water and made basic with 2N NaOH. The tetrahydrofuran is removed under vacuum and the residual aqueous mixture extracted with diethyl ether. The extract is waεhed with brine, dried (Na2≤θ4) and the εolvent removed to give 0.065 g of a colorleεε oil; one spot by thin layer chromatography (εilica gel) with ethyl acetate-hexane (1:2) aε εolvent (Rf 0.81) . Reference Example 28 1- r2- itro-5- ( ethoxycarbonyl . benzyl 1 -oyrr le-2- carboxaldehvάe To a εtirred slurry of 2.2 g of sodium hydride (60% in oil, washed with hexane) in tetrahydrcfuran is added at 0°C a εolution of 4.5 g of pyrroie-2- carboxaldehyde in 25 ml of tetrahydrofuran. After the addition iε complete, a εolution of 15 g cf ethyl 4- nitro-3-bromomethylbenzoate in 30 ml cf dry tetrahydrofuran is slowly added under nitrogen. The reaction mixture iε stirred at 20°C for 8 hourε and carefully quenched with water. The reaction mixture is extracted with chloroform which is washed with water, dried with Na2S04 and concentrated in vacuo tc give 12 g of the deεired product as a εolid; maεε εpectrum (M-H) 349. Reference Example 29 1- [2-Nitro-4- (ethoxycarbonyl)benzyl1 -oyrrcle-2- carboxaldehvde The conditionε of Reference Example 2S are uεed with ethyl 3-nitro-4-bromomethylbenzoate to give »L 13.0 g of the deεired product as a solid; masε εpectrum (M+H) 349. Reference Example 30 Ethyl 10. ll-Dihvdro-5H-pyrrolof2.1- cl ri, 41benzodiazeoine-7-carboxylate A solution of 10.0 g of 1- [2-nitro-5- (ethoxycarbonyl)benzyl] -pyrrole-2-carboxaldehyde in 150 ml of absolute ethanol containing 1.0 g of 10% Pd/C is hydrogenated in a Parr apparatus for 16 hourε under 40 pεi of hydrogen. The reaction mixture iε filtered through a pad of diatomaceouε earth and the filtrate concentrated in vacuo tc a residue of 5.5 g cf the desired product aε a εolid; maεε εpectrum (M-HJ25Ξ. Reference Example 31 Ethyl 10. ll-Dihvdro-5H-pyrrolor2.1- 1 r1.41benzodiazeoine-8-carbcxylate The hydrogenation conditionε cf Reference Example 30 are uεed with 1- [2-nitro-4- (ethcxycar- bonyl)benzyl] -pyrrole-2-carboxaldehvde tc give 5.C c cf the deεired product aε a εoiid; mass εpeccrum (M-H) 255. Reference Example 32 4-f (4-Methylohenyl)thiolbenzcic Acid A mixture of 6.0 g of 4-mercapto-tciuene and 9.2 g of potaεεium t-butoxide iε εtirred at room temperature under a nitrogen atmosphere in 50 ml cf dimethylsulfoxide for 10 minutes followed by the addition of 11.5 g of 4-bromobenzoic acid and 0.2 g cf copper metal. The reaction mixture iε εtirred at 210°C for 16 hourε. The reaction mixture iε poured over cruεhed ice and filtered through diatcmaceouε earth. The filtrate iε acidified with HCl until pH 2. The resulting εolid is collected, washed with water and 60 ml of petroleum ether to give 8.5 g of the desired product, m.p. 105-I07°C, M+H=245. Reference Example 33 4- ( Phenylthio)benzoic Acid The conditions to prepare Reference Example 32 cl384847 are used with 6.0 g of mercaptobenzene, 12.22 g of potassium t-butoxide and 13.15 g of 4-bromobenzoic acid to give 12.0 g of the desired product as a solid, m.p. 101-103°C; M+H=231. Reference Example 34 4- (Phenylthio)benzoyl Chloride A εolution of 2.0 g of Reference Example 33 in 30 ml of thionvl chloride under nitrogen iε refluxed for 40 minuteε. The volatileε are evaporated in vacuo and the reεidue evaporated two timeε with 30 ml of carbon tetrachloride to give the deεired product aε a reεidue which iε dissolved in 30 ml of methylene chloride and used in the next step. Reference Example 35 4- r (4-Methylohenyl . hiolbenzcyl Chloride The conditions to prepare Reference Example 34 are uεed with 2.0 g of Reference Example 32 and 30 mi of thionyl chloride to give 2.16 g cf the deεired product in a εolution of 30 ml of methylene chloride. Reference Example 36 4- (Benzoyl)benzoyl Chloride The conditions to prepare Reference Example 34 are used with 2.0 g of 4-benzoylbenzcic acid and 30 mi of thionyl chloride to give the deεired product in a εolution of 30 ml of methylene chloride. Reference Example 37 4-r f4-Methylphenyl) sulfonyllbenzoyl Chloride The conditionε to prepare Reference Example 34 are uεed with 2.0 g of Reference Example 38 and 30 ml cf thionyl chloride to give the deεired product in a solution of 30 ml of methylene chloride. Reference Example 38 4-r (4-Methyl p henyl) εulfonyllbenzoic Acid A mixture of 4.0 g of Reference Example 32, 11.3 g cf m-chloroperbenzoic acid in 100 ml of chloroform under nitrogen iε stirred at reflux for 16 hourε. The reaction mixture iε poured into water and the organic layer separated, washed with 2N HCl and water. The organic layer is dried ( a2S04) and evaporated to dryneεε in vacuo to give 6.5 g of the desired product as a yellowish oil. Reference Example 39 4- (Phenylsulfonyl .benzole Acid A mixture of 7.0 g cf Reference Example 33 and 11.5 g cf m-chloroperbenzoic acid in 80ml cf chloroform under nitrogen iε εtirred at reflux fcr 16 hourε. The reaction mixture iε evaporated in ** ac c and the reεidue suspended in 200 ml of ice water. The resulting insoluble εolid product iε collected and dried in a vacuum oven at 60°C to give 7.2 g cf the deεired product, m.p. 128-132°C. M-H=262. Reference Example 40 4- r (4-Methyloher.yl . sulfonylIbenzoic Acid Methyl Ester A εolution of 6.5 g of Reference Example 38 in 200 ml of methyl alcohol containing a few dropε of εulfuric acid is refluxed for 16 hourε. The volatileε are removed in vacuo and 150 ml of ice water added to the residue. The resulting εolid iε collected by filtration and washed with 200 ml cf water. The solid iε dried in a vacuum over at 60°C for 16 houre to give 3.5 g of a white fluffy product. Reference Example 41 4-r (4-Methylphenyl . sulfonyllbenzcio Acid A mixture of 2.5 g of Reference Example 40 is disεolved in 60 ml of 1:1 water:methane1 and 20 mi cf 5% NaOH and stirred at room temperature for 8 hourε. The voiatilee are evaporated in vacuo tc a residue which s stirred in 50 ml of ice water and acidified with about 20 ml of ION HCl solution. The resulting solid is collected, washed with 200 ml of water and dried in a vacuum over at 60°C to give 2.0 g of the desired product, M+H=277. Reference Example 42 4- ϊ (4-Methylphenyl . sulfonyl1benzoyl Chloride A mixture of 2.0 g of Reference Example 41 and 30 ml of thionyl chloride is heated at 80°C under nitrogen for 45 minutes. The volatiles are evaporated in vacuo to a reεidue which is evaporated with toluene and with carbon tetrachloride. The final reεidue iε diεsoived in 30 ml of methylene chloride to be used in the next εtep. Reference Example 43 4 ' - f2-Prooenyloxy) - f1 , 1 ' -biohenyl1 -4-carbcxylic Acid Ethyl Eεter A mixture of 10.0 g cf 4 ' -hydroxy- [1,1'- biphenyl] -4-carboxvlic acid, ethyl eεter is dissolved in 100 ml cf acetone and 8.02 g cf allyl bromide added under a nitrogen atmosphere. While stirring 15.0 c of potaεεium carbonate ie added and the reaction mixture refluxed for 16 hourε. The reaction mixture iε cccied to 0°C and poured into 200 ml of ice-water and extracted with chloroform (3 X 150 ml) . The combined extractε are washed with IN HCl and water, dried (Na2S04) and evaporated in vacuo to give 12.0 g cf the deεired product m.p. 89-92°C. M+K=283. Reference Example 44 4 ' - (2-Propenyloxy) - I " 1.1 ' -biohenyl 1 - -carboxylic Acid A mixture of 6.0 g of Reference Example 43 m 60 ml of ethanol and 30 ml of 5N NaOH iε εtirred at room temperature for 4 hourε. The reaction mixture iε pcured into 200 ml of ice water, acidified with HCl, extracted with chloroform (3 X 150 ml) , waεhed with saturated NaHC03 and water. The organic layer is dried ( Ka2ΞC i 76 and evaporated in vacuo to give 4.4 g of the άeεired product aε a solid, m.p. 360°C, M+K=255. Reference Example 45 4 ' - f2-Prooenyloxyl - fl, 1 ' -biphenyll -4-carbonyl chloride A. mixture of 9.0 g of Reference Example 44 in 45 ml of thionyl chloride is refluxed under nitrogen for 45 minuteε. The volatiles are evaporated in vacuo and the reεidue evaporated in vacuo from carbontetra- chloride (2 X 30 ml) to a reεidue which iε dissolved in 30 ml of methylene chloride for use in the next reaction. Reference Example 45 Tributvir2- (trifluoromethyl ■phenyl "1 Stannane To a solution of 10.0 g cf 2-brcmccrιfiucrc- methyibenzene under nitrogen in 100 mi of tetrahydro¬ furan while cooling in a dry ice-acetone bath is added dropwiεe 30.6 ml of a 1.6 M solution cf butyl lithium via syringe. Stirring iε continued for 1 hour. To the reaction mixture is added dropwise chloride in 30 ml cf tetrahydrofuran. additional hourε. The reaction mixture is quenched with 20 ml cf water and after εtirring for 20 minuteε, extracted with chloroform (3 X 100 mi) . The organic layer iε filtered through diatomaceouε earth and the filtrate waεhed with εaturated NaHCθ3 and water. The organic layer is dried (Na2Sθ4) and evapcrated in vacuc to give 16.8 g of the deεired product. MS 379.1 Reference Example 47 2- (Tributylεtannyl pyridine To a solution of 10.0 g cf 2-bromo-pyridme under nitrogen in 100 ml of tetrahydrofuran while cooling in a dry ice-acetone bath is added dropwise 47.0 ml of a 1.6 M solution of butyl lithium via syringe. Stirring iε continued for 1 hour. To the reaction mixture iε added dropwise 24.7 g cf tributyltin chloride in 30 mi of tetrahydrof ran and εtirred 1 7/ additional hour. The reaction mixture iε quenched with 20 ml of water and 100 ml additional water is added. After stirring for 20 minuteε the reaction mixture is extracted with chloroform (3 X 100 ml) . The organic layer iε filtered through diatomaceouε earth and the filtrate waεhed with saturated NaHCθ3 and water. The organic layer is dried (Na2≤θ4) and evaporated in vacuo to give 21.2 g of the desired product. MS 379.1 Reference Example 48 2- (Tributylstannyl) thiazole To a solution of 10.0 g of 2-bromothiazole under nitrogen in 50 ml of tetrahydrofuran while cooling in a dry ice-acetone bath iε added dropwiεe 36.6 ml of a 1.6 M solution of butyl lithium via syringe. Stirring is continued for 1 hour. To the reaction mixture iε added dropwiεe 29.8 g of tributyltin chloride in 20 ml cf tetrahydrofuran. Stirred 1 additional hour. The reaction mixture iε quenched with 20 mi of water and 50 ml additional water is added. After stirring fcr 20 minutes the reaction mixture iε extracted with chloroform (3 X 60 ml) . The organic layer iε dried (Na2S04) and evaporated in vacuo to give 11.7 g cf the deεired product. Reference Example 4? 10- r f 6-Chloro-3-pyridinyl)carbcnyl 1 -10 , 11-dihvdro-EH- pyrrolor2.1-cl Cl , 41benzodiazeoine To a solution of 1.0 g of 10, ll-dihydro-5H- pyrrolo[2, 1-c] [1, 4]benzodiazepine in 50 mi cf dry methylene chloride, under nitrogen, and 7.0 ml of triethylamine is added 1.43 g of 6-chicro-pyridine-3- carbonyl chloride. The reaction mixture iε εtirred at room temperature for 16 hours and poured into 100 mil of water. The organic layer iε εeparated, waεhed with 2% HCl, water, εaturated NaHCOs, and dried( a2Sθ4) . The solvent iε evaporated in vacuo to give a residue which iε cclumned on εilica gel by elution witr. 7:1 to 1:1 7Z ethyl acetate:hexane to give 1.76 g of the desired product as a yellowish crystalline solid.M+H=324. Reference Example 50 4 , 5-Dihvdro-4 , 4-dimethyl-2- (2-thienvD -oxazole A εolution of 30.4 g cf 2-aminc-2-methyl-l- propanol in 125 ml of methylene chloride is added dropwise to a solution of 25.0 g of 2-thiophenecarboxyl chloride in 125 ml of methylene chloride while maintaining the temperature below 20°C. The mixture iε εtirred at room temperature for 2 hourε and waεhed with water. The organic layer iε dried over MgSθ4 and evaporated in vacuo to a residue. The reεidue iε εuεpended in methylene chloride and 6 " . g cf tnionyl chloride added dropwise while maintaining the temperature below 30°C. The reaction mixture is stirred at room temperature for 18 hours and the vciatileε evaporated in vacuo to a residue which s dissolved in water. The aqueous solution is rendered alkaline whith 1N NaOH and extracted with ether. The organic layer is dried with MgS04 and concentrated in vacuo to give 21.1 g of the deεired product aε a yellowish oil. Reference Example El 4 , 5-Dihvdro-4, 4-dimethyl-2- r2- ■'tributylstannyl) -2- thienyll -oxazole To a εolution of 5.Og of 4, 5-dihydro-4, 4- dimethyl-2- (2-thienyl) -oxazole in 20 ml of ether is added dropwise 18.75 ml of butyl lithium while maintaining the temperature at -70°C with stirring under nitrogen. The reaction mixture iε εtirred at -70°C for 15 minutes and 30 minuteε at 0°C. The reaction mixture iε cooled to -70°C and 10.0 g of tributyl tin chloride added. The reaction mixture iε quenched with water and extracted with ether. The organic layer iε waεhed with water (2 X 100 ml) , dried and evaporated in v cuo to give 17.4 g of reεidue which iε purified by chromatography on εilica gel by eiuticn with 7:1 hexane:ethyl acetate to give 12.4 g of a yellowish oil. MS (M+H=472) the next step is example 19 Reference Example 52 4- (4-Methylphenoxy benzoic Acid To a solution of 4.36 g of 4-methyl-phenol in 70 ml of dry dimethylsulfoxide under nitrogen with stirring is added 9.0 g of pctasεium t-butoxide. After stirring for 15 minuteε, 0.1 g cf copper metal iε added followed by 10.0 g of 4-iodobenzoic acid. The reactantε are stirred under nitrogen while heating at 210°C for IE hourε. The cooled reaction mixture iε extracted with chloroform (2 X 900 ml) and the remaining water acidified with 2N HCl(pH=3) with ice bath ceding, tc give 8.1 g of the deεired product. MS (M÷H=229.0) Reference Exarr.de 53 4- ( 4-Methyloher.oχy'ι ber.zoyl Chloride A solution of 2.0 g of 4- (4-methylphencxy) - benzcic acid in 30 ml of methylene chloride iε added 1.67 g cf oxalyl chlcride and the mixture refluxed fcr 30 minutes with stirring under nitrogen. The reaction mixture iε evaporated in vacuo to a reεidue which iε evaporated with carbon tetrachicride (2 X 30 ml) . Reference Example 54 4- I " 4-Prooylohenyllbenzoyl Chloride A mixture of 2.0 g of 4- (4-propylphenylj - benzoic acid and 30 ml of thionyl chloride is εtirrεd at reflux for 45 minuteε. The reaction mixture iε evaporated in vacuo to a residue which iε evaporated from carbon tetrachloride (2 X 50 ml) to give a reεidue which iε diεεolved in methylene chloride. Reference Example 55 6-Hvdoxynicotinic Acid Methyl Eεter To 500 ml of methyl alcohol, cooled to 0-5°C iε added HCl gaε over 30 minuteε. The solution is allowed to reach room temperature and 50 g of 6- hydroxynicotinic acid added. The reaction mixture is 7 stirred at reflux for 2 days. The methyl alcohol iε removed in vacuo and the residue suspended in 200 ml of water and poured into 300 ml of saturated aqueous NaHCθ3. The insoluble crystals are collected by filtration, washed with 500 ml cf water and dried under vacuum at 60°C to give 53.9 g of the deεired product Reference Example 56 Methyl 6-hvdroxypyridine-3-carboxylate, o-triflate A stirred solution of 8.0 g of pyridine and 5.0 g of 6-hydroxynicotinic acid methyl ester in 50 mi of methylene chloride is cooled tc 0°C under nitrogen while 22.0 g of trifluoromethanesulfonic anhydride iε added. The reaction mixture is refluxed for 16 hourε, evaporated in vacuo to a reεidue which iε stirred with 200 ml of ice water and the solid collected. The solid is dried in a vacuum oven at 30°C to give 7.0 g cf the deεired product. Reference Example 57 2- (Tributylstannyl ■ thicohene A solution cf 8.4 g of thicohene in 200 mi cf ether is stirred, cooled to 0°C under nitrogen while 48.0 g cf butyl lithium is added dropwiεe via εyringe. After εtirring for 1 hour, the reaction mixture iε cooled to -78°C and 35.0 ml cf tributyl tin chloride iε added dropwise via εyringe. Following εtirring at room temperature for 30 minuteε, the reaction mixture iε quenched with 60 ml of water, poured over crushed ice and extracted with ether (3 X 200 ml) . The organic layer is dried and evaporated in vacuo to give 46.2 g cf the desired product aε a reεidue. Reference Example 58 Methyl 6- (2-thienyl pyridine-3-carboxylate A εolution of 2 " .0 g of (methyl 6-hydroxypyridine-3- carboxyiate, o-triflate) and 5.23 g of 2-(tributyl- stannyl) thicohene in 50 ml of dry toluene iε εtirred under nitroσen at reflux for It hourε i the p reεence of 7S tetrakis (triphenylphosphine)palladium(O) . The reaction mixture is diluted with 50 ml cf chloroform and filtered through a pad of diatomaceouε earth. The filtrate iε evaporated in vacuo to a residue which is extracted and decanted (2 X 100 ml) with 1:1 ether:petroleum ether. The combined extracts are evaporated in vacuo to give 1.6 g of the deεired product aε a reεidue. Reference Example 59 6- (2-Thienyl)pyridine-3-carbcx * /lic acid A εolution of 2.0 g of methyl 6- (2- thienyl)pyridine-3-carboxylate in 100 ml of methyl alcohol and 50 ml of 5N sodium, hydroxide iε εtirred at room temperature for 16 hourε under nitrogen. The reaction mixture iε evaporated i vacuc tc about one quarter of the volume and then diluted with 1E0 ml cf cold water. The pH iε adjuεted to 4 with acetic acid and the deεired white product collected, waεhed with 400 ml of ccid water until neutral. The εolid iε waεhed with 50 ml cf petroleum ether and dried under vacuum tc 40°C to give the deεired product. Reference Exampl 6 6- (2-Thienyl .pyriάine-2-carbor.yl chloride A mixture of 1.8 g cf 6- (2-thienyi)pyridιne- - carboxylic acid in 50 ml cf thicnyl chloride iε refluxed under dry conditionε for 1 hour. The reaction mixture iε evaporated to dryness and evaporated again from 50 mi of carbon tetrachloride to a reεidue. The reeidue iε diεεolved in 60 ml of methylene chloride and uεed further reactionε. Example 1 10. ll-Dihvdro-10- T4- (2-thienvi benzoyll -5H-oyrrolo r 2 , 1- cl ri , 41benzodiazeoine A mixture of 1.64 g cf 10, ll-dihydre-10- (4- iodobenzoyi) -5K-pyrrolo [2, 1-c] [1, 4jbenzodiazεpine, 1.9 g of 2-tri-n-butylεtannyi thiopher.e and 200 mg cf tetrakis (triphenylphoεphine)palladiu < Z in 200 ml of 7 toluene is refluxed under nitrogen for 16 hours. The reaction mixture is evaporated in vacuo to a reεidue which iε purified by column chromatography on εilica gel by elution with 5:1 hexane:ethyl acetate to give 1.2 g of the desired product as a solid. Mass spectrum: M+H:371. Example 2 10.11-Dihvdro-lO- \ - (2-nitroohenyl)benzoyl! -5H- pyrrolo[2 , 1-cl fl , 41benzodiazeoine A mixture of 3.0 g of 10, ll-dihydrc-10- [4- (tributylεtannyl)benzovl] -5K-pyrrolo[2, 1-c] [1, 4]benzc- diazepine, 200 mg of tetrakis (triphenylphosphine) - palladium(C) and 2.0 g cf l-bromc-2-nitrobenzene in 200 ml of toluene is refluxed for 16 hourε. The reaction mixture iε filtered and the filtrate evaporated in vacuo to a reεidue which iε purified by column chromatography on εilica gel by elution with 30% ethyl acetate-hexane to give 1.2 g cf the deεired product aε a εciid. Maεε εpectrum: M-^H:410. Example " * 1 , ll-Dihvdro-10- r - ■ 2 , 5-difluorophenyl ■ benzoyl! -5H- pyrrolof2 , 1-ci r 1, 4 " benzodiazeoine A mixture of 1.5 g cf 10, ll-dihydre-10- [4- (tributylεtannyl)benzoyl] -5H-pyrrclo[2, 1-c] [1, 4]ber_zo- diazepine, 1 ml of 3 , 5-difluoro-1-brcmobenzene and 200 mg of tetrakiε (triphenylphosphine)palladium(0) m 200 ml of toluene is refluxed for 16 hours. The reaction mixture iε filtered and the filtrate evaporated in vacuo to a reεidue which iε purified by column chrcmatcgraphy on εilica gel by elution with 30% ethyl acetate-hexane to give 700 mg of the deεired product aε a εolid. Maεs spectrum: M+H:401. Example 4 10. ll-Dihvdro-10- f4- (phenylethvnyl) -5H-oyrrolo \2 .1- cl 1 , 41benzodiazeoine A mixture of 2.0 g cf 10, ll-dihydro-10- [4- iodobenzoyl) -5H-pyrrolo[2, 1-c] [1, 4]benzodiazeoine, 1.0 g of phenylacetylene and 200 mg of Pd(II) chloride iε refluxed in 250 ml of acetonitrile for 4 hours. The reaction mixture is cooled to room temperature and the resulting yellow crystalline solid collected, dried and crystallized from methyl alcohol to afford 1.2 g cf the desired product. Mass spectrum: M-*-H:389. Example 5 10 , ll-Pihvdro-10- f4- .2-methyloher.yl benzoyl1 -5H- pyrrolo \ 2 , 1-ci ri , 4 1 benzodiazeoine A mixture of 2.0 g cf IC, ll-dihydre-10- (4- iodobenzoyl) -5H-pyrrolo[2, 1-c] [1, 4]benzodiazeoine, 3.0 g of 2- (tributylstannyl) toluene and 200 mg cf tetrakiε- (triphenylphosphine)palladium(O) in 200 ml cf toluene iε refluxed for 16 hourε. The reacticn mixture iε evaporated in vacuo to a reεidue which iε purified by column chromatography on εiiica gel by elution with 30% ethyl acetate-hexane to give 1.0 g of the deεired product aε a solid. Maεε spectrum: M+H:379. Example 6 10, ll-Dihvdro-3- r (dimethyla ino.methyl1 -10-r4-(2- thienyl) benzoyl1 -5H-oyrrolo 2 , 1-cl fl, 41benzodiazeoine A mixture of 400 mg cf 10, li-dihydro-10- [4- (2- thienyDbenzoyl] -5H-pyrrolo[2, 1-c] [1, 4]benzodiazepine, 10 ml of 40% formalin and 10 ml of 40% N,N-dimethylamine in 50 ml cf 1:1 tetrahydrofuran:methyl alcohol iε refluxed for 3 hourε. The reaction mixture iε evaporated in vacuo to a reεidue which iε extracted with chloroform, washed with water, dried over Na2Sθ , filtered and the filtrate evaporated in vacuo to give a residue which iε purified by column chromatography on εiiica gel by elution with 30% ethyl acetate-hexane tc give 300 mg of the desired product as a solid. Maεε spectrum: M+H:428. Example 7 5- f f1.1 ' -Biphenyll -4-ylcarbonyl . -5 , 10-dihvάro-4H- pyrazoloT5, 1-cl I " !, 41benzodiazeoine To a εtirred εolution of 185 mg of 5,10- dihydro-4H-pyrazolo[5, 1-c] [1, 4]benzodiazeoine in 50 ml of methylene chloride containing 2.0 ml of triethylamine iε εlowly added a solution cf 300 mg cf 4-biphenyl- carbonyl chloride in 10 ml of methylene chloride at room temperature. The reaction mixture iε εtirred at room temperature for 16 hourε and evaporated in vacuo tc give a reεidue. The reεidue iε extracted witr. chloroform., waεhed with water, dried over 2Sθ4 # filtered and the filtrate evaporated in vacuo to give a reεidue which is purified by column chromatography cn εiiica gel by elution with 30% ethyl acetate-hexane to give 2E0 mg cf the deεired product as a εoiid. Maεε εpectrum: M-H:Ξ56. Examde 8 10 , ll-Dihvdro-10- r \ 2 ' - < riflucrcrrethyl' r1 , 1 ' -biohenyl " - 4-yll carbonyl-EH-oyrrclc r 2 , 1-c 1 ' 1 " benzodiazeoine To a solution cf 2.0 g cf 1 , li-dihydrc-10- (4- lodobenzcyl) -5H-pyrrolo[2, 1-c] [1,4]benzodiazeoine and 4.2 g of m-trifluoromethyltributyltm m 100 ml cf toluene and 30 ml of N,N-dimethylformar.ide under nitrogen iε added 0.5 g of tetrakis (triphenylphos¬ phine)palladium and the mixture is heated tc 120°C fcr 12 hourε. The toluene iε evaporated in vacuo and the oily residue diluted with 50 ml cf chloroform and filtered through diatomaceouε earth. The filtrate s washed with water (3 X 50 ml; , dried(Na2Sθ4 ; and evaporated in vacuo to give a residue which iε columned on silica gel by elution with 7:1 to 1:1 ethyl acetate:hexane to give 1.75 g cf the deεired product as a eolid, m.p. 138-141°C ; M-K=423.4; M- a=455.4. 7? Example 9 10. ll-Dihvdro-10- T4- (2-pyridinyl)benzoyll -5H- pyrroloT2 , 1-cl ri , 41benzodiazeoine To a solution of 2.0 g of 10, li-dihydrc-10- (4- iodobenzoyl) -5H-pyrroio [2, i-c] [1, 4]benzodiazeoine and 4.39 g of 2- [ (tri-n-butyl) stannyl]pyridine in 30 ml of toluene under nitrogen iε added 0.2 g cf tetrakis (tri¬ phenylphosphine)palladium and the mixture heated tc 120°C for 16 hourε. The toluene iε evaporated in vacuc and the oily reεidue diluted with 50 ml cf chloroform and waεhed with water, dried(N 2Sθ4) , filtered through diatomaceouε earth and evaporated in vacuc tc give a reεidue which iε columned cn εilica gel by elution * .-. * ιtn 7:1 to 1:1 ethyl acetate :hexane tc give 1.44 g cf the deεired product aε a solid, m.p. 17ϋ-172 c C;>!-H=3c6.1; M+Na=388.1. 10 , 11-Dihvdro-lC- r 4- (2-thiazolyl .benzoyl ' " 1 To a solution cf 1.1 g of 10 , ll-dinydro-10- v 4- iodobenzoyl) -5H-pyrroio[2, i-c] [1, 4]benzodiazeoine and 1.49 g of 2- (tributyiεtannyl) th azcle (Reference Example 48) in 50 ml of toluene under nitrogen iε added 0.2 g cf tetrakis (triphenylphcεphine) alladium and the mixture heated to 120°C for 16 hours. The toluene is evaporated in vacuo to a reεidue which is columned on εiiica gel by elution with 7:1 to 1:1 ethyl acetate:hexane to give 0.62 g of the desired product aε an amphorcuε εolid;M+H=372.3 ; M+Na=3 5.3. 10 , ll-Dihvdro-10- f4- I " ■ 4-methyloher.yl^ thio " ber.zcv pyrrolo \ 2 .1-cl r l , 41benzodiazeoine To a εolution of 1.0 g cf 10, 11-dihydrc- pyrrolo[2, 1-c] [1, 4]benzodiazeoine in 50 ml cf dry methylene chloride, under nitrogen, and coded to added droowiεe a solution cf 2.50 g cf 4- ι 4-metr.y phenyl) thio]benzoyl chloride in 30 mi cf methylene chloride. A 5.0 ml portion of tri-ethylamine iε added and the reaction mixture stirred at room temperature for 16 hourε. The reaction mixture iε diluted with 50 ml cf chloroform and washed with 50 ml each of water, 2N HCl, water, saturated NaHCθ3 and water. The organic layer is dried (Na2S04) and columned on silica gel by elution with 7:1 to 3:1 ethyl acetate:hexane tc give 1.96 g of the desired product aε a εolid. M-H 411.2 M->-Na 433.2. Example 12 10 , ll-Dihvdrc-10- f4-Pher.ylεulfonyllbenzoyl! -5H- oyrrolof2 , 1-cl .1,41benzodiazeoine To a solution cf 1.0 g cf 10, li-dihydro-5H- pyrroio [2 , 1-c] [1, 4] benzodiazeoine m 30 ml cf dry methylene chloride, under nitrogen, and cooled to 0°C iε added dropwise a εolution cf 1.82 g cf 4- (pher.yl- sulfonyl) benzovl chloride m 20 ml cf methylene chloride. A 7.0 mi pcrcicr. cf tri-ethy_amιne lε added and the reaction mixture εtirred at room temperature fcr 16 hourε. The reaction mixture iε diluted with 52 ml cf chloroform and waεhed with 50 ml each cf water, 2K HCl, water, εaturated NaHCCj and water. Tne crganic layer is dried (K 2S04) and columned cn εiiica gel by elution with 7:1 to 3:1 ethyl acetate:hexane tc give 2.2 g cf the άeεired product aε a solid. M-H 429.2 M-Na 451.2. Example 13 10. ll-Dihvdro-10- T4- r (4-methylphenyl, sul cnyl " benzoyl ' - 5H-oyrroioι " 2.1-c! ri , 41benzodiazeoine A mixture of 2.13 g of 4- [ (4-metnylphenyi) - εulfonyl]benzoyl chloride (Reference Example 42) and 1.0 g of 10, li-dihydro-5H-pyrroio[2, 1-c] [1, 4]benzodiazepιne in 30 ml of methylene chloride containing 7 ml cf triethylamine iε εtirred under nitrogen atmosphere for 16 hourε. The reaction mixture is diluted with ? ml cf chloroform and washed with 2N HCl, water, εaturated NaHCO" and water. The organic layer s dried vKa^SC. 3/ and columned on silica gel by elution with 7:1 to 3:1 ethyl acetate:hexane to give 1.3 g of the deεired product as a εolid. M+H 443.2;M÷Na 465.2. Example 14 10. ll-Dihvdro-10- r \4 ' - (2-prooenylcxyi f1.1 ' -biohenyl! -4- yll carbonyll -5H-oyrrolor2 , 1-cl r1 , 4 ' 'benzodiazeoine To a εolution of 3.3 g of 10, li-dihydrc-5H- pyrrolo[2, 1-c] [1, 4]benzodia∑epine in 60 ml cf dry methylene chloride, under nitrogen, and cooled to 0°C iε added 22.0 ml of triethylamine followed by a solution of 1.2 equivalents cf 4 ' - (2-prcpenyloxy) - [1, 1 ' - biphenyl] -4-carbonyl c ' nleride in 20 ml cf methylene chloride. The reaction mixture is εtirred at room temperature fcr 16 hourε. The reaction mixture s diluted with 50 ml of chloroform, and waεhed with 52 ml each cf water, 2N HCl, water, εaturated >ϊaHCC2 d water. The organic layer iε dried (Na2S ) and cclumr.ed cn εilica gel by elution with 7:1 tc 3:1 ethyl acetate:hexane to give 4.8 g of the deεired product aε a εciid. M---H 421.2 M÷Na 442.2. Example 15 10 , ll-Dihvdro-10- T4- .ohenylthio ■benzoyl " -EH-oy rolc " 2.1- c1 ' 1,4 " benzodiazeoine To a εolution cf 1.0 g cf 10 , il-dihydro-5H- pyrrolo [2, 1-c] [1, 4]benzodiazeoine in 50 ml cf dry methylene chloride, under nitrogen, and ceded to 0°C iε added 5.0 ml of triethylamine followed by a solution cf 2.16 g of 4- (phenylthio)benzovl chloride (Reference Example 34) in 30 ml of methylene chloride. The reaction mixture iε εtirred at room temperature for 16 hours. The reaction mixture iε diluted with 50 ml cf chloroform and washed with 50 ml each cf water, 2N HCl, water, saturated NaHCOs and water. The organic layer is dried (Na2Sθ4) and columned cn εiiica gel by elution with 7:1 to 3:1 ethyl acetate:hexane to give 1.92 g cf the deεired product as a solid. M-H 397.1 M-Ka 419.1. Example 16 10- f4-3enzoylbenzoyl -10 , ll-cihvάro-5H-cyrrolc '2,1- c1 f1 , 41benzodiazeoine A mixture of 2.16 g cf 4- (benzoyl)benzovl chloride (Reference Example 36) and 1.0 g of 10,11- dihydrc-5H-pyrrolo[2, 1-c] [1, 4]benzodiazepine in 20 mi cf methylene chloride containing 7 ml of triethylamine is stirred under nitrogen atmosphere for 16 hourε. The reaction mixture is diluted with 50 ml cf chloroform and waεhed with 2N HCl, water, εaturated NaKCθ3 and water. The organic layer iε dried (Na2S ) and columned cn silica gel by elution with 7:1 to 2:1 ethyl acetate:hexane tc give 1.8 g cf the deεired product aε a solid. M-"-H 292.2,*M- j -Na 415.2. Example 1 " pyrrolo " 1 2- 1 To a mixture cf C.5 g of 4, 5-dιhydrocyrrcic- _ -ir.cxaline and 2.96 g cf 4-ticher.ylcarconyi chlcnde in 50 ml cf metnylene chloride under argcr. is added 7.0 ml of triethylamine followed X εtirring at room temperature fcr 16 hourε. The reaction mixture lε diluted with 50 ml cf chloroform and waεned witn water, 2K HCl, εaturated NaHCC'3 and water. The organic layer is dried (Na2Sθ4) and columned cn εilica gel by elution with 7:1 to 1:1 ethyl acetate:hexane to give C.S7 g cf the deεired product ae a εolid. M-H 351.2 ,-M-ι-Na 372.2. Example 18 10 , ll-Dihvdro-10- f4- ■ 4-methylohencxy>benzoyli -5H- pyrrolo \ 2 , i-cl r 1, 4ibenzodiazeoine To a εtirred εolution cf 1.0 g cf 10,11- dihydrc-5H-pyrazolo[5, 1-c] [1, 4]benzodiazepine m 30 ml cf methylene chloride, under nitrogen, while cooling to C°C is added dropwiεe 20 mi of triethylamine ::..:we: oy a solution of 1.2 equivalents cf 4- (4-r.ethyiphenox * /^ - benzovl chloride in 10 ml of CH2CI (Reference Examp_e 53) prepared from Reference Example 52 and thionyl chloride. The reactants are stirred at room temperature for 16 hours and concentrated in vacuc to a reεidue. The reεidue iε dissolved in methylene chloride, washed with water, 2N HCl, water, saturated aqueous NaHCO j , water and dried(MgSθ4) and evaporated in vacuo to give 2.2 g of the desired product. MS (M-*-H=395.1) Example 19 10- ([1,1' -Biohenyl! -4-ylcarbonyl . -10 , ll-dihvάro-5H- pyrrolo [ 2 , 1-cl fl , 41benzodiazepine A solution cf 0.9 g cf 10, ll-dihydro-5H- pyrazolo [2 , 1-c] [1, 4]benzodiazepine in 30 ml cf methylene chloride is cooled to 0 C C and 1.6 mi cf triethylamine added. A solution cf 1.2 equivalents cf 4-bιpnenyl- carbonyi c ' nleride in 10 ml of CH2CI2 iε added and the reaction mixture εtirred at room temperature for 16 houre. The reaction mixture lε diluted v. * itn 50 ml of chloroform and washed with 20 ml each cf water, 2K HCl, water, εaturated aqueous MaHCC3 and water. The crgar.ie _c- _r lε cried and eva orated in vacuc The reεidue iε purified by column chromatography cn εiiica gel by elution with 3:1 hexanerethyl acetate to give 1.5 g cf the desired product. Example 20 10- < ri , 1 ' -Biohenyl1 -4-ylcarbonyl . -10 , 11-άihvdro-K.K- di ethyl-5H-oyrrolci " 2.1—c1 r l,4ibenzodiazeoine-3- me hanamine A εolution of 0.6 g of 10- ([1, 1 ' -biohenvl] -4- ylcarbonyl) -10, ll-dihydro-5H-pyrrolo[2, i-c.] [1, 4]benzodi¬ azepine in 50 ml of 1:1 methyl alcohol*.tetrahydrofuran iε εtirred under nitrogen while 10 ml cf a 30% solution of formaldehyde, 10 mi cf a 40% solution of dimethyl- amine and 2 drops of acetic acid iε added. The reaction mixture iε εtirred at room temperature for 16 ncurε then extracted with chlorofor (3 X 100 mi) and the organic layer waεhed with saturated aqueous NaHCCjil X 52 ml, , water (2 X 50 ml) , dried and evaporated in vacuo to give 0.68 g of a residue which iε εtirred with petroleum et ' ner to give 0.62 g of the deεired product aε a cryεtalline εolid, m.p. 85-87°C. Example 21 10.11-Dihvdro-lO- r f4 ' -orooyl fl , 1 ' -biphenyl! -4- yl) carbonyll -5H-oyrrolor2 , 1-cl [1 , 41benzodiazeoine To a stirred solution of 2.0 g of 10,11- dihydro-5H-pyrrolo [2, i-c.] [1, 4]benzodiazepine in 20 l cf methylene chloride, under nitrogen, while cooling to 0°C iε added dropwise 30 ml of triethylamine followed by a solution cf 4 ' - (propyi ) i 1, 1 ' -biphenyil -4-carbcnyl : mi cf The reaction mixture tε poured m ice water and extracted with methylene chlcride < 2 X 50 ml) Tne organic layer is, waεhed w th water, 2X citric acid, saturated aqueous NaHCC;, water and άriedJMgΞC ) and evaporated in vacuo to give a residue which is purified by column chrcmatcgrapr.y on εilica gel with etnyl acetate-hexane to give 1.4 g of the desired product aε a crystalline εolid, m.p. 11£-120°C. MS M-H=427.2; Example 22 10 , ll-Dihvdro-10- T2- f 2-thιenyl . pyriάin-5-yl ^ carbon * * 1 " - 5H-pyrrolc T2 , 1-cl ri , 41 benzodiazeoine A solution cf 5 mmol cf 10 , il-dihydro-ΞH- pyrazolo [2 , 1-c] [1, 4 ] benzodiazepine in 20 ml cf methylene chlcride is cooled to 0°C and 10.0 ml cf triethylamine added. A solution cf 6 mmcl of Reference Example 60 is added and the reaction mixture εtirred at rccm temperature for 16 hourε. The reaction mixture is diluted with 60 ml cf chloroform and waεhed with 40 rl each of water, εaturated aqueous NaHCC2 and water. Tne organic layer is dried and evaporated n vac o to a residue. The residue is purified bv column τs chromatography on silica gel by eluticn with 3:1 hexane:ethyl acetate to give the deεired product. UTILITY TESTING Binding Aεεav to Rat Heoatic VI Receptorε Rat liver plasma membranes expressing the vasopressin Vi receptor subtypes are isolated by sucrose density gradient according to the method de scribed by Lesko et al . , (1973) . These membranes are quickly suspended in 50.0 mM Tris.HCl buffer, pH 7.4, containing 0.2% bovine serum albumin (BSA. and 0.1 m_*. phenylmethylsulfonylfluoride (PMSF) and kept frozen at -70 C C until ueed in εubεequent binding experiments. For binding experiments, the following iε aided tc the weliε cf a ninety-six well format micrctiter plate: 100 μl of 100.0 ml-! Tris.HCl buffer containing 10.0 mi! MgCl2, C.2% heat inactivated ESA and a mixture cf pro teaεe inhibitors: ieupeptin, 1.0 mg %; aprctinin, 1.2 mg %; 1, 10-phenanthreline, 2.0 mg %,* trypεir. inhibitor, 10.0 mg % and 0.1 m>! PMSF, 20.0 μl cf [phenylalanyl- 3,4,Ξ,- 2 H] vasopressin (S.A. 45.1 Ci/mmcle ' ι at 2.8 nX, c * .nd the reaction initiated by the addition, of 80 μl cf tissue membranes containing 20 μg cf tissue protein. The piateε are kept undisturbed cn tne bench top at room temperature for 120 min. tc reach equilibrium. Non-specific sampleε are aεεayed in the presence cf 0.1 μM of the unlabeled antagonist phenyiaianylvaεcpreεεin, added in 20.0 μl volume. For test compoundε, theεe are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 μl volume to a final incubation volume cf 200 μl . Upon completion of binding, the content of each well is filtered off, using a Erandel®, cell Harvester (Gaithersburg, MD) . The radioactivity trapped cr. the filter disk by the ligand-receptcr complex is cu -..-•=_ bv licuiά scintillation ceuntinc m a Packard I U Counter, with an efficiency of 65% fcr tritium. The data are analyzed for IC50 values by the LUNDON-2 program for competition (LUNDON SOFTWARE, OH) . Bindinσ Assav to Rat Kidnev Medullary V~_ Receotcrs Medullary tissueε from rat kidneys are diε εected out, cut into εmall pieceε and soaked in a 0.154 mM sodium chloride solution containing 1.0 mM EDTA with many changes of the liquid phase, until the solution is clear of blood. The tiεsue is homogenized in a 0.25 M sucrose solution containing 1.0 mM EDTA and 0.1 mM FMSF using a Pctter-Elvehjem homogenizer with a teflon pestle. The hcmogenate iε filtered through εeverai layers (4 layers) of cheese cloth. Tne filtrate iε rehcmcgenized using a dounce homogenizer, with a tight fitting peεtie. The final hcmogenate ie centrifuged at 1500 x c for 15 min. The nuclear pellet iε diεcarded ecentnrugeo. at ..lUt'j x c pin.- * outer part IΞ εuεpenαeα m a ε»..a a...cunt or Ξ S. . _ mM Tris.HCl buffer, pH 7.4. The protein content iε determined by the Lewry' ε method (Lowry et al . , C. Ξicl. Chem., 1953; . The membrane εuεpenεicn 1= εtored at -70 C C, in 50.0 mM Triε.HCi, containing 0.2% inactivated ESA and 0.1 ml! PMSF in aliqucts cf 1.0 ml containing 10.0 mg protein per ml of suspension until use in subεeσuent binding experiments. Fcr binding experiments, the following iε added in μl volume to weliε of a 96 well format cf a micretiter plate: 100.0 μl cf 100.0 ml-'. Triε.HCi buffer containing 0.2% heat inactivated ESA, 10.0 mM MgCl2 an: a mixture cf proteaee inhibitors: ieupeptin, 1.0 mg %, * aprotinin, 1.0 mg %,* 1, 10-phenanthroline, 2.C mg %, * trypεin inhibitor, 10.0 mg % and 0.1 XX. FMSF, 20.0 μl of H Argmine 8 , vasopressin (S.A. " 5.0 Ci/mmole. at *1 80.0 μl of tissue membranes (200.0 μg tissue protein) . The plates are left undisturbed on the bench tc for 120 min to reach equilibrium. Non-specific binding iε assessed in the presence of 1.0 μM cf unlabeied ligand, added in 20 μl vclume. For test compoundε, these are solubilized in 50% dimethylsulfoxide (DMSO and added in 20.0 μl volume to a final incubation volume cf 200 μl . Upon completion of binding, the content cf each well iε filtered off, uεing a Erandel, cell Harvester (Gaithersburg, MD) . The radioactivity trapped cn the filter diεk by the ligand-rece tcr complex iε aεεesseά by liquid scintillation counting in a Packard ZS Coun ter, with an efficiency cf 65% for tritium. The data are analyzed fcr IC50 values by the LUNDCN-2 program fcr competition (LUNDON SOFTWARE, OH) . The results cf thiε teεt on representative compcundε of this invention are εhown in Table I . Radicliσand Eindinα Experiments with Human Platelet Membraneε (a) Platelet Membrane Preparation: pla. Ξource: Hudson Valley Eiecd Services, Westcr.escer Medical Center, Valhalla, NY) are thawed to rocm temperature. The tubes containing the PR? are centrifuged at 16,000 x g for 10 min. at XZ and the supernatant fluid discarded. The platelets resuεpend- ed in an equal volume of 50.0 mM Triε.HCi, pH 7.5 con¬ taining 120 mM NaCl and 20.0 mM EDTA. The suspension iε recentrifuged at 16,000 x g fcr 10 min. This waεh- inσ step is repeated one more time. The wash diεcarceo. and the lysed pellets homogenized in lev: ionic strength buffer of Tris.HCl, 5.0 M, pH 7.5 containing 5.0 mX EDTA. The homogenate is centrifuged at 39, CCC x g for 10 min. The resulting pellet iε reεuεpended m Triε.HCi buffer, 70.0 mM, pH 7.5 and recentrifuged at 39,000 x g fcr 10 min. Tne final pellet 1= reεuεpended *9 in 50.0 mM Triε.HCi buffer pH 7.4 containing 120 mM NaCl and 5.0 mM KCl to give 1.0-2.0 mg protein per ml of suspension. (b) Eindinσ to Vasopresεin VI receptor εubtvoe in Human- Platelet Membranes : In wells of a 96 well format microtiter plate, add 100 μl of 50.0 mM Tris.KCl buffer contain¬ ing 0.2% ESA and a mixture of proteaεe inhibitors (aprotinin, leupeptin etc.) . Then add 20 μl of [^H]Ligand (Manning cr Arg^Vascpressin) , to give final concentrations ranging from 0.01 to 10.0 nM. Initiate the binding by adding 80.0 μl cf platelet εuεpensicn (approx. 1C0 μg protein' . Mix all reagents by pipetting the mixture up and down, a few times. Non specific binding is measured m the prεεence of 1.0 1M cf uniabeled ligand (Manning cr Arg^Vascpressin, . Let the mixture εtand undisturbed at room temperature for ninety (90) min. Upon this time, rapidly filter cff the incubate under vacuu suction over G?'Ξ filters, using a Erandel Harvester. Zeter ir.e the radioactivity caught on the filter disks by the addition cf liquid scintiliant and counting m a liquid scintillatcr. Bindinc to Membranes cf Mouεe Fibroblast Cell L ne .LV-2* Transfected with the c NA Expressing the Human V2 Vaεooressin Receptor (a) Membrane Preparation Flasks of 175 ml capacity, containing attached cells grown to confluence, are cleared of culture medium by aspiration. The fiaεks containing the attached cellε are rinεed with 2x5 ml cf phosphate buffered saline (PES) and the liquid aspirated cff each time. Finally, 5 ml cf an enzyme free dissociation Hank's baεed solution (Specialty Media, Inc., Lafayette, NJ) is added and the fiaεkε are left undisturbed fcr 2 min. Tne content cf all fiaεkε iε poured into a centrifuge tube and tne eel. 300 x g for 15 min. The Hank's based solution is aspirated off and the cells homogenized wit ' n a polytron at setting #6 for 10 sec in 1 .0 mM Tris.HCl buffer, pH 7.4 containing 0.25 M sucrose and 1.0 mM EDTA. The homogenate is centrifuged at 1500 x g for 10 min to remove ghoεt membranes. The supernatant fluid is cen¬ trifuged at 100,000 x g for 60 min to pellet the receptor protein. Upon completion, the pellet is re- suspended in a small volume of 50.0 mM Triε.HCi buffer, pH 7.4. The protein content iε determined by the Lowry method and the receptor membranes are suspended in 50. C mM Triε.HCi buffer containing 0.1 mM phenylmethyiεui- fonylflucride (PMSF) and C.2% bovine εerum albumin (BSA) to give 2.5 mg receptor prctein per mi cf suspension, (b) Receptor Eir.dir.c Fcr binding experiments, the following is added in μl volume to wells cf a 96 well format cf a microtiter plate: 100.0 μl of lOC.O M Triε.HCi buffer containing 0.2% heat inactivated ESA, 10.0 mM MgCl2 and a mixture cf preteaεe inhibitors: leupeptin, 1.0 mg%,* aproti in, 1.0 mg %,* 1, 10-phenanthroline, 2.0 mg %,* trypεin inhibitor, 10.0 mg % and 0. I mM FMSF., 20.0 μl of [ κ] A.rgir_ine~ , vasopresεin (S.A. 75.0 Ci/mmole) at 0.8 nM and the reaction initiated by the addition cf 80.0 μl of tissue membranes (200.0 μg tissue protein) . The plates are left undiεturbed on the bench top fcr 120 min to reach equilibrium. Non εpecific binding iε asseεεed in the preεence cf 1.0 μM cf unlabeied ligand, added in 20 μl volume. For teεt ccmpounds, these are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 μl volume to a final incubation volume cf 200 μl . Upon completion of binding, the content cf each- well iε filtered off, using a Brandei, cell Harvester (Gaithersburg, MD) . The radioactivity trapped cr. the filter disk by the ligand-receptcr complex is assessed by liquid scintillation counting in a Packard LS Counter, with an efficiency of 65% fcr tritium. The data are analyzed for IC50 values by the LUNDON-2 program for competition (LUNDON SOFTWARE, OH) . Table I Binding Aεsav to Rat Heoatic V]_ Receptors and Rat Kidne * . Medullary " Receotorε or *Bindinσ to Vτ_ Receotcr Subtvoe in Human Platelet and **Bindinσ to Membranes cf Mouse Fibroblast Cell Line(LV-2. Tranεfected with the cDNA Exoresεinα the Human V Receptor 2 Ex.No. Structure ICcp ( - .C- - ** (LLM' r ? : 92 C.C63 ' 15llM 0.4 9 13 1UM(51% 0-CH.CH--CH. 10L _ M , S%; . 14 16 I0μM(82%)* lμi>.(42% * 9 19 0.0C29" 0.39 C .96 ' Vasopressin V Antagonist Activit y in Conεcicuε Hvdrated Rats Conεciouε hvdrated ratε are treated with com¬ pounds under εtudy from 0.1 tc 100 mg/kg orally cr vehicle. Two to four ratε are uεed for each compound. One hour later, arginine vasopressin (AVP, antidiuretic hormore, ADH) dissolved in peanut oil is administered at 0.4 μg/kg intraperitonealiy. Two ratε in each teεt would not receive arginine vasopressin but cr.ly the vehicle (peanut oil) to serve aε water-loading control. Twenty .minuteε later each rat iε given 20 ml/kg cf άeionized water orally by gavage and lε placed indi¬ vidually in a metabolic cage equipped with a funnel and a graduated giaεε cylinder to eciiect urine fcr four hourε. Urine volume iε measured and cεmeiality analyz ed by uεe cf a Fiεke One-Ten oε er.eter (Fiεke Aεscc, Norwood, MA, USA) . Urinary sodium., pccaεεium, and chlcride are analyzed by uεe cf icn-εpecific electrodeε in a Eeck an E3 (Electrolyte 3) Analyzer. In the following results, decreased urine volume and decreased cεmclaiity relative to AV?-ccntrol indioateε activity. The results cf this teεt cn representative compounds cf this invention are show m Table II . Table II Vasooreεεin V2 Antagonist Activity In- Conscious Hvdrated Ratε Ex. No Dose N Urine Osmolality (mg/kg) Volume (mOεm/kg- (ml/4 hrs; 78 13.3±0.3 229^6 6 12.1±1 497^53 4 12.4-0.8 361^30 76 2-0.2 1226-58 1 10 2 1148 2 2 3 2 4 10 3 5 IC 2 10 2 10 G 10 10 2 12 10 2 13 10 2 14 10 2 ~> ' 15 10 2 16 10 2 c 1022 17 10 2 10.3 929 18 10 2 °19 19 10 2 20 10 2 i-3L 21 10 2 1247 * Water-load control .-. -eon: ** Water-load Control+DMΞOαO- t £> 0 Vasopressin Vj_ Antagonist Activity in Consciouε Ratε Conεciouε rats are restrained in a supine position with elastic tape. The area at the base of the tail is locally anesthetized by subcutaneouε in filtration with 2% procaine (0.2 ml) . Using aseptic technique the ventral caudal tail artery iε iεoiated and a cannula made of PE 10 and 20 (heat-fused) tubing iε paεεed into the lower abdominal aorta. The cannula iε εecured, heparinized (1000 i.u./cc), eealed and the wound cloeed wit ' n one or two εtitcheε cf Dexon 4-0. The caudal vein iε alεc cannulated in t'ne same manner for intravenous drug administration. The duration cf the surgery is approximately 5 minuteε. Additional local anesthesia (2% procaine cr lideeaine) iε provided aε needed. The animals are placed in plastic restraining cages in an upright position. The cannula iε attached tc a Statham F23Dt preεsure transducer and pulsatile blood pressure iε recorded. Increase cf systolic bleed pressure responses to arginine vasopressin 0.01 and 0.2 international unit (I.U.) (35G I.U.=i mg) injections are recorded prior to any drug (compoun j ad iniεtration, after which each rat iε doεed orally with compounds under study 0.1-100 mg/kg (IC cc/kgj cr in ravenously 0.1-30 mg/kg (1 cc/kg) . The vasopreεεin in "* ectιcnε are repeated 30,60,90,120,180,240 and 300 min. later. Per¬ centage cf antagonism by the compound iε calculated uεing the pre-drug vasopreεεin vaεopreεεor response aε 100%. The reεultε of thiε teεt on representative compounds of thiε invention in which the doεe, the maximum % inhibition and the time in minutes, are εhown in Table III . 161 Table III VASOPRESSIN (VAS) VASOPRESSOR RESPONSE Ex. No. e (min) 1 3 4 7 9 11 14 16 17 18 20 Oxytocin Receptor Eindinα (a) Membrane Preparation Female Sprague-Dawley ratε weighing approxi¬ mately 200-250 g are injected intramuscularly (i.m.) with 0.3 mg/kg cf body weight cf άiethyiεtilbeεtrcl (DES) . The rats are sacrificed 18 hourε later under pentobarbital aneεtheεia. The uteri are diεεected out, cleaned of fat and connective tissues and rinεed in 50 ml of normal saline. The tissue pooled from six ratε is homogenized in 50 ml of 0.01 mM Trie.HCl, containing 0.5 mM dithiothreitol and 1.0 mM EDTA, ad uεted to Xr. 7.4, using a polytron at setting 6 with three paεεes cf 10 εec each. The hcmogenate is paεsed through two (l 1 layers cf cheesecloth and the filtrate centrifuged at 1000 x g for IC min. The clear supernatant is removed and recentrifuged at 165,000 x g for 20 min. The re¬ sulting pellet containing the oxytocin receptors iε re- euεpended in 50.0 mM Triε.HCi containing 5.C m MgCl~ at pH 7.4, tc give a protein concentration cf 2.5 g/ l cf tissue suspension. This preparation is used in sub¬ sequent binding aεεayε with [--H]Oxytocin. (b) Radioliαand Binding Binding cf 3 , 5- [-H] Oxytccm < ;-H]CT' tc itε receptors lε dene in mierctiter plates using ;-H!CT, at various concentrations, in an assay buffer cf 50. mM Tris.HCl, pH 7.4 and containing 5.0 M MgCl:. and a mixture of prctease inhibitors: ESA, C.l mg,- aprotinm, 1.0 mg; 1, 10-phenanthroline, 2.0 mg,- trypεin, 10. C mg; and PMSF, 0.3 mg per 100 ml cf buffer εduticn. Ncn- εpecific binding iε determined in the presence of 1.0 uM ur.labeled CT. The binding reaction is terminated after 60 min. , at 22°C, by rapid filtration through glasε fiber filters uεing a Erandel, cell harvester (Biomedical Research and Development Laboratories, Inc., C-aithersburg, MD) . Competition experiments are conducted at equilibrium uεing 1.0 nM . -κ;cτ and '63 varying the concentration of the displacing agents. The concentrations of agent displacing 50% of [ 3 H]OT at its εites (IC50) are calculated by a computer assisted UNDON-2 program (LUNDON SOFTWA-RE INC., Ohio, USA). t o The results of this assay on representative examples are shown in Table IV. Table IV Oxytocin Binding Assav Ex. No. Dose (μM) % Inhibition IC50 (μM) t 10 UM 2 10 100 0-.04S_ O.00: 3 10 89 2.6 Δ 10 62 10 100 0.23 10 100 c= _ . . 100 r - ' 10 10 77 2.5 11 10 86 1.8 12 10 69 13 10 67 14 10 67 15 10 98 2.1 16 10 100 0.11 17 10 92 1.09 IS 10 99 0.12 19 10 81 0.043 20 10 100 0.11 21 10 68 22 10 98 0.48 The compounds of the present invention can . used in the fcrm of salts derived from pharmaceutical! cr physiologically acceptable acids cr bases. These salts include but are not limited to the following: εaitε with inorganic acids such as hydrochloric acid, εulfuric acid, nitric acid, phosphoric acid and, as t. case may be, such organic acids aε acetic acid, cxali: acid, euccinic acid, and maleic acid. Other εaltε include εaltε with alkali metalε cr alkaline earth n>S metalε, such aε sodium, potassium, calcium or magneεium or with organic bases. The compounds can also be used in the form of esters, carbamates and other convention¬ al "pro-drug" forms, which, when administered in such form, convert to the active moiety in vivo. When the compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like, and may be adminiεtered orally in such forms as tablets, capsules, dispersible powders, gran¬ ules, cr suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups contain¬ ing, . for example, from about 10 to 50% cf sugar, and elixirε containing, for example, from about 20 tc 50% ethanol, and the like, or parenterally in the form, cf εteriie injectable εoluticn or suspension containing from about 0.05 to 5% suspending agent in an isotcnie medium. Such pharmaceutical preparations may contain, fcr example, from about C.05 up tc about 90% cf the active ingredient in combination with the carrier, mere usually between abcut 5% and 60% by weight. The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity cf the condition being treated. However, in general, satisfactory resultε are obtained when t ' ne compoundε of the invention are administered at a daily dosage cf from about 0.5 to about 500 mg/kg of animal body weight, preferably given in divided doεee twc to four timeε a day, or in sustained release form. For most large mammalε the total daily doeage iε frcm about 1 to 100 mg, preferably from about 2 to 80 mg. Dcεage forms suitable for internal use comprise frcm about 0.5 tc 500 mg of the active compound in intimate admixture with a εolid or liquid pharmaceutically acceptable car rier. This dosage regimen may be adjusted to provide f ύ X the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may¬ be proportionally reduced aε indicated by the exigen¬ cies of the therapeutic situation. These active compounde may be adminiεtered orally as well as by intravenous, intramuscular, or subcutaneouε routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellu¬ lose, sucroεe and kaolin, while liquid carrierε include sterile water, polyethylene glycols, non-ionic surfac¬ tants and edible cilε such as corn, peanut and sesame oils, aε are apprcpriate to the nature of the active ingredient and the particular form cf administration deεired. Adjuvants customarily employed in. the pre¬ paration cf pharmaceutical compositions may be advanta geouεly included, such as flavoring agents, cclcring agents, preserving agents, and antioxidantε , fcr exam¬ ple, vitamin E, ascorbic acid, EHT and EHA. The preferred pharmaceutical compositions fro the standpoint cf ease cf preparation and ad.inis traticn are sclid compoεitionε, particularly tabletε and hard-filled cr liquid-filled capsules. Cral admin¬ istration cf the compounds is preferred. Theee active compoundε may alεo be adminis¬ tered parenterally or intraperitoneally. Solutions or suspensions cf these active compounds aε a free baεε or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such aε hydroxy propylcelluloεe. Diεperεionε can aiεe be prepared in giycercl, liquid polyethylene glycclε and mixtures thereof m oils. Under ordinary conditions cf stcrage and uεe, theee preparation contain a preservative tc prevent the growth of microorganisms. The pharmaceutical forms suitable for ιn;eet- able uεe include εterile aqueouε solutions cr disper- εior.ε and sterile powders for the extemperar.eeuε pre- 10 1 paration of sterile injectable solutions or disper¬ sions. In all cases, the form must be sterile and must be fluid to the extent that easy εyringability exists. It must be stable under the conditions of manufacture and storage and must be preserved againεt the contam¬ inating action of microorganisms εuch aε bacteria and fungi. The carrier can be a εolvent cr diεperεicn medium containing, for example, water, ethanol, polyol(e.g., glycerol, propylene glycol and liquid polyethylene glycol) , suitable mixtures thereof, and vegetable oils. The new tricyclic non-peptide vasopressin antagonists cf this invention are useful in treating conditions where decreased vasopressin levels are deεired, εuch aε in ccngestive heart failure, in diεeaεe conditions with excesε renal water reabεor tion and in conditions with increased vascular resistance and coronary vaεoconstriction. In particular, the vaεcpreεεin antagonists cf this invention are therapeutically useful in the treatment and/or prevention of hypertension, cardiac insufficiency, coronary vaεoεpaεm., cardiac ischemia, renal vasoεpaεm, liver cirrhcεis, congestive heart failure, nephritic syndrome, brain edema, cerebral ischemia, cerebral hemorrhage-stroke, thrombosis- bleeding and abnormal stateε cf water retention. In particular, the oxytocin antagonists cf this invention are useful in the prevention cf preterm labor and premature birth which is a significant cause of infant health problems and infant mortality.

Claims: What is claimed is: 1. A compound selected from those cf the general formula I: FORMULA I wherein. Y is a moiety selected from; -(CH2)r . ~ wherein n is an integer 0 cr 1, and A-Ξ is a moiety εelected from. wherein m iε an integer frcm 1 tc 2 ; and the moietv: represents: (1) phenyl or substituted phenyl optionally substituted by one or two subεtitutentε εeleeted from (C1-C3) lower alkyl, halogen, amino, (C1-C2) lower alkoxy cr (C1-C3) lower alkyl mino; (2) a 5-membered aromatic (unεaturated) heterocyclic ring having one heteroatom selected from 0, N or S; (3) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen; (4) a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (5) a £-membered aromatic (unsaturated) heterocyclic ring having one ύ f nitrogen atom together with either one oxygen cr one εulfur atom; wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C1-C3)lower alky, halogen or (C1-C3)lower alkoxy; the moiety: is a five memoereα aromatic .unεaturateα) nitrogen containing heterocyclic ring wherein I, E and F are selected frcm carbon cr nitrogen and wherein the carcc atcms may be optionally substituted by a substituent εelected from halogen, (C1-C3) lower alkyl, hydroxy, -CCCI3, -CCCF3, no - (C!^) q -0- lower alkyl(C C 3 ) , -(CH,) — OH -CHC, amine, (C1-C3) lower alkoxy and (C1-C2) lower alkylamino, -CONK- (C1-C3) lov;er alkyl (C1-C2 ) , -CON[lows alkyl (C1-C3 ) ] 2; q iε one cr twc; R iε independently εelected from hydrogen, -CH3 and -C2H5; R-*- iε a moietv of the formula: -C-Ar wherein Ar iε "/ wherein R^ iε εelected from wherein L is o, s , sc , S02 , -co¬ rn? - , K' is CH cr N; X lε 0, S, N-lower alkyl (C1-C3 ) and ' iε εelected from 0, Ξ, NH, N-lower alkyl {C1-C3 v and N-benzyl; R 4 ie εelected from hydrogen, lower alkyl (C1-C3 ) , -CO- lower alkyl (C1-C3) ; R-*- and R^ are εeiected from hydrogen, (C1-C3) lower alkyl, (C1-C3) lower alkoxy and halogen; pβ iε selected from hydrogen, lower alkyl (C1-C2 ) , lower alkoxy(C1-C3) -0-CH2-CH=CH2 and halogen; F 7 iε εeieoted from hydrogen, lower aIkyl<Cι-C3 ) , halogen, 0-iower alkyl (C1-C3) and CF3 ; PX and F. s are independently selected from hydrogen, lower alkyl (C1-C3 > , -Ξ-lcwer alkyl (C1-C3 , , halogen, -ITH-lower alkyl (C1-C3 , , -CCF3 , " 2 -OK, -CN, -Ξ-CF3, -NO2, -NH2 , O-lower alkyl (C1-C3 ) , CC- iower alkyl (C1-C3) and CF3 ; and t ' ne pharmaceutically acceptable salts thereof. 2. A compound according to Claim 1 wherein n is 0 cr I and m is 1 or 2. 3. A compound according to Claim 1 wherein A-B iε 4. A compound according to Claim 1 '.•/herein the mcietv iε phenyl cr substituted phenyl optionally εubεti by one cr twc εubstitutentε εeiected frcm (C1-C3, alkyl, halogen, amine, (C1-C3J lower alkoxy cr ( Z'_ C2 ) lower alkylammo. . A compound according tc Claim 1 wh. the moietv ie a 5-membered aromatic (unsaturated) heterccyeiio ring having one heteroatom εelected from C, N cr S cpticnally substituted by one or two substitutentε εeleeted from. optionally εubstituted by (C1-C3) lower alkyl, halogen cr (C1-C3) lower alkoxy. 6. A compound according tc Claim 1 wherein the moiety tβ is a 6-membered aromatic (unsaturated) heterocyclic rinς having one nitrogen atom wherein the ring is optionally substituted by (C1-C3) lower alkyl, halogen or (Cχ~ C3) lower alkoxy. 7. A compound according to Claim 1 wherein the moiety is a 5 cr 6-membered aro Θ matic (unsatur neterec, ring having two nitrogen atoms wherein optionally substituted by (C1-C3) lower • _-_.". / _ , ..C-—^.-. ****.. • _- - Zι ) lower alkoxy. £ . A compound aocer ing to the moiety is a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom, wherein the 5-membered heterocyclic ring is optionally substituted by (C1-C3) lower alkyl, halogen or (C1-C3) lower alkoxy. 9. A compound according tc Claim 1 wherein the moietv it iε a five membered aromatic (unεaturated) heterocyclic ring in which D, E, and F are carbon wherein one of the carbon atomε is optionally subεtituted by a substituent selected from halogen, (C1-C3) lower alkyl, hydroxy, -COCI3, -COCF3, o / -C-0 -lower alky C.-C 8 ) , — (CH,) N^ ■ (CH 2 ) q -o- lower al yK^ -C 8 ) , -(CH,) — OH 0 C— lower alkyl(C C 3 ) . — CH,— -CHG, amine, (C1-C3) lower alkoxy and ( Cι ~ C; cwer alkvlaminc, -CONK- (C1-C3 ) lower alkyl -CC r icwe: alkyl (C1-C3) ] 2; q is one or two; R iε independentiy εelected from hydrogen, -CK3 and -C2H5. 10. A compound according to Claim 1 wherein t ' ne moiety iε a five membered aromatic (unεaturated) heterocyclic ring in which D iε nitrogen and E, and F are carbon; wherein one cf the carbcn atoms iε optionally substituted by a substituent selected from halogen, (Ci- C j icwer alkyl, and (C1-C3) lower alkoxy. 11. A compound according to Claim 1 wherein Y is -(CK2) -4* n is 0 or 1 wherein the moiety is phenyl or substituted phenyl optionally εubεtitutεd by one cr two substitutentε εelected frcm (C1-C3) lower alkyl, halogen, amine, (C1-C3) lower alkoxy or (Cι~ C" ) lower alkvlamino; iε a five membered aromatic (unεaturated) heterocyclic ring in which D, E, and F are carbcn wherein one cf the carbon atomε iε optionally εubεtituted by a substituent selected from halogen, (C1-C3) lower alkyl, hydroxy, -COCI3, -COCF3, (C^) q -θ-lower alkyKC C 3 ) , -(CH,) — OH - N N / \ ■ CH N, I C ■ (CH,) α -N N R. N • N 2 q \ / -CHO, amino, (C1-C3) lower alkoxy and (C1-C3 > alkylamine, -CONK- (C1-C3) lower alkyl (C1-C31 , -CON[lower alkyl (C1-C3 ) ] 2; g is one or two; Rt is mdep :dentIv selected from hydrogen, -CH3 and -C~H= . 12. The compounds according tc wherein Y is -(CH2)n _ ; r * s 0 or :ιetv iε phenyl cr subεtituted phenyl optionally substituted by one or two substitutents εelected frorr. (C1-C3) lower 11 1 alkyl, halogen, amino, (C1-C3) lower alkoxy cr (Ci* C3) lower alkylamino; the moiety iε a five membered aromatic(unεaturated) heterecycl: ring wherein D iε nitrogen and E and F are carbcn wherein one of the carbon atomε iε optionally εubεtituted by a εubεtituent εelected from halogen, C3) lower alkyl and (C1-C3) lower alkoxy. 13. The compoundε acecrding to Claim 1 wherein Y iε -(CH2)n _ ; r - i 0 cr 1; the moiety ie a 5-membered aromatic (unεaturated) heterocyclic r: having cne heteroatom selected frcm C, or S wherein t; ring iε optionally εubεtituted by (C1-C3) lower alkyl, halogen or (C1-C3) lower alkoxy; the mciety iε a five membered aromatic(unεaturated) heterocyclic ring where D, E, and F are carbcn wherein one cf the carbon atomε is optionally εubεtituted by a εubεtitue: selected from halogen, (C1-C3) lower alk * y1, hydroxy, -COCI3, -COCF3, '/ fr - ■ (C^^-O-lower al yK^-C 8 ) , -(CH,) — OH ( -CHC, amino, (C1-C3) icwer alkoxy and (C1-C3J lower alkylamino, -CONK- (C1-C3) lower alkyl (C1-C3) , -CON[lower alkyl (C1-C3) ] 2; Q is one or two; R c iε independently εelected from hydrogen, -CH3 and -C2K5. 14. The compoundε according to Claim 1 wherein Y iε -(CH2)n~; n iε 0 or 1; t ' ne moiety iε a 5-membered aromatic Θ (unεaturated) heterocyclic ring having one heteroatom selected from C, or Ξ wherein the rino is optionally suostituted bv C3 ) lower alkvl , / / ? halogen or (C1-C3) lower alkoxv; the moiety iε a five membered aromatic (unsaturated) heterocyclic ring where D iε a nitrogen atom and E, and F are carbon wherein one cf the carbon atomε iε optionally εubεtituted by a εubεtituent εeiected from (C1-C3) lower alkyl, halogen or (C1-C3) lower alkoxy. 15. A compound εelected frcm these of t ' ne general formula I : FORMULA I wherein Y -(CH2)r.~ wherein n iε 0 cr 1; A-E iε a oietv selected from wherein r * is 1 or 2; and the moiety: Θ /2 ύ is phenyl or substituted phenyl optionally εubεtituted by one or two subεtitutentε selected from (C1-C3) lower alkyl, halogen, amino, (C1-C3) lower alkoxy or (Cι~ C3) lower alkylamino; the moiety: iε a five membered aromatic (unεaturated) heterocyclic ring wherein E, E and F are carbon wherein cne cf the carbcn atoms is optionally εubεtituted by a substituent selected frcm halogen, (C1-C3) lower alkyl, hydroxy, -COCI3, -COCF3 , / 2 / U -C-0 — lower alky ^-C 8 ) f — (CH,) N^ (CS-^) q -0- lower alkyl(C C 3 ) , -(αy — OH -CHC, amino, (C1-C3) lower alkoxy and <Cι-2 1 lower alkyiaminc, -CONK- (C1-C3 ) lower alkyl (C1-C3 ) , -CON[iowe: alkyl (C1-C3 ) ] 2; Q one or two; R iε independently selected from hydrogen, -CH3 and -C2K5; pβ iε a moietv of the formula: -C-Ar wherein Ar iε J 2Z wne:rein R c iε εelected from wherein L iε 0, S, SO, SO2 , -CO-, -CH - —C≡C— ; K' iε CH cr N; X iε 0, S, N-lower alkyl (C1-C3) and V, "' iε εelected from 0, S, NH, N-lower alkyl (C1-C3 ■ and N-benzyl, • iε εeiected from hydrogen, lower alkyl (C1-C ) , -CO- lower alkyl (C1-C3) ; R 1 and R 2 are εeleeted frcm hydrogen, (C1-C3) lower alkyl, (C1-C3) lower alkoxy and halogen; R- iε εeiected from hydrogen, lower alkyl (C1-C3 ) , lower alkoxy (C1-C3) -0-CH2*-CK=CH2 and halogen; P. 7 iε εelected frcm hydrogen, lower alkyl (C1-C3) , halogen, C-lower alkyl (C1-C3) and CF3; R 8 and F- are independently eelected from hydrogen, lower alkyl (C1-C3) , -Ξ-lower aik-/l (Ci -Ci, ) , halogen, -NH-lower alkyl (C1-C3 ; , -CCF3 , /23 -OH, -CN, -S-CF3, -Nθ2, - K2, O-lower alkyl (C1-C3) , CO- lower alkyl (C1-C3) and CF3 , * and the pharmaceutically acceptable salts thereof. 16. A compound selected from those cf the general formula I: FOF-MULA I wherein Y is -(CH2)n~ wherein n is 0 cr 1 ,- A-Ξ is a moietv selected from and — ■ < C -V;ΓN- wherein m is 1 cr 2; and the moietv: is phenyl cr subεtituted Θ phenyl cptienaliy substitute: by one or two εubεtitutente εelected frcm (Cι-C3)iowe: alkyl, halogen, amino, (C1-C3) lower alkoxy or (C - C3) lower alkylamino; the moietv: - • - <* is a five membered aromatic (unεaturated) nitrogen containing heterocyclic ring wherein D is nitrogen and E and F are carbon and wherein the carbcn atomε may be optionally εubεtituted by a substituent selected frcm halogen, (C1-C3) lower alkyl, (C1-C3) lower alkoxy;?. 3 moietv of the formula: -C-Ar wherein A.r is wne:rein R« εelected from I2S wherein L is 0 , S , SC2 , — C≡C— ; K' iε CH or N; X iε C, S, N-lower alkyl (C1-C3) and ' iε εεlected frcm 0, S, NH, N-lower alkyl (C1-C3 ■ and N-benzyi; R" iε εelected frcm hydrogen, lower alkyl (C1-C ) , - ZZ - lower alkyl (C1-C3) ; P. 1 and pβ are εeieeted frcm hydrogen, (C1-C3) lower alkyl, (C1-C3 dower alkoxy and halogen; pβ iε selected from hydrogen, lower alkyl (C1-C3 ) , lower alkoxy (C1-C3) -0-CH2*-CH=CH2 and halogen; F. 7 iε εelected from hydrogen, lower alkyl (C1-C3 ) , halogen, G-iower alkyl (C1-C3) and CF3 ; R 8 and R 9 are independently εelected from hydrogen, lower alkyl (C1-C3) , -Ξ-lower alkyl (C1-C3 ) , halogen, -NH-lower alkyl (C1-C3) , -OCF , -OK, -CN, -S-CF3, -NC2, -NK2. 0-lower alkyl (C1-C3 ) , CC- iower alkyl (C1-C3) and CF3; and the pharmaceutically acceptable εalts thereof. 17. A compound selected frcm thoεe cf t ' ne general formula I : 2 > FORMULA I wherein Y is -(CH2)n~ wherein n is 0 cr 1 A.-B iε a moietv εelected from wnere m is _ cr z; and the moietv-. iε a 5-membered aromatic (unεaturated) heterocyclic having cne heteroatom εeleeted from C, cr S; wnerei: ring iε optionally εubεtituted by (C1-C3) lower halogen cr (C1-C3) lower alkoxy; t ' ne moietv: containing heterocvclic rinα wherei. carbon wherein the carbon atomε may be optionally substituted by a εubεtituent εeiected from halogen , C3 ) lower alkyl , hydroxy , -COCI3 , -COCF3 , -(CH 2)' q -0- lower alkyl (C -CJ ( ^) q — OH • ■ C -CHC, am.inc, (C1-C3) lower alkoxy and (C1-C3) lower alkylaminc, -CONK- (C1-C3) lower alkyl (C1-C3 ) , -CON[lower alkyl (C1-C3 ) j 2 ; Q is one cr two; ?: 0 iε independently selected frcm hydrogen, -CH3 and -C2H5; R-*- iε a moiety of the formula: -C-Ar wherein Ar ie -Z g wne rein R^ iε εelected f rom wherein L is C , Ξ , ςQ~* -CC - — c≡c— K' is CH cr N; X iε 0, S, N-lower alkyl (C1-C3) and ' iε εεlected from 0, S, NH, N-lower alkyl (C1-C3) and N-benzyl; R 4 iε εelected from hydrogen, lower alkyl (C1-C3) , -CC- iower alkyl (C1-C3) ; R-*- and R 2 are εelected frcm hydrogen, (C1-C3) lower alkyl, (C1-C3) lower alkoxy and halogen; R5 iε εeiected from hydrogen, lower alkyl (C1-C31 , lov;er alkoxy(C1-C3) -0-CH2~CK=CH2 and halogen; R 7 iε εeleeted from hydrogen, lower alkyl (C1-C3) , halogen, C-iower alkyl (C1-C3) and CF3 ; R B and P.- are independently eeleoted from hvdroσen, lower alkvl (C *1 -C3 ) , -Ξ-lower /2 ? alkyl (C1-C3) , halogen, -NH-lower alkyl (C1-C3) , -OCF3 , -OH, -CN, -S-CF3, -NO2, -NH2, O-iower alkyl (C1-C3) , CO- lower alkyl (C1-C3) and CF3 ,- and the pharmaceutically acceptable εaltε thereof. IS. A compound εeiected frcm thcεe of the general formula I: FORMULA I wherein Y iε -(CH2)n _ wherein n lε 0 cr 1; A-Ξ iε a ciety εelected frcm wnere: 1 cr 2 ΠG Γ. -LS V : iε a 5-membered aromatic Θ (unεaturated) heterocyclic ring having one heteroatom εeiected from 0, or S; the moiety: t3 θ iε a five membered aromatic (unεaturated) nitrogen containing heterocyclic ring wherein D iε nitrogen and E and F are carbon and wherein the carbcn atomε may be optionally εubεtituted by a εubεtituent εeleeted from halogen, (C1-C3) lower alkyl, (C1-C3)lower alkox * ,*?.-*- is a mcietv cf the fcrmula: -C-Ar wner m wnerei εeiecteα t: ;m 13 / wnerem i s O , Ξ , ΞC so 2 ■ c≡c- ¥. ' is CH cr N; X iε 0, S, N-lower alkyl (C1-C3) and v: ' iε εelected frcm 0, S, NH, N-lower all-yl (C1-C ) and N-benzyl; P." ie εeiected from hydrogen, lower alkyl (C1-C3 ) , -CC- lower alkyl (C1-C3) ; R 1 and PX are εeieeted from hydrogen, (C1-C3) lower aik * _l, (C1-C3; Icwer alkory and halogen; pβ ie εeieeted from hydrogen, lower alkyl (C1-C3) , lower aikcxy(Cι-C3) -0-CH2-CK=CH2 and halogen; R 7 iε εeieeted frcm hydrogen, lower alkyl (C1-C3) , halogen, 0-lower alkyl (C1-C3) and CF3; R ε and β are independently εeiected from hydrogen, lower alkyl (C1-C3) , -S-lower alkyl (C1-C3) , halogen, -NH-lower alkyl (C1-C3) , -OCF3 , -OH, -CN, -S-CF3, -NO2, -NH2- O-iower alkyl (C1-C ) , ZZ- iower alk-yl (C1-C3 ) and CF3 ; and the pharmaceutically acceptable εaltε thereof. 19. A compound εeiected frcm t ' noεe cf the general formula I : '32 FORMULA I wherein Y iε -(CH2)n~ wherein n is 0 o: A-B iε a moiety eelected from wnerein m lε _ or and the moietv: lε a c-memoereα aromatic lur.satura: ieter: rmc having one nitrogen; tne moietv: iε a five membered aromatic(unεaturated) nitrogen containing heterocyclic ring wherein E, E and F carbcn and wherein the carbon atoms may be cpticnally /33 substituted by a εubεtituent εelected from halogen, (C; C3) lower alkyl, hydroxy, -COCI3, -COCF3, -C-0 -lower alkyl(C,-G j ) , / \ (CH 2 ) q - N " (CH - N ■ (CK,) -N O 2 q \ / -(CH 2 ) q -θ- lower alkyl (C. -Q.) ■ (<>y q — OH N / \ CH 2 -N I CH-N (CH 2,)'q -N N -R N N \ / -CMC, amine, (C1-C3) lower alkcxy and (C1-C3) lower alk-ylamino, -CONK- (C1-C3 ) lower alkyl (C1-C3) , -CCM.iewξ alk * yl (C1-C3 ) ] 2-' Q is one cr two; R iε independently εelected frcm hydrogen, -CK3 and -C2H5; pβ iε a moietv of the formula: -C-Ar wherein Ar iε / •3 V wherein iε εelected from wr.ert .n L i ε C , Ξ , co -CO- ■ H2 - . — c≡≡c— K' iε CH cr N; X iε C, S, N-lower alk-yl (C1-C3) and ' iε εelected from 0, S, NH, N-lower alkyl (C1-C3) and N-benzyl; pβ iε εelected from hydrogen, lower alkyl (C1-C3) , -CO- lower alkyl (C1-C3) ,* pβ and pβ are εεlected from hydrogen, (C1-C3) lower alkyl, (C1-C3) lower alkoxy and halogen; R- iε εεlected from hydrogen, lower al.yi (C1-C3) , lower alkoxy(C1-C3) -0-CH2-CH=CK2 and halogen; R 7 is εelected from hydrogen, lower alkyl (C1-C3 ) , halogen, C-lower alkyl (C1-C3) and CF3; R s and P.- are independently eeiected from hydrogen, lower alkyl (C1-C3 ; , -Ξ-lower i]-ς . v * i (C1-C3 ) , halogen, -NH-iower alkyl (C1-C3) , -OCF3, ι3S -OK, -CN, -S-CF3, -NO2, -NH2, O-lower alkyl (C1-C3) , CO- lower alkyl (C1-C3) and CF3 , * and the pharmaceutically acceptable saltε thereof. 20. A compound εelected from thoee of the general formula I : FORMULA I wherein Y iε -(CHc)n- wherein n iε 0 cr 1 ■ A-E iε a moietv εelεcted frcm wherein m iε 1 or 2 and the moietv: ie a a 6-membered aromatic (unεaturated) heterocyclic ring having one nitrogen; t ' ne moietv: l3 is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring wherein D,iε nitrogen and E and F are carbon and wherein the carbcn atoms may be optionally subεtituted by a substituent εelected frcm halogen, (C1-C3) lower alkyl, and (C1-C3)lower alkoxy,- R J iε a moietv cf the formula: -C-Ar wnerem Ar lε iε εelected from /3 7 wne. — c≡c- K" is Cr. cr N; X iε C S, N-lower alkyl (C1-C ) and V. 7' iε εeiected from C, Ξ, NH, N-icwer aikvi (Ci -C ** P.- iε selected frcm hydrogen, lower alkyl (C1-C3 ) , -CC- iower alkyl (C1-C3 ) ; R- and pβ are selectee from hydrogen, ( 21-C3 ) lower alkyl, (C1-C3) lower alkoxy and halogen; F. D iε εelected from hydrogen, lower alkyl (C1-C3 ) , lower alkoxy (C1-C3) -0-CH2*-CK=CH2 and halogen; P. 7 ie εeiected from hydrogen, lower alkyl (C1-C3) . halogen, O-lower alkyl (C1-C3) and CF3 ,* R 8 and R 9 are independentiy εeiected from hydrogen, lower alkyl (C1-C3) , -S-lower alkyl (C1-C3) , halogen, -NH-lower alkyl (C1-C3) , -CCF3, -OK, -CN, -Ξ-CF3, -NC2, -NH2, O-lower alk * /l (C1-C3 ) , CO- lower alkyl (C1-C3) and CF3 ; and the pharmaceutically acceptable ealtε thereof. 21. The compound according tc Claim 1Ξ 10, ll-dihydro-10- [4- (2-thienyi)benzovl] -5H-pyrrolo .2,1- c] [1, 4]benzodiazepin . '38 22. The compound according to Claim 15 10,11- dihydro-10- [4- (2-nitrophenyl)benzovl] -5H-pyrrolo [2, 1- c] [1,4]benzodiazepine. 23. The compound according tc Claim 15 10, ll- dihydre-10- [4- (3 , 5-difiuorophenyl)benzovl] -5H- pyrrolc[2 , 1-c] [1,4]benzodiazepine. 24. The compound according to Clai 15 10,11- dihydro-10- [4- (phenylethynyl) -5H-pyrrolo [2,1- c] 1, 4]benzodiazepine. 25. The compound according to Claim 15 10,11- dihydrc-10- [4- (2-methylphenyl)benzovl -ΞH-pyrrolc [2,1- c] [1 , jbenzodiazepine . 26. The compound according to Claim 15 10,11- dihydro-3- [ (dimethyiamino)methyl] -10- [4- (2- thien l) benzovl] -ΞH-pyrrolo [2, 1-c] [1,4]benzodiazepine 27. The ccmpound according to Claim 16 5- ([1,1' -biohenvl] -4-ylcarbonyl) -5 , lC-dihydro-4K- pyrazolo . Ξ , 1-c] [1,4]benzodiazepine. 2Ξ. The compound according to Claim 15 10,11- dihydro-13- [ [ 2 ' - {triflucromethyl) [1,1' -biphenyl] -4- yl] carbonyl-5H-pyrrclc[2, 1-c] [1,4]benzodiazepine. 29. The compound according to Claim 15 10, ll- dihydre-10- [4- (2-pyridinyl)benzcyij -ΞH-pyrrolc [2,1- c] [1,4]benzodiazepine. 30. The compound according to Claim 15 10,11- dihydro-10- [4- (2-thiazolyl)benzovl] -5H-pyrrcic [2,1- c] [1,4]benzodiazepine. 31. The compound according to Claim 15 10, ii-dihydro-10- [4- [ (4-methylphenyl) thic]benzcyi-5H- pyrrolo[2 , 1-c] [1, 4]benzodiazepine. 32. The ccmpound according to Claim 15 10, ll-Dihydro-10- [4-phenylεulfonyl]benzovl] -5H- pyrroio [2, 1-c] [1, 4]benzodiazepine. 33. The compound according to Claim. 15 10,11- dihydro-10- [4- [ (4-methylphenyl) sulfonyl]benzovl] -5H- pyrrclo [2, 1-c] [1,4] benzodiazepine. J3? 34. The compound according to Claim 15 10,11- dihydro-10- [ [4 ' - (2-propenyloxy) [1,1' -biphenyl] -4- yl]carbonyl] -5H-pyrrolo [2, 1-c] [1, 4]benzodiazepine. 35. The compound according to Claim 15 10,11- dihydro-10- [4- (phenylthio)benzoyl] -5H-pyrrolo[2, 1- c] [1, 4]benzodiazepine. 36. The compound according to Claim 15 10- (4-benzoylbenzoyl) -10, ll-dihydro-5H-pyrrolo [2, 1- c] [1, 4]benzodiazepine. 37. The compound according to Claim 15 5- ([1,1' -biphenyl] -4-ylcarbonyl) -4, 5-dihydro-pyrrolc [1,2- a] quinoxaiine. 26. The compound according to Claim 15 10, ll- dihydre-10- [4- (4-methyl-phenory)benzovl] -ΞH-pyrrolc [1 , 1- c] [1,41benzodiazepine. 39. The compound according to Claim 15 10- ([1,1' -biphenyl] -4-ylcarbonyi) -10, ll-dihydro-5H- pyrrclo [2 , 1-c] [1 , 4]benzodiazepine. 40. The compound according tc Claim 15 10- ([1,1' -biphenyl] -4-yicarbonyl) -10, 11-dihydro-N, - dimethyl-5H-pyrrolo[2 , 1-c] [1,4]benzodiazepine-3- methanamine. 41. The compound according to Claim 15 10,11- dihydro-10- [ (4 ' -propyl [1,1' -biphenyl] -4-yi) carbonyl] -5H- pyrroio[2, 1-c] [1,4]benzodiazepine. 42. The compound according to Claim 15 10,11- dihydro-10- [5- [ (2-thienyl)pyridinyl " j carbonyl] -5K- pyrrolo[2, 1-c] [1, 4]benzodiazepine. 43. A pharmaceutical compcεitien uεeful fcr treating diεeaεeε characterized by excess renal reabεcrption of water aε well ae ccngeεtive heart failure, liver cirrhosis, nephrotic syndrome, central nervous system injuries, lung diseaεe and hypcnatremia in a mammal ccmprieing a εuitable pharmaceutical carrier and an. effective amount of a compound cf Claim 1. /y 44. A method of treating diseases characterized by escεsε renal reabεorption cf water aε well aε congeεtive heart failure, liver cirrhosis, nephrctic εyndrome, central nervcuε εyεtem injurieε, lung disease and hyponatremia in a mammal comprising administering a compound of Claim 1 to said mammal in ar. amount effective to alleviate the condition. 45. A proceεε for preparing a compound selected from those of the general formula I: FOP-M LA Z ;herein Y iε a moiety εelected from; - X ' r-2 ,~ wnerein n .ε an integer 0 cr 1, and A-Ξ is a moietv εeiected frcrr wherein m iε an integer from 1 to 2; and the moietv: repreεentε: (1) phenyl cr εubεtituted phenyl optionally εubεtitutεd by one or twc εubεtitutentε εelected fror (C1-C3) lower alkyl, halogen, ammo, (C1-C3) lower aikexy or (C1-C3) lower alkylaminc; (2) a Ξ-membered aromatic '9/ (unεaturated) heterocyclic ring having one heteroatom eelected from 0, N cr S; (3) a 6-membered aromatic (unεaturated) heterocyclic ring having one nitrogen; (4! a 5 or 6-membered aromatic (unεaturatεd) heterocyclic ring having two nitrogen atomε; (5) a 5-membered aromatic (unεaturated) heterocyclic ring having one nitrogen atom together with either one oxygen cr one εulfur atom; wherein the 5 cr 6-membered heterocyclic ringe are optionally subεtituted by (C1-C3) lower alkyl, halogen or (C1-C3) lower alkoxy; the moietv: iε a five membered aromatic (unεaturated) nitrogen containing heterocyclic ring wherein Z , E and F are εeiected from carbcn cr nitrogen and wherem the careen atoms may be optionally εubεtituted by a substituent εelected frcm halogen, (C1-C3) lower alkyl, hydroxy, -CCC1-, -CCCF3, 'VA (C-^-O-lower alkyKC. -C 8 ) , -(CH,) — OH -CHO, amino, (C1-C3) lower alkoxy and (C1-C3) lower alkylaminc, -CONK- (C1-C3 ) lower alkyl (C1-C3 ) , -CON[lev * . alkyl (C1-C3 ) ] 2; ie one or twc; Rt iε independently εeiected from hydrogen, -CH3 and -C2H5; P.~ iε a moietv cf the formula: -C-Ar wherein Ar ie wherein R 6 • «. selectee t: / 43 wnerem b cn02 , -ro- — c≡c— K' is CH cr ; X iε 0, S, N-lower alkyl (C1-C3 j and w ' iε εεiected from C, S, NH, N-iower alkvl(C"-. and N-benzyi r."= ιε εε_ect. freπn hydrogen , lowξ k-vl(C- icwer alky! (C1-C3 ) ; PX and R .-? are εelected fro.., hydrogen, (C1-C3) lower alkyl, (C1-C3; lower lkory a halogen; R- iε εelected from hydrogen, lower alkyl (C1-C 1 , 1 alkoxy (C1-C3) -0-CH2-CH=CK2 and halogen; F. 7 frcm hydrogen, lower alkyl (C1-C3 ) , halogen, C-lower alkyl (C1-C3) and CF3; R 8 and R 9 are independently εelected from hydrogen, lower alkyl (C1-C3 ) , -Ξ-lewe: alkyl (C1-C3) , halogen, -NK-lower alkyl (C1-C3 ) , -0CF;. -OH, -CN, -S-CF3, -NO2, -NH2, 0-lov/er alkyl (C1-C3 ) , lower alkyl (C1-C3) and CF3 ,* which cc priseε reactinς compound cf the formula: /yy wit ' n a compound of the formula o Ar-C—Q where ~ is a nalogen cr an activating grou , wr.icn reεults from conversion cf an aryl oarbcxylic acid t mixed anhydride cr crcm activation wi h a pe tide coupling reagent, to give compcundε cf the Formula I

Inventors: ALBRIGHT JAY DONALD, GROSU GEORGE THEODORE, VENKATESAN ARANAPAKAM MUDUMBAI, ALBRIGHT, JAY, DONALD, GROSU, GEORGE, THEODORE, VENKATESAN, ARANAPAKAM, MUDUMBAI
Applicants: AMERICAN CYANAMID CO, AMERICAN CYANAMID COMPANY
Application year: 1996
Main classification: C07D487
IPC codes: A61K31, A61P1, A61P11, A61P13, A61P15, C07D487