LV12497B - Triciklisku diazepīnu vasopresīna un oksitocīna antagonisti - Google Patents

Triciklisku diazepīnu vasopresīna un oksitocīna antagonisti Download PDF

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LV12497B
LV12497B LVP-00-13A LV000013A LV12497B LV 12497 B LV12497 B LV 12497B LV 000013 A LV000013 A LV 000013A LV 12497 B LV12497 B LV 12497B
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alkyl
halogen
nied
lower alkyl
ist
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LV12497A (en
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Jay D. Albright
Marvin F. Reich
Phaik-Eng Sum
Efren Guillermo Delos Santos
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American Cyanamid Company
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Description

1. Field ot the Invention s This invention relates to new tricyclic non-peptide vasopressin antagonists vvhich are uselul in treating conditions vvhere decreased vasopressin Ievels are desired, such as in congestive heart failure, in disease conditions vvith excess rēnai water reabsorption and conditions vvith increased vascular resistance and coronary vasoconstriction.
2. Background of the Invention
Vasopressin is released from the posterior pituitary either in response to increased plasma osmolarity detected by brain osmoreceptors or decreased blood volume and blood pressure sensed by lovv-pressure volume receptors and arterial baroreceptors. The hormone exerts its actions through tvvo vvell defined receptor subtypes: vascular V, and rēnai epithelial V2 receptors. Vasopressin-induced antidiuresis, mediated by rēnai epithelial V2 receptors, helps to maintain normai plasma osmolarity, blood volume and blood pressure.
Vasopressin is involved in some cases of congestive heart failure vvhere peripheral resistance is increased. V-, antagonists may decrease systemic vascular resistance, increase cardiac output and prevent vasopressin induced coronary vasoconstriction. Thus, in conditions with vasopressin induced increases in total peripheral resistance and altered local blood flovv, V, -antagonists may be therapeutic aģents.
The blockade of V2 receptors may be useful in treating diseases characterized by excess rēnai reabsorption of free vvater. Antidiuresis is regulated by the hypothalamic release of vasopressin (antidiuretic hormone) vvhich binds to specific receptors on rēnai collecting tubule celis. This binding stimulates adenylyl cyclase and promotes the cAMPmediated incorporation of vvater pores into the luminal surface of these celis. V2 antagonists may correct the fluid retention in congestive heart failure, liver cirrhosis, nephrotic syndrome, Central nervous injuries, lung disease and hyponatremia.
Elevated vasopressin Ievels occur in congestive heart failure vvhich is more common in older patients vvith chronic heart failure. ln patients vvith hyponatremic congestive heart failure and elevated vasopressin Ievels, a V2 antagonist may be beneficial in promoling free vvater excretion by antagonizing the action of antiduretic hormone. On fhe basis of the biochemical and pharmacological effects of the hormones antagonists of vasopressin are expected to be ther30 apeutically useful in the treatment and/or prevention of hypertension, cardiac insufficiency, coronary vasospasm, cardiac ischemia, rēnai vasospasm, liver cirrhosis, congestive heart failure, nephrotic syndrome, brain edema, cerebral ischemia, cerebral hemorrhage-stroke, thrombosis-bleeding, abnormal States of vvater retention.
The follovving prior art references describe peptide vasopressin antagonists; M. Manning et al.. J, Med. Chem., 35, 382(1992); M. Manning et al., J. Med, Chem.. 35, 3895(1992); H. Gavras and B. Lammek, U.S. Patent 5,070,187 (1991); M. Manning and W.H. Sawyer, U.S. Patent5,055,448(1991); F.E. Ali, U.S. Patent4,766,108(1988); R.R. Ruffolo et al., Drug News and Perspective, 4(4), 217, (May)(1991). P.D. VVilliams et al., have reported on potent hexapeptide oxytocin antagonists [J, Med, Chem., 35.3905(1992)] vvhich also exhibit weak vasopressin antagonist activity in binding to V, and V2 receptors. Peptide vasopressin antagonists suffer from a lack or oral activity and many of these peptides are not selective antagonists since they also exhibit partial agonist activity.
Non-peptide vasopressin antagonists have recently been disclosed, Y. Yamamura et al., Science, 252.579(1991);
, Y. Yamamura et al.. Br. J. Pharmacol., 105, 787(1992), Ogavva et al., (Otsuka Pharm Co., LTD.) EP 0514667-A1; JP
04154765-A; EPO 382185-A2; and W09105549. Carbostyril derivatives and pharmaceutical compositions containing the same are disclosed by Ogavva et al., (Otsuka Pharm. Co.) in EP 470514A. Non-peptide oxytocin and vasopressin antagonist have been disclosed by Merck and Co.; M.G. Bock and P.D. VVilliams, EP 0533242A; M.G. Bock et al., EP
0533244A; J.M. Erb, D.F Verber, P.D. VVilliams, EP0533240A; K. Gilbert et al., EP 0533243A.
Premature birth can cause infant health problems and mortality and a key mediator in the mechanism of labor is the peptide hormone oxytocin. On the basis of the pharmacological action of oxytocin, antagonists of this hormone are useful in the prevention of preterm labor, B.E. Evans et ai., J. Med. Chem., 35, 3919(1992), J. Med. Chem., 36, 3993 (1993) and references therein. The compounds of this invention are antagonists of the peptide hormone oxytocin and are useful in the control of premature birth.
The present invention relates to novel tricyclic derivatives vvhich sxhibit antagonist activity at V, and/or V2 receptors and exhibit in vivo vasopressin antagonist activity. The compounds also exhibit antagonists activity of oxyfocin receptors.
SUMMARY OF THE INVENTION
This invention relates to nevv compounds selected from those of the general formula I:
Ο
vvherein Υ is a moiety selected from; -(CH2)„- vvherein n is an integer from 0 to 2,
I II — CH I ewera I ky I (c,-c3) and -C— :
A-B is a moiety selected from
-(CH2)„N- and -N-(CH2)mvvherein m is an integer from 1 to 2 provided that vvhen Y is -(CH2)n- and π is 2, m may also be zero and vvhen n is zero, m may also be three, provided also that vvhen Y is -(CH2)„- and n is 2, m may not be tvvo; and the moiety:
represents: (1) fused phenyl or fused substituted phenyl optionally substituted by one or tvvo substituents selected from (C,-C3)lower alkyl, halogen, amino, (CrC3)lower alkoxy or (CrC3)lower alkylamino; (2) a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from Ο, N or S; (3) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (4) a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having tvvo nitrogen atoms; (5) a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; vvherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C1-C3)lower alkyl, halogen or (C1-C3)-lower alkoxy;
the moiety:
is a five membered aromaticf unsaturated) fused nitrogen containing heterocyclic ring vvherein D, E and F are selected from carbon or nitrogen and vvherein the carbon atoms may be optionally substituted by a substituent selected from halogen, (C1-C3)loweralkyl, hydroxy, -COCI3, COCF3,
II
C-O-I.r.r «IkrliC^C,),
-(CH,),
0.
(CH,) /“λ
N 0
V_/
-(CH,),-0-I·»«r e|k7l(C,-Ca). -(CH,),OH, il —C- l»w«r «lkyl(C,-C,) , r=\
/—\
V/·-
-CHO, amino, (C1-C3)loweralkoxy, (Cļ-C3)loweralkylamino, CONH-loweralkyl(C-,-C3), and-CON[loweralkyl(C1-C3)]2; q is one or tvvo; Rb is independently selected from hydrogen, -CH3 or -C2H5;
R3 is a moiety of the formula:
II — C-Ar vvherein Ar is a moiety selected Iram the group consisting of
vvherein X is selected from O, S, NH, NCH3 and NCOČH3;
R4 is selected Trom hydrogen, lovver alkyl(C-,-C3), -CO-lower alkyl(Cļ-C3),
-SO2lower alkyt(C1 -C3); R1 and R2 are selected from hydrogen, (Cļ -C3)lower alkyI, (Cļ -C3)lower alkoxy and halogen; R5 is selected from hydrogen, (C1-C3)Iower alkyl, (C-,-C3)lower alkoxy and halogen;
R® is selected from (a) moieties of the formulae:
i. «. i. i. *b
Γ ι* Γ i* i‘ *NC«Ar', -eoAAf. -AeOCHt*r'. -KCANAr'.
-CHjCOAr·, -»C0-(CH,).-·,·I··I»»Iļ
I*
-NHS02-lower alkyl(C.,-C8) straight or branched,
-NHSO2-lower alkenyl(C1-C8) straight or branched, wherein cyctoalkyl is defined as C3-C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -C2HS,
-(CHj) -N /«b
-(CHj)q-N
-<ch2),-n
-(ch2 ) „
-(CH2)q-O-lower alkyl(C7 -C3) and -CH2CH2OH, q is ons or tvvo, and R,, R2 and Rb ara as harainbafora dafinad;
(b) a moiety of the formula:
vvherein R2 is as hereinbefore defined;
(c) a moiety of the formula:
ib
-N-CO J vvherein J is Ra, lovver alkyl(C,-Cg) branched or unbranched, lower alkenyl(C,-C8) branched or unbranched, Olovver alkyl(C,-Cg) branched or unbranched, -O-lower alkenyl(C,-Cg) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or -CH2-K vvherein K is (0,-03) l°wer alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
-N '' E \ _ / g—r wherein 0', E', F' and G are selected from carbon or nitrogen and vvherein the carbon atoms may be optionally substituted vvith halogen, (C,-C3)lower alkyl, hydroxy, -CO-lower alkyl(C, -C3), CHO, (C,-C3)lower alkoxy, -CO2lower alkyl(C,-C3), and Ra and Rb are as hereinbefore defined;
(d) a moiety of the formula:
-M-COCHAr ’
I
«.
vvherein R„ is selected Iram halogen, (C,-C3) lovver alkyl, -O-loweralkyl(C,-C3). OH,
Ο
II
-4-C-lavar aIkτI(C,-Cj).-S-i.w«r αIkjI(C,-C,),
wherein Ra and Rb ara as hereinbefore defined and Ar' is selected from moieties of the formula:
and
vvherein W is selected from O, S, NH, N-lower alkvi-fCļ-CJ, NCO-lower alkyl(C,-C3), and NSO2lower alkirl-fC, C3);
R7 is selected from hydrogen, lovver alkyl(C1-C3), halogen, O-lower alkyl(C,-C3) and CF3;
R8 and R9 are independently selected from hydrogen, lovver alkyl(C1-C3), -S-lower alkyl(C1-C3), halogen, -NH lovver alkyl(C,-C3), -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, O-lower alkyl(C,-C3),
II
-C-Iowar α I ky I (C,-C3) , and CF3 and;
R'° is selected from hydrogen, halogen and lovver alkyl(C,-C3), and the pharmaceutically acceptable salts thereof
DETAILED DESCRIPTION OF THE INVENTION
VVithin the group of the compounds defined by Formula I, certain subgroups of compounds are broadly preferred Broadly preferred are those compounds vvherein R3 is the moiety:
II
-CAr and Ar is selected from the moiety
Rs
vvherein Rs, Rs and Π7 are as hereinbefore defined.
Especially preferred are compounds vvherein R3 is the moiety
II
-CAr and Ar is selected from the moiety
R® is
-HCOAr ?'
-CONAr
-NCOCH.Ar *,
-NCONAr'.
-CHjCOAr · . -NCO-(CHj)a-eyeI··Iky I ;
II
-NH-C-0-Iewer ο I kyI(C,-Cg) etrelght ar branehed,
II
-HH-C-lewsr αIkyI(Cļ-C,) etrelght er brenched,
-NHSOj-levcr elkyl(C,-Cg) afrafghf «r branched,
II
-HH-C-O-I ewar βIk·nyI(C,-Cg) atralght er branehcd,
II
-MH-C-law<r α I kaity I (C,-C() «tralghl er branched,
-NHSO2-lower alkenyl(C1-C8) straight or branched, vvherein cycloalkyl is defined as C3-C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra and Rb are as hereīnbefore defined; and Ar* is selected from the moieties;
vvherein R8, R9 and W are as hereinbefore defined.
Also especially preferred are compounds vvherein Y in Formula l is -(CH2)n- and n is zero or one; A-B is
-(CHzk-N-K3 °r R 3 - N - ( C H 2 )„and R4. R5, R®, R7, RB, R9 and R10 are as hereinbefore defined; and m is an integer from 1-2.
The most preferred of the compounds of Formula I are those vvherein Y is -(CH2)n- and n is one; A-3 is
-CH2-N-R3 or r3-n-CH2R3 is the moiety
II
-CAf
Ar is the moiety
RJ
R7 r Γ ι* Γ Γ
-MCOAr·, -CONAr', -MCOCH,Ar·, -MCOMAr', ί'
-CH,COAr', -NCO-(CM,),-·»«I··IkrIi
II
-NH-C-O-1 ava r alkflfCj-C,) a-t r«l|bt ar kraaakaM,
II
-NM-C-lawar «lbyl(C|-C,) llriljkl ar kraaakaM, -NHSO,-Iever alkvl (C,-€,) atrel|kl ar kriukil,
II
-NH-C-O-1 mr aIkeayI(C,-C,) alral|kl ar kraaakaM,
-NH-C-laaar aI ka7 I (C,-C,) atralfkl ar kraaakaM,
-NHSO2-lower alkenyl(C1 -C8) straigth or branched,
-(CH2)n-cycloalkyl vvherein cyc!oalkyl is defined as C3-C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra and Rb are as hereinbefore defined; and Ar' is «·
vvherein Rs, R8 and R9 are as previously defined.
The most highly braadly preferred of the compounds of Formula I are those vvherein Y is -(CH2)n- and n is zero or one; vvherein the moiety
is a fused phenyl, substituted phenyl, thiophene, furan, pyrrole or pyridine ring; A-B is
-(CH2)m-N-R3 or R3-N-(CH2)mm is one vvhen n is one and m is tvvo vvhen n is zero;
D, E, F, R1, R2, R4,, Rs, R7, R8, R9, R10, are as previously defined; R3 is the moiety
Ο
II
-CAr vvherein Ar is
and R6 is selected from the group ?·
-MCOAr·
-COMAr'
-NCOCM.Ar'
*. *k
Γ lk
-NCOMAr’
Γ
-CMjCOAr ' , -NCO-(CH,),-afalatlkjIi
II
-MΜ-C-β-1·«·r aI kf I (C,-Ct) atralfkt «r OraaakaM,
II
-MM-C-laaar alkflfCļ-C,) atral|bt ar braaakaM, -NHSOg-lavar <lkjl(Cj-Ce) alratfkl ar kraaahaM,
II
-NH-C-O-1arar a I kawy I (C,-C,) alralfkt ar kraaahak, β
II
-MH-C-laaar a I kaafI(C,-C,) alratfkl ar kraaakak.
-NHSO2-loweralkenyl(C,-C8) straight or branched, vvhere Ar1 is selected from the group
and W', Ra, Rb and cycloalkyl are as previously described.
More particularly preferred are compounds of the formulae:
vvherein the moiety:
is selected from a phenyl, thiophene, furan, pyrrole or pyridine ring; R3 is the moiety:
II
-CAr vvherein Ar is the moiety:
R*
R® is
Γ 1' I’ |· 1’
-HCOAr*. -COMAr·, -NCOCMjAr*, -KCOKAr’,
-CH:COAr·, -NCe-(Cat)a-«Ml«*lkrl i
II
-HH-C-O-I«IIr « I kr<(C,-C,) 11a 11k» ar kraaakai,
II
-kH-C-1aaar aIkyI(C,-C,) alralghl kraaahatf,
-ΜΗίΟ,-Ι «««r · I k T1 ( C,-C,) al ralghl ar kraaakat,
II
-KH-C-O-Iaaar aIkaayI(C,-C,) alralgkl ar braaahag,
II
-KH-C-1aaar a I keΜ I(C,-C,) a ( r« 1g h» ar krantkak,
-NHSO2-lower alkanyl(C,-C8) straight or branched, and Ar' is selected from the moieties:
vvherein Ra, Rb, Rs, R7, R8, R9, cycloalkyl and W are as hereinbefore described; R11 is selected from hydrogen, halogen, (Ci-C3) lovver alkyl, hydroxy,
II
-C- I o w β r 01^71(0,-03),
-CHO, and (Cļ-C^lovver alkoxy; and R12 is selected from hydrogen, (Cļ-C^lovver alkyl, halogen and (C,-C3)lower alkoxy.
Also particularly preferred are compounds of the formulae:
vvherein m is one or tvvo; the moiety:
is selected from a phenyl, thiophene, furan, pyrrole or pyridine ring; R3 is the moiety:
II
-CAr vvherein Ar is the moiety:
R»
R® is ι’ ι' |· ι* |·
-NCOAr*, -CONAr*, -NC0CH,Ar*. -NCONAr*,
-CH,COAr', -NCO-{CM,)„-·,«1«·Ik yIļ
II
-MH-C-O-1 ava r « lky I (C,-C,) itralglīt ar kraaakatf,
II
-NH-C-lavar alk7l(C,-C,) atralghl ar kraaakak, -NHJO,-Iever alkyl(C,-C,) alralghl ar kraaakaN,
-MN-C-O-Iavar aI kaa7I(C,-C,) alralghl ar kraaahak,
II
-NH-C-lavar a 11an7I(C,-C,) ilrilgkt ar krerieheg.
-NHSO2-lower alkenyl(C, -CB) straight or branched, (CH2)„ cycloalkyl; Ar* is selected from the moieties;
vvherein Ra, Rb, Rs, R®, R®, R9, cycloalkyl and W are as hereinbefore defined;
R” is selected from hydrogen, halogen, (C,-C3) lovver alkyl, hydroxy,
II 4g -C-lavar aIkr I (C,-C,).
-CHO, and (C,-C3)lower alkoxy; and
R12 is selected from hydrogen, (C,-C3)lower alkyl, halogen and (C,-C3)lower alkoxy. More particularly preferred are compounds of the formulae:
R3 is the moiety:
ο
II
-CAr vvherein Ar is the moiety:
R®is
I Γ r I* r
-HCOAr·, -CONAr', -HCOCHjAr*. -NCONAr',
-CHjCOAr·, -MCO-(I·«IkyI;
II
-HH-C-O-Isw·r alkyl(C,-Ca) straight tr kraashsd,
II
-HH-C-lavar alkrl(C,-C,) straight tr brsnshsd, -HHSOj-lsvtr alkyl(C,-Cg) straight ar kranehek,
II
-HH-C-O-I aier βIkanj I (C,-C,) straight ar branehad,
II
-HH-C-laaar a I hanyI(C,-C() atralght ar hranahad,
-NHSO2-lowar alkenyl(C1 -C8) straight or branched, vvherein cycloalkyl is defined as C3-C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Fb is hydrogen;
Ra is independently selected from hydrogen, -CH3, -C2H5 or -(CH2)qN(CH3)2; Ar1 is selected from the moieties:
vvherein q, Ra, Rb, R5, R7, R8, R9, R11 and W are as hereinbefore described;
R’2 and R’3 ara indapandanlly selected trom bydrogen, (C1-C3) lovver alkyl, halogen, amino, (C,-C3) lovver alkoxy or (Cļ-Ca) lovver alkylamino.
Also particularly preferred are compounds of the formulae:
vvherein m is one or tvvo;
R3 is the moiety:
II
-CAr vvherein Ar is the moiety:
R6 is
f. J»
Γ«
I* I'
-HCOAr', -COMAr1, -MCOCHjAr', -HCOMAr’,
-CHjCOAr
-MCO-(CHj)(-cχcIeaIkχIj
II
-MH-C-0-I·»·r elkyl(Ct-Ca) etralght nr branched.
II
-HH-C-Ioaer gIkχI(C,-C,) etrafght tr branched,
-HHSOj-loncr alkyl(Ct-C() etralght «r branehcd,
II
-MH-C-O-Iaver eIkeηχI(C,-C() etralght ar branehcd,
II
-MH-C-lc»ar αIkenχI(C,-C() etralght ar branehcd.
-NHSO2-lower alkenvIfC,-C8) straight or branched, vvherein cycloalkyl is defined as C3-C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Fļ, is hydrogen;
Ra is independently seiected from hydrogen, -CH3, -C2H5 or -(CH2)qN(CH3)2; and Ar1 is seiected from the moieties:
vvherein q, Rs, R7, R8, R8, R11 and W are as hereinbefore defined;
R12 and R13 are independently seiected from hydrogen, (CrC3) lovver alkyl, halogen, amino, (Ci-C3)lower alkoxy or (Cļ -C3)lower alkylamino.
Most particulariy preferred are compounds of the formulae:
vvherein the moiety
is selected from a phenyl, thiophene, furan, pyrrole or pyridine ring vvherein the phenyl ring may be optionally substituted vvith one or tvvo substituents selected from (Cļ -C3) lovver alkyI, halogen, amino, (Cļ -C3) lovver alkoxy and (C7 -C3) lovver alkylamino,
R3 is the moiety:
o
II
-CAr vvherein Ar is the moiety:
-NHSO2-lower alkyl(C,-C8) straight or branched, -NHSO2-lower alkenyl(C,-C8) straight or branched, vvherein cycloalkyl is defined as C3 to Ce cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -C2H5,
-(CH2)q-O-lower alkyl(CrC3), -CH2CH2OH; q is one or tvvo; Rb is independently selected from hydrogen, -CH3 and -C2H5; (b) a moiety of the formula:
-N-COJ wherein J is Ra, lovver alkyl(C,-C8) branched or unbranched, lovver alkenvIfCļ-Cj) branched or unbranched, Olovver alkyl(C1-C8) branched or unbranched, -O-lower alkenyl(C,-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or -CH2-K vvherein K is (C,-C3) lovver alkoxy, haiogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety.·
-ΛΕ' \ _ /,
G—F' wherein D', E', F' and G are selected from carbon or nitrogen and vvherein the carbon atoms may be optionally substituted vvith haiogen, (C,-C3)lower alkyl, hydroxy, -CO-tovver alkyl(CrC3), CHO, (C-ļ-C^tovver alkoxy, -CO2lovver alkyl(C, -C3), and Ra and Rb are as hereinbefore defined; R1 and R2 are independently selected from hvdrogen, (Cļ-Cgjlovveralkvl, (C,-C3) lovver alkoxy and haiogen;
(c) a moiety of the formula:
-H-COCHAr' .1 vvherein Ra is selected from haiogen, (C,-C3) lovver alkyl, -O-lovver alkvKCļ-C^, OH,
II
-O-C-lo».r a l ky I ,-S-Iow«r aIkyI(C,-C3),
b
-NH(CHj)q-COH^ s
and Ra, Rb ara as hereinbefore defined; and Ar' is selected from the moieties:
vvherein X is selected from O, S, NH, NCH3, NCOCH3;
R® is selected from hydrogen, (C1-C3)lower alkyl, (C,-C3)lower alkoxy, and halogen;
R7 is selected from hydrogen, lovver alkyl(C3-C3), halogen, O-lower alkyl(C,-C3) and CF3;
R® and R9 are independently selected from hydrogen, lovver alkyl(C1-C3), -S-lower alkyl(C1-C3), halogen, -NHlovver alkyl(CrC3), -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, O-lower alkyl(C,-C3),
II
-0-C- low«r α I ky I (C,-Cj) .
and CF3;
R” is selected from hydrogen, halogen, (C1-C3)lower alkyl, hydroxy, COCI3, COCF3,
II
-C-O-liT«f «Iky((Cj-Cj)»
-(CH,)
(CH,),
‘(CH,),
,
-<cH,),-o-i««.r «ikTi (c,-c,). -(ch,),oh.
o
II —cir «Ikjrl ( C,-C,) .
r=\
-ΕΗ,-Η^^ζ,Η f=\
-(CH,),-M ~(CH,),-
CHO, and (C,-C3)lower alkoxy; q is one or tvvo;
W' is selected from O, S, NH, N-lower alkyl(C1-C3), NCO-lower alkyl(C., -C3) and NSO2-lower alkyl(C-, -C3). and the pharmaceutically acceptable salts thereof.
vvherein m is one or tvvo; and the moiety:
is selected from a phenyl, thiophene, furan, pyrrole and pyridine ring; R3 is the moiety:
II
-CAr vvherein Ar is the moiety:
R7
R® is selected from (a) moieties of the formula:
-NHSO2-iower alkyl(C,-C8) straight or branched,
-NHS02-lower alkenyl{C1-C8) straight or branched, vvherein cycioalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, C2HS,
-(CH2)q-O-lower alkvHCļ-C^, CH2CH2OH; q is one or tvvo;
Rb is independently selected from hydrogen, -CH3 and -C2H5;
(b) a moiety of the formula;
-N-COJ vvherein J is Aa, lovver alkvifCļ-Cg) branched or unbranched, lovver alkenvifCļ-Cg) branched or unbranched, Olovver alkyl(CrC8) branched or unbranched, -O-lovver alkenvUC^Cg) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or -CH2-K vvherein K is (Cļ-C3) lovver alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
vvherein D‘, E', F' and G are selected from carbon or nitrogen and vvherein the carbon atoms may be optionally substituted vvith halogen, (C1-C3)lower aikyl, hydroxy, -CO-lower alkyl(C-, -C3), CHO, (C1-C3)lower alkoxy, -CO2lovver alkyl(C1-C3), and Ra and Rb are as hereinbefore defined; R1 and R2 are independently selected from hydrogen, (Cļ-C^lovver alkyl, (CrC3) lovver alkoxy and halogen;
(c) a moiety of the formula;
-N-COCHAr vvherein Rc is selected trom halogen, (Cj-C-j) lovver alkyl, -Ο-lovver alkyl(C1 -C3), OH,
II
-0-C - I o we r elkyl(C,-Cj).-S-lawer alkyl(C,-C3)t
-s-(ch2)
R„ b
-o-(ch2)2nx and Ra, Rb are as hereinbefore defined; Ar’ is selected from the moieties:
R vvherein X is selected from O, S, NH, NCH3, NCOCH3; vvherein Rs is selected from hydrogen (C,-C3)lower alkyl, (C,-C3)lower aikoxy, and halogen;
R7 is selected from hydrogen, lovver alkyl(C1-C3), halogen, O-lower alkyl(C,-C3) and CF3;
R8 and R9 are independently selected from hydrogen, lovver alkyl(Cļ-C3), -S-lower alkyl(C1-C3), halogen, -NHlower alkyl(CrC3), -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, O-lovrer alkyl(CrC3),
II
-0-C-low«r ο I k y I ( C ,-C 3 .
and CF3;
R11 is selected from hydrogen, halogen, (C1-C3)lower alkyl, hydroxy, COCI3, COCF3,
-(CH,),- ir. -(εκ,Ι,-κ^^ , -(CH,),-(CH,),-O-I.».r «IkrI(c,-c,j. -{eM,),0H,
/~\
CHO, and (C1-C3)ioweralkoxy; q is one or tvvo;
R12 is selected from hydrogen, (Cļ-Cgļlovver alkyl, halogen and (C,-C3)lower alkoxy; W is selected from O, S, NH, N-lower alkyl(C.,-C3), NCO-lower alkyl(C,-C3) or NSO2-loweralkyl(C1-C3), and the pharmaceutically acceptable salts thereof.
R3 is the moiety:
II
-CA r vvherein Ar is the moiety:
R3
CJ-'·
II7
RS
Re is selected Irom (a) moieties of the formula:
-NHS02-lower ailc/lfCļ-Cg) straight or branched,
-NHS02-lower alkenyl(C1 -Ce) straight or branched, vvherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R„ is independently selected from hydrogen, -CH3, -C2H5,
-(CHJq-Nx
-(ch2),-n (ch2)„-n
-(CH2)q-O-lower alkv^Cļ-Ca), -CH2CH2OH; q is one or two; Rb is independently selected from hydrogen, -CH3 and -C2H5; and (b) a moiety of the formula:
-N-CO J vvherein J is Ra, lovver aikyl(C,-C8) branched or unbranched, lovver alkenyl(C1-C8) branched or unbranched, Olovver alkyl(C1-C8) branched or unbranched, -O-lower alkenyl(C1-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or -CH2-K vvherein K is (Cļ-Cg) lovver alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
vvherein θ', E', F' and G are selected from carbon or nitrogen and vvherein the carbon atoms may be optionally substituted vvith halogen, (0η-03)Ιον/θΓ alkyl, hydroxy, -CO-lovver alkyl(C-|-C3), CHO, (C1-C3)lower alkoxy, -CO2lovver alkyl(C1-C3), and Ra and Rb are as hereinbefore defined; R1 and R2 are independently selected from hydrogen, (C,-C3)lower alkyl, (C,-C3) lovver alkoxy and halogen;
(c) a moiety of the formula:
-N-COCHA r’ vvherein Rc is selected from halogen, (C,-C3) lovver alkyl, -O-lower alkyl(C-|-C3), OH, o
-o-cow e r a I ky I ( C,-C3),-5 - I0w·Γ α I k y I ( C , - C -) ,
-S-(ch2)2-n
-NH ( CH2)q-CON
-0-(CHj )2
b b
and Ra, Rb are as hereinbefore defined; and Ar' is selected from the moieties:
wherein X is selected from O, S, NH, NCH3, NCOCH3; R5 is selected from hydrogen (C-,-C3)lower alkyl, (C, -C3) lovver alkoxy, and halogen;
R7 is selected from hydrogen, lovver alkyl(C-| -C3), halogen, O-lower aH^lfCļ-C^ and CF3;
R8 and R9, independently selected from hydrogen, lovver alkyl(CrC3), -S-lower alky!(C·, -C3), halogen, -NH-lower alkyl(CrC3), -OCF3, -OH, -CN, -S-CF3, -NOZ, -NH2, O-lower alkyl(CrC3),
II
-O-C-low.r α I ky I (C,-C3) .
and CF3;
R11 is selected from hydrogen, halogen, (C1-C3)lower alkyl, hydroxy, COCI3, COCF3,
Ο
II ζ’*
-C-O-I.»»r < I ky I (C,-C,). -(CH,),H
-(ch,),-./^ -(eH,),-^^ . -(=«:),-( CH, ),-0-I au r α I k j I ( C, - C ,) . -(CH,),OH.
r~\ * 0, <_/
II — C- I our β lky I (C,-C,) ,
CHO, and (Cļ-C3)loweralkoxy; q is one or tvvo; R12 and R13 are independently selected from (C,-C3)lower alkyl, hydrogen, halogen, amino, (C,-C3)lower alkoxy or (C1-C3)lower alkylamino; W is selected from Ο, S, -NH, NHlovverall^liCļ-Cļj), NCO-lovver alkyl(Cļ-C3) or NSO2 lovver alkyl(C,-C3), and the pharmaceutically acceptable salts thereof.
vvherein m is one or tvvo; R3 is the moiety:
II
-CAr vvherein Ar is the moiety:
-MHSO2-lower alkyl(C1-C8) straight or branched,
-NHSO2-lower alkenyl(C, -C8) straight or branched, vvherein cycloalkyl is defined as C3 to C8 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independently selected from hydragen, -CH3, -C2HS,
-(CH2)q-0-lower alkyf(CrC3), -CH2CH2OH; q is one or tvvo; Rb is independently selected from hydrogen, -CHa and -C2H5; (b) a moiety of the formula:
-N-CO J vvherein J is Ra, lovver alkyl(C,-Cg) branched or unbranched, lovver alkenyl(C,-C3) branched or unbranched, Olower alkyl(C1-C8) branched or unbranched, -O-lower alkenyl(C1-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or -CH2-K vvherein K is (Cļ-C3) lovver alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
-N
D / >Ei
vvherein D‘, E', F' and G are selected trom carbon or nitrogen and vvherein the carbon atoms may be optionally substituted vvith halogen, (C.,-C3)lower alkyl, hydroxy, -CO-lower alkvifCļ-C-j), CHO, (C1-C3)lower alkoxy, -CO2lovver alkyl(CrC3), and Ra and Rb are as hereinbefore defined; R1 and R2 are independently selected from hvdrogen, (C,-C3)lower alkyl, (CrC3) lovver alkoxy and halogen;
(c) a moiety of the formula:
-N-COCHAr' I
R.
vvherein Ro is selected from halogen, (C,-C3) lovveralkyl, -O-lovver alkyl(C1-C3), OH.
-0-C-low«r elkyl(C,-C3),-S-low.r eikyl(C,-Cj), Rb Rb
-NH(CHZ) -CON^Rb -0-(CH2)2H<'Rb Rb ’ Rb and Ra, Rb are as hereinbefore defined;
and Ar' is selected from the moieties:
vvherein X is selected from O, S, NH, NCH3, NCOCH3;
R5 is selected from hydrogen, (C-ļ-C3)lower alkyl, (Cļ-C3)lower alkoxy, and halogen;
R7 is selected from hydrogen, lovver alkyl(C1-C3), halogen, O-lower alkyl(C-, -C3) and CF3;
R8 and R9 are independently selected from hydrogen, lovver alkyl(C1-C3), -S-lovver alkyl(C, -C3), halogen, -NHloweralkyl(CrC3), -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, O-lower alkyl(C,-C3),
II
-O-C- I owe r ο 1 kyI(C,-C5).
and CF3;
Rn is selected from hydrogen, halogen, (C-,-C3)loweralkyl, hydroxy, COCI3, COCF3,
-0-l»«.r «IkvKe^Cj).
’v (CH,),-lT . -(CH,),/“λ * 0 ,
-{CH,),-O-I.».r ' I kr I (C,-C,) . -(CH,),OH, —c- l»»«r ·Ikr >(C,-Ca} , r=\ f—\
-(CH,),-H H«, .
-(CH,),- H
CO
CHO, and (C, -C3)loweralkoxy; q is one or tvvo; and W is selected from O, S, NH, N-lower alkyl(C, -C3). NCO-lovver alkyl(C,-C3), or NSO2-lower alkyt(Cļ -C3);
R12 and R13 are independently selected from hydrogen, (C1-C3)lower alkyl, halogen, amino, (CrC3)lower alkoxy or (C1 -C3)lower alkylamino, and the pharmaceutically acceptable salts thereof.
vvherein Y is -(CH2)n-;
m is one vvhen n is one; and m is one or tvvo vvhen n is zero; R3 is the moiety:
o
II
-CAr vvherein Ar is the moiety;
R3 •R*
R7
R® is selected from (a) moieties of the formula:
-NHSO2-lower alkyl(C1-C8) straight or branched,
-NHSO2-lower alkenyl(Cļ-C8) straight or branched, vvherein cycloalkyl is defined as C3 to C8 cycloaikyl, cyclohexenyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -CZHS,
-(ch2),-n
-(CH2)q-N
-(CH2)q-N
-(CH2)q-N
-(CH2)q-O-lovver alkyl(C,-C3), -CH2CH2OH; q is one or tvvo; Rb is independently selected from hydrogen, -CHa and -C2H5; and (b) a moiety of the formula:
-N-COJ vvherein J is Ra, lovver alkyl(C., -Ca) branched or unbranched, lovver alkenyl(C1-CB) branched or unbranched, Olovver alkyl(Cļ-C3) branched or unbranched, -O-lovver aikenyl(C1-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or -CH2-K vvherein K is (C,-C3) lovver alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
vvherein D*. E’, F' and G are selected from carbon or nitrogen and vvherein the carbon atoms may be optionally substituted vvith halogen, (C-j-C3)lower alkyl, hydroxy, -CO-lovver alkyl(C-ļ-C3), CHO, (C1-C3)lower alkoxy, -CO2lower alkyl(Cn -C3), and Ra and Rb are as hereinbefore defined; R1 and R2 are independently selected from hydrogen, (C.,-C3)loweralkyl, (Cļ^) lovver alkoxy and halogen;
(c) a moiety of the formula:
-H-COCHAr' vvherein Ro is selected from halogen, (C,-C3) lovver alkyl, -0-lower alkyl(Cļ-C3), OH,
II
-O-C-lo»«r ο I It y I ( C,-C j ) ,-S - I o»s r α I k τ I ( C,-C, ) ,
-S-( CH,) j-<Rb and Ra, Rb are as hereinbefore defined; and Ar' is selected from the moieties:
vvherein X is selected from O, S, NH, NCH3 and NCOCH3;
Rs is selected from hydrogen (Cļ-C3)lower alkyl, (C,-C3)lower alkoxy, and halogen;
R7 is selected from hydrogen, lovver alkyl(C1-C3), halogen, O-lower alkyl(CrC3) and CF3;
R8 and R9 are independently selected from hydrogen, lovver alkyl(C,-C3), -S-lower alkyl(C,-C3), halogen, -NHloweralkyl(C1-C3), -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, O-lower alkyl(C,-C3),
II —O-C- I ovre r α I ky I ( C , — C.
and CF3;
R11 is selected from hydrogen, halogen, (C1-C3)lower alkyl, hydraxy, COC!3, COCF3,
-C-O-laaar al»fl{C,-C,), -(CH,),ni o
’ΐ’,-Χχ/1 · , -(CH
-(CH,),-0-levar .IkrI(C,-C,), -(CH,),OH, κ o .
\_y —c-Ι·* alkjlfCļ-e,) , -CH,
Λ=Λ f=\ ,-H^M .
r='
\3/~C=^
CHO, and (CrC3)lower alkoxy; q is one or tvvo; R12 is selected from (C,-C3)lower alkyl, hydrogen, halogen, and (C1-C3)loweralkoxy; W is selected from O, Š, -NH, N-lower aū^lfCļ-Cg), NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(Ci -C3), and the pharmaceutically acceptable salts thereof.
vvherein Y is -(CH2)n; n is one vvhen m is one and m is tvvo vvhen n is zero; R3 is the moiety:
-CA r vvherein Ar is the moiety;
-aR® is selected from moieties of the formula:
1'
1' i* r
-HCOAr ·, -CONAr*, -NCOCKjAr·, -NCONAr*,
I’
-CHjCOAr·. -NC0-(CHj),-«r«I··Ik»I;
.1 .<
I
-Ν-ΪΟ,-
»*
-H-SOjCH,
-H-F
-NH-C-O-i·»r atkyl(e,-Cj) ·IttIglal ar kraaakaN,
II
-NH-C-laaar alkj I (Ct-C(, tfralfhl tr kraaahaf,
-NHSOj-laatr alkyi(C,-C,} ·1ra 11kt ar kratckaf,
II
-NH-C-O-Iaaar aIbaarI(C,-C,) a I ra 1|kI ar braaakaf,
II
-NN-C-laaar aIkaayI(C,-C,J al ralfhl ar kraaahaN,
-NHS02-lower alkenyl(C, -C8) straight or branched,
R1 and R2 are independently selected from hydrogen, (C, -C3) lovver alkyl, (C,-C3)lower alkoxy and haiogen; vvherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independantly selected from hydrogen, -CH3, c2h5.
-tCH> ·
-(CH2)q-N
-(CH2)q-O-lower alkyl(C,-C3), CH2CH2OH; q is one or tvvo;
Rb is independently selected Irom hydrogen, -CH3 and -C2HS; and Ar1 is selected from the moieties:
R5 is selected from hydrogen, (C1-C3)lower alkyl, (Ci-C3)lower alkoxy, and halogen;
R7 is selected from hydrogen, lovver alkyl(C.|-C3), halogen, O-loweralky and CF3;
R® and R9 are independently selected from hydrogen, lovver alkyl(C,-C3), -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(CrC3), -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, O-lower alkyl(CrC3),
-O-C-lv*jr o lkyI(C,-Cj).
and CF3;
R11 is selected from hydrogen, halogen, (C,-C3)loweralkyl, hydroxy, COCI3, COCF3, o
II — C-0 — t· .r a IkT I (¢,-6,). -{CH,),I<
-(CH2 ),-<>->···' · »Ιί τ ι ( c, -C, ) , -( CM, ) ,0H ,
II —C™i ·»·?
f=\
/.....M /-’ r~\
N X» .
v_y
CHO, (C,-C3)lower alkoxy and q is one or tvvo; R12 is selected from (C,-C3)lower alkyl, hydrogen, halogen, and (Cļ-C3)lower alkoxy; W' is selected from O, S, -NH, N-lower alkyl(C1-C3), NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(C,-C3);
and the pharmaceutically acceptable salts thereof.
FP is the moiety:
vvherein Ar is ths moiety:
R® is selected from (a) moieties of the formula;
SS
II
-CAr
R. R,
I* I
-MCOAr*. -COMAr*
I · I I
-MCOCHjAr *, -HCOMAr *
-CHjCOAr1, -MC0-(CH2)a-eyeI»αIkyI;
-M-P
R1
-NHSO2-lower alkyl(Cļ-Ca) straight or branched,
-NHSOz-lower alkenyl(C, -C8) straight or branched, vvherein cycloalkyl is defined as C3 to C8 cycloalkyl, cyclohexenyl or cyclopentenyl; R, is independently seiected from hydrogen, -CH3, -C2HS,
-(CH2) -N^Rb ’ Rk
-(CH2)q-N
-(CH2)q-O-lower alkyl(Cļ-C3), -CH2CH2OH; q is one or tvvo; Rb is independently seiected from hydrogen, -CH3 and -C2HS; and (b) a moiety of the formula;
-N-CO J vvherein J is Ra, lovver alkyl(C,-C8) branched or unbranched, lovver alken^fCļ-Ca) branched or unbranched, Olovver alkyl(C,-C8) branched or unbranched, -O-lower alkenyl(Cļ-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or -CH2-K vvherein K is (C,-C3) lovver alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
ΰ
-l·/
vvherein D', E', F* and G are selected trom carbon or nitrogen and vvherein the carbon atoms may be optionally substituted vvith halogen, (C,-C3)lowar alkyl, hydroxy, -CO-lower alkyl(C·, -C3), CHO, (Ci-C3)lower alkoxy, -CO210 lovver alkyl(C1-C3), and Ra and Rb are as hereinbefore defined; R1 and R2 are independently selected from hvdrogen, (C1-C3)lower alkyl, (C.,-C3) lovver alkoxy and halogen;
(c) a moiety of the formula:
is
vvherein Re is selected from halogen, (C,-C3) lovver alkyl, -O-lower from alkyl(Cļ -C3), OH,
II
-0-C-low.r olkyl(C,-Cj).-S-low.r αIkyI(C,-C3 ) , Rb
-NH(CH2) -C0<Rb -0 - ( C Hj ) z Rb ‘ Rb and Ra, Rb are as hereinbefore defined;
and Ar' is selected from the moieties:
so vvherein X is selected from O, S, NH, NCH3 and NCOCH3;
R5 is selected from hydrogen (C,-C3)lower alkyl, (C,-C3)lower alkoxy, and halogen;
R7 is selected from hydrogen, lovver alkvifCļ-C3), halogen, O-lower alkyl(C-,-C3) and CF3;
R8 and R9 are independently selected from hydrogen, lovver alkyl(C,-C3), -S-lovver aikyl(C,-C3), halogen, -NHloweralkyl(CrC3), -OCF3, -OH, -CN, -S-CF3, -NOa, -NH2, O-loweralkyl(C,-C3), ο
li
-O-C-l«wer ο I Ic y I ( C , - C 3 ) .
and CF3;
R” is selected from hydrogen, halogen, (Cļ-C3)lower alkyl, hydroxy, COCI3, COCF3,
II
-C-O-l i«ir βIkyI(C,-C,). -(ΟΗ,),Μζ.
*V (ΟΗ,Ϊ,-Η^ · -(CH,),'
/~\
-(ΟΗ,ί,-Η^Ο
-(CH,),-Ο-I·»·r α I k, I (C,-C,) , -(CH,),OH.
II —C- Ι·«·γ « I ky I (C,-C,, .
. -ΟΗ,-Η^^,Η .
F=\ f=\
-CHj-H^H . -CH,-HX^ -CCH,),-^., .
(CH,),- /
CHO, and (C,-C3)lovveralkoxy; q is one or tvvo; R12 and R13 are independently selected from (C,-C3)lower alkyl, hydrogen, halogen, amino, (C1-C3)loweralkoxy or (C,-C3)lower alkylamino; Wis selected from O, S, -NH, N-lower alkyl(C, -C3), NCO-toweralkyl(C,-C3) or NSO2 lovver alkyl(C,-C3), and the pharmaceutically acceptable salts thereof.
Compounds of this invention may be prepared as shovvn in Scheme 1 by reaction of tricyclic derivatives of Formula 3a and 3b vvith a substituted or unsubstituted 4-nitrobenzoyl chloride 4 to give the intermediates 5a and 5b. Reduction of the nitro group in intermediates 5a and 5b gives the 4-aminobenzoyl derivatives 6a and 6b. The reduction of the nitro group in intermediates 5a and 5b may be carried out under catalytic reduction conditions (hydrogen-Pd/C; Pd/Chydrazine-ethanol) or under Chemical reduction conditions (SnCķ-ethanol; Zn-acetic acid; TiCI3) and related reduction conditions knovvn in the art for converting a nitro group to an amino group. The conditions for conversion of the nitro group to the amino group are chosen on the basis of compatability vvith the preservation of other functional groups in the molecule.
Reaction of compounds of Formula 6a and 6b vvith aroyl chloride or related activated aryl carboxylic acids in solvents such as chloroform, dichloromethane, dioxane, tetrahydrofuran, toluene and the like in the presence of a tertiary base such as triethylamine and diisopropylethylamine or pyridine and the like, affords the compounds 8a and 8b vvhich are vasopressin antagonists.
Scheme l
5a
5b
Scheme 1 (Cont'd)
6q Sb
Ar'COCI ~“
Ar 'CHjCOCI eye I oaIkyI(CHj)bCOCI — Ar'NCOCI
I ’b
R* - NHCOAr · ; -NHCOCHjAr·;
-NHCO(CHl)ļ|cycloalkyl ; -NHCON-Ar’
Reaction ot tricyclic derivatives of Formula 6a and 6b vvith either a carbamoyl derivative 9 or a isocyanate derivative JO gives compounds (Scheme 2) of Formula 11a and 11b vvhich are vasopressin antagonists of Formula I vvherein R® is
-NHCONAr
I
Scheme 2
6a 6b — 0 — II
CI-C-NAr’
I o r Rb
O-C-NAr'
1a b Hb
Reaction ot tricyclic derivatives of Formula 6a and 6b with arylacetic acids, activated as the acid chlorides _I2, anhydrides, mixed anhydrides or activated vvith knovvn activating reaģents, gives compounds 13a and 13b (Scheme 3).
Scheme 3 α
II
Cl-C-CH2Ar'
I 2
6b
13a
13b
The compounds of Formula I vvherein Y, A-B, Z, R1, R2 and R3 are as defined and the Ar moiety of R3 (-COAr) is
may be prepared, as shovvn in Scheme 4, by reacting an activated ester of the indole-5-carboxylic acids 14 vvith tricyclic derivatives 3a and 3b. The indole-5-carboxylic acids 14 may be activated by preparing the anhydride, a mixed anhydride or reacting vvith diethyl cyanophosphonate, Ņ,Ņ-carbonyldiimidazole or related peptide coupling reaģents. As an example, the derivative 15 may be prepared by the acid 14 and Ņ,Ņ-carbonyldiimidazole in tetrahydrofuran; the solvent is removed and the derivative reacted vvith 3a or 3b at 100’ C to 120’ C vvithout a solvent. Alternatively, 3a and 3b may be reacted with 15 in a solvent such as toluene or xylene at reflux temperatures. The activating reaģent for the indole acids _14 is chosen on the basis of its compalibility vvith the R4 group and its reactivity vvith the tricyclic derivatives 3a and 3b to give the vasopressin antagonists 16a and 16b,
R»
R7 vvherein R6 is
-NX \ / N—N may be prepared as shovvn in Scheme 5 by first converting derivatives Sa and Sb into the intermediates 17a and 17b and then reacting these intermediates vvith sodium or lithium azide to give the products 18a and 18b.
Scheme 5
Altematively, the products 18a and 1Bb may be prepared by coupling tetrazole derivatives of the Formula 19 vvith tricyclic derivatives 3a and 3b (Scheme 6). The tetrazole carboxylic acids are activated for coupling to the tricyclic compounds 3a and 3b by reaction with peptide coupling reaģents, by conversion to the acid chlorides, anhydrides or mixed anhydrides.
Scheme 6
As an alternative method for synthesis of compounds of this invention as depicted in Formula I vvherein Y, A-B, 0,
E, F and Z are as previousfy described and R3 is
II
-CAr is the coupling ot aryl carboxylic acids 20 vvith the tricyclic derivatives 3a and 3b to give 21a and 2t b.
The aryI carboxylic acids are activated tor coupling by conversion to an acid chloride, bromide or anhydride or by first reacting vvith an activating reaģent such asŅ,Ņ-dicyclocarbodiimide, diethyl cyanophosphonate and related peptide type* activating reaģents. The method of activating the acids 20 for coupling to the tricyclic derivatives 3a and 3b is chosen on the basis of compatibility vvith other substituent groups in the molecule. The method of choice is the conversion of the aryl carboxylic acids 20 to the corresponding aroyl chloride. The aryl acid chlorides 22 may be prepared by Standard procedures knovvn in the art, such as reaction vvith thionyl chloride, oxalyl chloride and the like. The so coupling reaction is carried out in solvents such as halogenated hydrocarbons, toluene, xylene, tetrahydro(uran dioxane in the presence of pyridine or tertiary bases such as triethylamine and the like (Scheme 7). Alternatrvely, the aroyl chlorides 22, prepared trom the aryl carboxylic acids 20, may be reacted vvith derivatives 3a and 3b in pyridine vvith or vvithout 4-(dimethylamino)pyridine.
In general, when the aryi carboxylic acids 20 are activated with Ņ,Ņ-carbonyldiimidazole and other 'peptide type' activating reaģents, higher temperatures are required than vvhen the aroyl chlorides are used. The reaction may be carried out in a higher boiiing solvent xylene or vvithout a solvent (100°C to 150’C).
Scheme 7
3α Ο Ο — II II
ArC-OH ArC-CI
22 vh« r« I n Ar I ( α* prtvleualf d · ( I n · d
A r
21a 21b
Scheme 8
The starting materiāls 3a and 3b in the foregoing Schemes 1 -7 may be prepared as foliovvs. In accordance vvith Scheme 8, alkylation of heterocycles of structural type 24 vvith an alkylating moiety such as 23 gives intermediates 25. The heterocvcle 24 may contain an a-carboxaldehyde function or an a-carboxylic and/or ester function as shovvn in Scheme 8. Where the intermediate 25 (R15=H) contains an a-carboxaldehyde group, hydrogenation vvith palladium-on-carbon gives reduction and ring closure in one step to give 29.
In derivatives 25 vvhere R15 is an a-carboxylic and/or an a-carboxylic ester function, the intermediate amino acid derivative 27 is first isolated and then ring closed. The ring closure of derivatives 27 may be carried out by heating or by activation of the acid function (27:R1S=OH) for ring closure. The cyclic lactams 28 are conveniently reduced vvith diborane or lithium aluminum hydride to give intermediates 29. Reaction of tricyclic derivatives 29 vvith aroyl chlorides (ArCOCI), vvhere Ar is as hereinbefore defined, gives diazepines 26.
Tricyclic derivatives of structural type 36 may be prepared as shovvn in Scheme 9. Formylation of 32 under knovvn conditions in the literature, such as Vilsmeier formylation, gives intermediates 35 vvhich on reduction and ring closure affords tricyclics 37.
VVhere Z is a fused substituted or unsubstituted phenyl group, the procedure gives pyrrolo(1,2-aļ quinoxalines 35. These derivatives 36 and 37 may be reacted vvith aroyl chlorides (ArCOCI) vvherein Ar is as previously defined or vvith a substituted or unsubstituted 4-nitrobenzoyl chloride or vvith a nitrogen protecting group, such as benzyloxycarbonyl chloride to give compounds 38 and 39. The compounds 38 and 39 mav be reacted vvith chlorine, bromine or halogenating reaģents such as N-chlorosuccinimide, N-bromosuccinimide and the like to give compounds 40 and 41 vvherein R17 is a halogen atom. The derivatives 38 and 39 may be formylated and acetylated to give produets 40 and 41 vvherein R17 is a CHO or a -COCH3 group. Halogenation, formylation and acetylation of derivatives 38 gives 1-substituted pyrrolo[ 1,2-a]quinoxalines. The derivatives 38, 39, 40 and 41 vvherein R16 is a substituted or unsubstituted 4-nitrobenzoyl group are reduced to give the 4-aminobenzoyl derivatives 42d and 43d vvhich are reacted vvith reaģents Ar'COCI, ArOHjCOCI or
Ar ’-MCOCI ;
vvherein Ar' and Rb ars as previously hereinbefore defined, to give tricyclic diazepines 44 and 45.
SshgffiĢ 9
Scheme 9 fcont'd;
ha I βJ«n +
(CH,)jH-CHCI Cl
CHjCOCI:F»CIj
a) ArCO
R17 - halagtn, CHO b) Ph-CHjOCO
-COCHj
R,7-ha 1 «gan , CHO -COCH,
e) NOj-^_^-CO
R7 B 3
Ί) R
NH,
CO
Scheme 9 (cont'd)
42d 43d
R · α g · n i
Ar ' COCI
Ar ’CH-COCI 1
Ar * NCOCI I
b
The compounds of this invention vvherein R3 is the moiety:
and the Ar group is the moiety:
and R6 is a
R
II I
-C-H-Ar group, vvherein Aa, Rs, R7 and Ar' are as previously hereinbefore defined, are synthesized as shovvn in Scheme 10. The tricyclic derivatives 46 and 47 are reacted vvith the mono methyl terephthaloyl chloride 48 to give the aroylated methyl ester compounds 49 and 50. Hydrolysis of the methyl esters 49 and 50 gives the acids 5ļ and 52 vvhich are activated for coupling by conversion to an activated ester or converted to the acid chlorides 53 and 54. Reaction of the acid chlorides 53 and 54 vvith the amines, vvherein Ra and Ar' are as hereinbefore defined gives the derivatives 55 and 56.
Scheme 10
Preparation ot some t ricyc lic diazepines useful for starting materiāls for the synthesis of compounds of this invention are shovvn in Schemes 6 and 9. Other tricyclic diazepines are prepared by literature procedures or by methods knovvn in the art or by procedures reported for the synthesis of specific knovvn tricyclic diazepines. These diazepine ring systems discussed belovv vvhen subjected to reaction conditions shovvn in Schemes 1, 2, 3, 4, 5, 6, 7, 9 and 10 give the compounds of this invention.
The tricyclic diazepine ring system, lO.II-d^dro-SH-imidazop.l-cļļl^ļbenzodiazepine,
H is reported by G. Stetancich, R. Silvestri and M. Artico, J. Het. Chem. 30, 529(1993); ring substitution on the same ring system is reported by G. Stetancich, M. Artico, F. Carelli, R. Silvestri, G. deFeo, G. Mazzanti, I. Durando, M. Palmery, IL Farmaco, Ed. Sc., 40, 429(1965).
X - H, -OCH,, -ΟΟΗ,Ο,Η,; T-H, Cl, -OCH,; X, Y - O-CHj-OThe synthesis ol 9,10-dihydro-4H-turo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-9-one
is reported by F. Povazunec, B. Decroix and J. Morei, J. Het. Chem. 29, 1507(1992) and is reduced to give the tricyclic heterocycle 9,10-dihydro-4H-furo[2,3-e]pyrrolo(1,2-a][1,4]diazepine.
The trīcyclic 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine ring system is reported by L. Cecchi and G. Filacchioni, J. Het. Chem., 20, Θ71 (19S3);
The synthesis of 9-oxo-9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine is reported by A. Daich and B. Decroix, Buli. Soc. Chim. Fr 129, 360(1992);
and is reduced vvith boron-dimethylsutfide to give 9,10-dihydro-4H-pyrrolo[1,2-aJthieno[2,3-e][1,4]diazepine.
Also reported by A. Daich and B. Decroix is 5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e][1,4Jdiazepine
vvhich is also reduced to give 4,10-dihydro-5H-pyrrolo-[1,2-a]thieno[3,2-e][1,4]diazepine s
Reported by B. Decroix and J. Morei, J. Het. Chem., 28, 81(1991) are pyrrolo[l,2-a]thieno[3,2-e][1,4]diazepine;
and pyrrolo(1,2-a]1hieno[2,3-e][1,4]diazepine. Reduction by hydrogen-Pd/c or Chemical reduction vvith reaģents such as sodium cyanoborohydride and acetic acid gives the dihydro tricyclic heterocycles
The synthesis of the tricyclic 1,5-benzodiazepine ring system, 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine, has been reported by F. Chimenti, S. Vomero, R. Giuliano and M. Artico, IL Farmaco, Ed. Sc.. 32, 339(1977). Annelated 1,5-benzodiazepines containing five membered rings have been revievved by A. Chimirri, R. Gitto, S. Grasso, A.M. Monforte, G. Romeo and M. Zappala, Heterocvcles, 36, No. 3, 604(1993), and the ring system 6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepine is described.
H
The preparation of 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-ones from 1,2-dihydro-3H-4-dimethylamino-1,5-benzodiazepin-2-ones has been described by M. DiBroccio, G. Roma, G. Grossi, M. Ghia, and F. Mattioli Eur. J. Med. Chem; 26, 489(1991). Reduction ol 5,6-dihydro-4H-[1,2,4ļtriazolo[4,3-a][1,5]benzodiazepin-5-ones vvith diborane or lithium hydride gives the tricyciic 5,6-dihydro derivatives.
is The compounds oi this invention and their preparation can be understood further by the follovving examples, but should not constitute a iimitation thereof.
Example 1 20 N-f4-(5H-Pvrrolof2.1-cli1.4lbenzodlaz3pin-10(nHi-vlcarbonvHoh9nvll-2,3-difluorobanzamida
To a stirred solution of 0.350 g of 2,3-difluorobenzoyl chloride in 5 ml of methylene chloride is added 0.346 ml of triethylamine. After stirring for 3 minūtes, 0.500 g of 10,11 -dihydro-l 0-(4-aminobenzoyl)-5H-pyrrolo(2,1 -c]f1,4Jbenzodiazepine is added and stirring continued for 72 hours. The reaction mixture is filtered and the solid washed with methylene chloride. The solid is saved. The combined filtrate is vvashed vvith water, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried vvith Νβ^Οψ filtered and evaporated in vacuo to give 100 mg of a solid. The tvvo solids are combined and dried to afford 790 mg of the desired product as a solid, m.p. 252-258* C.
Example 2
N-f4-(5H-Pyrrolof2,1 -cll 1,4lbenzodiazepin-10(11 H)ylcarbonyl)phenvll-2-methoxybenzamide
To a stirred solution of 0.362 g of 2-methoxybenzoyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0’ C. After stirring for 3 minūtes, 0.500gof 10,l1-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo(2,1-c][1,4] benzodiazepine is added and stirring continued for 16 hours at room temperatūra. The reaction mixture is diluted vvith 45 ml of methylene chloride and vvashed vvith vvater, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried vvith Na2SO4, filtered through hydrous magnesium siiicate and evaporated in vacuo to give a solid which is purified by cryetallization from ethyl acetate to give 0.430 g of the desired product as a crystalline solid, m.p. 185-188*0.
Example 3
2-Methyl-N-f4-(5H-pvrrolof2,1 -cll 1,4ļ-benzodiazepin-10( 11 H)-ylcarbonvl)phenvllbenzamide
To a mixture of 1.93 g of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0*
C is added 1.13 ml of triethylamine. After stirring for 3 minūtes, a mixture of 1.0 g of 10,11-dihydro-5H-pyrrolo(2,1-c] [1,4]benzodiazepine in 5 mi of methylene chloride is added. The cooling bath is removed and after about 30 minūtes a complete solution is obtained. The reaction mixture is allowed to stir at room temperature for 48 hours and the volatiles are concentrated ļņ vacuo to a residue. The residue is dissolved in 100 ml of ethyI acetate and vvashed vvith vvater, 2N citric acid, aqueous NaHCOg and brine. The solution is dried vvith Na2SO4 and the volatiles concentrated in vacuo to so give 3.0 g of a residue. A 300 mg sample of the residue is purified by thick layer chromatography using 10% ethyl acetate-methylene chloride to give 160 mg of the desired product. The remainder of the crude material is purified by flash chromatography using 10% ethyl acetate in methylene chloride to give the desired product as a residue vvhich is crystallized from ethyl acetate 1o give 800 mg of the desired product as vvhite crystais, m.p. 212-215°C.
Exampla 4
N-f4-(5H-pvrrolof2,1 -clf 1.4lbenzod!azepin--10( 11 H)-vlcarbonvl)phenyll-2,5-dichlorobenzamide
To a soiution ot 414,5 mg ot 2,5-dichlorobanzoyl chloride in 5 ml of methylene chloride is added 276 μΙ of triethylamine. After stirring at 0° C for 3 minūtes 400 mg of the 10,11<fihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4] benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 3 hours. The voiatiies are concentrated jņ vacuo to give a residue vvhich is dissolved in athyl acetate and vvashed vvith vvater, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried vvith Na2SO4 and concentrated in vacuo to a residue vvhich is purified by thick layer chromatography by elution vvith 1:1 ethyl acetate-hexanes to give a residue. The residue is crystallized from ethyl acetate to give 220 mg of the desired product as vvhite crystals, m.p. 216-220’C.
Examplo 5
N-14-(5H-pyrrolof2,1 -clf 1,4ļbenzodiazepin-10(11 H)-vlcarbonyl)phenvl1-3-methvl-2-thiophenecarboxamide
To a soiution of 318 mg of 3-methyl-2-thiophenecarbonyl chloride in 5 ml of meihylene chloride at 0’C is added 346 μΙ of triethylamine. After stirring for 3 minūtes, 500 mg of the 10,11 -dihydro-10-(4-aminobenzoyl)-5H-pyrrolo(2,1 -c] [1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The voiatiies are concentrated in vacuo to give a residue vvhich crystallizes from ethyl acetate to afford 800 mg of solid. The solid is dissolved in methylene chloride vvashed vvith vvater, 2N citric acid, 1M NaHCO3 and brine. The organic layer is filtered through hydrous magnesium silicate, dried vvith Na2SO4 and concentrated in vacuo to give a residue vvhich crystallizes from ethyl acetate to afford 400 mg of the desired product as a vvhite solid, m.p. 232-235’C.
Example 6
N-f4-(5H-pvrrolof2,1-cl[1.4lbenzodiazepin-10(11H)-vlcarbonvl)phenvn-2.4-dichlorobenzamide
To a soiution of 415 mg of 2,4-dichlorobenzoyl chloride in 5 ml of methylene chloride at 0° C is added 346 μΙ of triethyiamine. After stirring for 3 minūtes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The voiatiies are concentrated in vacuo to give a residue vvhich is dissolved in ethyl acetate, vvashed with vvater, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried vvith Na2SO4, filtered and concentrated in vacuo to give a residue vvhich is crystallized from ethyl acetate to give 420 mg o, the desired product as a crystalline solid, m.p., 210-212’C.
Example 7
N-14-(5H-pyrrolof2,1 -clf 1,4ļbenzodiazepin-10(11 H)-vlcarbonyl)phenvH-2-chlorobenzamid9
To a soiution of 347 mg of 2-chlorobenzoyl chloride in 5 ml of methylene chloride at 0’ C is added 346 μΐ of triethylamine. After stirring for 3 minūtes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyi)-5H-pyrrolo-[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature (or f 8 hours. The voiatiies are concentrated in vacuo to give a residue vvhich is dissolved in methylene chloride, washed vvith vvater, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried vvith Na2SO4, filtered and concentrated in vacuo to give a residue vvhich is crystallized trom methylene chloride to give 525 mg of the desired product as a vvhite crystalline solid, m.p. 228-230’C.
Example 8
N-f4-(5H-pvrrolof2,1 -clf 1,4lbenzodiazepln~10( 11 m-vlcarbonvl)phenvll-2-fluorobenzamide
To a soiution of 314 mg of 2-fluorobenzoyl chloride in 5 ml of methylene chloride at 0’ C is added 346 μΙ of triethylamine. After stirring for 3 minūtes, 500 mg of 10,11 -dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1 -c]( 1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The voiatiies are concentrated in vacuo to give a residue vvhich is dissolved in methylene chloride, vvashed vvith vvater, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried vvith Na2SO4, filtered and concentrated Jņ vacuo to give 620 mg of the desired product as a crystalline solid, m.p. 257-260°C.
Example 9
2-Chloro-N-f4-(5H-pyrrolof2,1 -clf 1,41-benzodiaz8pin-10(11 H)-y IcarbonvDphenvIlbenzeneacetamide
S A mixture of 0.273 g of 2-chlorophenylacetic acid is stirred at room temperature for 2 hours. The volatiles are evaporated in vacuo to a residue vvhich is distilled vvith toluene several times. The residue is dissolved in 10 ml of methylene chloride containing 0.26 ml of triethylamine and vvhile stirring 0.485 g of 10,11 -dihydro-10-(4-aminobenzpyl)5H-pyrrolo(2,1-cJ1,4]benzodiazepine added. The reaction mixture is stirred at room temperature for 18 hours. The volatiles are removed and the residue dissolved in ethyl acetate vvhich is vvashed vvith vvater, 1N HCI, 1M NaHCO3 and brine. The organic layer is dried and evaporated to a residue vvhich is purified by flash chromatography using t :1 ethyI acetate-hexane to give the desired product as a yellow solid, m.p. 99-103°C.
Example 10 t -(2-Nitrophenyl)-1 H-pyrrole-2-carboxaldehyde
To a solution of 3.76 g o, 1-(2-nitrophenyl)pyrrole in 20 ml of N,N-dimethylformamide at O’C is added dropvvise vvith stirring 3 ml of phosphorus oxychloride. Stirring is continued for 30 minūtes and the reaction mixture is heated at 90’ C for 1 hour. After cooling to room temperature the mixture is treated vvith crushed ice and the pH adjusted to 12 20 vvith 2N sodium hydroxide. The resulting suspension is filtered, vvashed vvith vvater and dried to give 5.81 g of the desired product as a light yellow solid m.p. 119’-122’C.
Example 11
2® 4.5-Dihvdro-pyrrolo-[ 1,2-al-quinoxaline
To a solution of 1.0 g of 1 -(2-nitrophenyl)-1 H-pyrrols-2-carboxaldehyde in 40 ml of ethyl alcohol and 40 ml of ethyl acetate, under argon, is added 40 mg of 10% Pd/C. The mixture is hydrogenated at 40 psi for 2 hours and filtered through diatomaceous earth. The fiitrate is concentrated iņ vacuo to a residue vvhich is dissolved in ether and treated oo vvith hexanes to give 0.35 g of the desired product as a beige solid m.p. 1O8’-11O’C.
Example 12
4-f (2-Methvlbenzovltaminolbenzoic acid 35
A mixture of 43.42 g of ethyl 4-aminobenzoate and 40.8 g of 2-methylbenzoyl chloride in 150 ml of dichloromethane is cooled in an ice bath and 26.56 g of triethylamine is added dropvvise. After the addition, the solution is stirred at room temperature overnight. The mixture is poured into vvater and the organic layer separted. The organic layer is vvashed vvith vvater, 1N HCI, 1M NaHCO3 and dried over Na2SO4. The solvent is removed and the solid slurried vvith ethyl acetate and filtered to give 57 g of ethyl 4-{(2-methylbenzoyi)amino]benzoate as ciystals, m.p. 110-115’C. A mixture of 50.7 g of the preceding compound in 2Θ0 ml of ethyl alcohol and 55 ml of 10N NaOH is refluxed for 5 minūtes. The mixture is cooled to room temperature, diluted vvith 200 ml ol vvater and acidified vvith concentrated hydrochloric acid (pH 1 -2). The mixture is filtered and the solid vvashed vvith vvater and dried to give 51 g of the desired product as vvhite crystals, m.p. 270-275’C.
Example 13
4-f(2-Methvlbenzoyi)amino1benzovl ch loride so A mixture of 10.3 g of 4-[(2-methylbenzoyl)aminoJ benzoic acid and 32 ml of thionyl chloride is refluxed for 1.5 hours. The solution is concentrated in vacuo. Toluene is added and the solvent removed in vacuo. Toluene is added and the mixture chilled and filtered to give the desired product as a yallovv solid, 135-141°C.
Example 14
2-Methyl-N-f4-(pvrrolof1,2-alquinoxalin-5(4H)ylcarbonyl)phanvl1benzamide
Amixtureof 0.51 gof 4-[(2-methylbenzoyl)amino]benzoyl chloride and 0.36 g of 1,1'-carbonyldi/m/cfazote/n6 ml of tetrahydrofuran is stirred at room temperature for 1 hour. To the reaction mixture is added 0.17 g ot 4,5-dihydropyrrolo[1,2-a]-quinoxaline follovved by heating at reflux for 60 hours. The volatiles are concentrated in vacuo to a residue vvhich is dissolved in ethyl acetate. The organic layer is vvashed vvith 1N HCI, 1M NaHCOj, brine. dried vvith Na2SO4 and filtered through hydrous magnesium silicate. The volatiles are concentrated in vacuo to a residue vvhich is chromatographed by eiution vvith 1:2 ethyl acetate-hexanes to give 0.14 g of the desired product as a vvhite solid, m.p. 206-207’C.;
MASS SPEC (Cl) 408(MH+).
Table I
The follovving Examples are prepared using the conditions of Example 14 vvith the appropriately substituted aroyl
chloride
Example No. Compound
15 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-chlorobenzamide
16 N-[4-(pyrrolo[l,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2,5-dichlorobenzamide
17 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide, m.p. 200°-202°C
18 N-{4-(pyrrolo{1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-chloro-4-methylbenzamide
19 N-[4-(pyrrolo[1,2-aJquinoxalin-5(4H)-ylcarbonyl)phenyl]-2-methyl-4-chlorobenzamide
20 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2,4-dimethylbenzamide
21 N-[4-(pyrrolo{1,2-a]quinoxalin-5 (4H)-ylcarbonyl)phenyl]-2,3-dimethylbenzamide, m.p. 216°-220°C
22 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-methoxybenzamide
23 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-trifluoromethoxybenzamide
24 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2,4-dimethoxybenzamide
25 N-f4-(pyrrolof1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2,6-dimethoxybenzamide
26 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenylJbenzamide
27 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2,6-dichlorobenzamide
28 N-(4-(pyrrolo(1,2-aJquinoxalin-5(4H)-ylcarbonyl)phenylJ-2,6-dimethylbenzamide
29 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-(methylthio)benzamide
30 N-[4-(pyrrolo{1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-methyl-3-thiophenecarboxamide
31 N-[4-(pynOlo[1,2-aļquinoxalin-5(4H)-ylcarbonyl)phenylJ-3-methyl-2-thiophenecarboxamide
32 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-methyl-3-furanecarboxamide
33 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-3-methyl-2-furanecarboxamide
34 N-[4-(pyrro)o(1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]benzeneacetamide
35 N-{4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-chlorobenzeneacetamide
36 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-methylbenzeneacetamide (yellow foam); Anal. Calc'd for C27H23N3O2: C, 76.9; H,5.5; N, 10.0; Found: C, 75.6; H,6.0; N,9.4
37 N-[4-(pynolo[1,2-a]quinoxalin-5(4H)-yicarbonyl)phenyl]-2-methyl-3-thiopheneacetamide
Example 38
N-(2-Nitrobenzoyl)pvrrole-2-carboxaldehyde
To an ice bath cooled solution of 5.6 g of 2-pyrrolecarboxaldehyde in 40 ml oi tetrahyaroiuran is added 2.4 g oi 60% sodium hydride in mineral oil. The temperature eievates to 40° C. After stirring for 20 minūtes a solution of 11.0 g of 2-nitrobenzoyi chloride in 20 ml ot tetrahydrofuran is added dropvvise over 20 minūtes. After stirring in the cold for 45 minūtes, the reaction mixture is poured into ice vvater and ether then filtered. The cake is vvashed vvith additional ether. The tvvo phase filtrate is separate and the ether layer dried and concentrated in vacuo to give 10 g of a residue as a dark syrup vvhich is scratched vvith ethanol to give crystals vvhich are collected by filtration, vvashed vvith ether and then dried to afford 3.2 g o, solid, m.p. 95-99° C.
Example 39
10,11 -Pihvdro-5H-pyrrolof2,1 -clf 1.4ļbenzodiazepin-5-one
A mixture of 1.5 g of N-(2-nitrobenzoyl)pyrrole-2-carboxaldehyde in 50 ml of ethyl acetate, 2 drops ot concentrated HCl and 0.3 g of 10% Pd/C is shaken in a Parr apparatus under hydrogen pressure for 1.75 hours. The mixture is filtered, 0.4 g of 10% Pd/C added and the mixture shaken in a Parr apparatus under hydrogen pressure for 2 hours. The reaction mixture is filtered through diatomaceous earth and the filtrate concentrated in vacuo to give 1.0 g of a yellow oii. The residue is purified on thick layer chromatography plates by elution vvith 4:1 ethyl acetate:hexane to give 107 mg of the desired product as an oily solid.
Example 40
2-Methvl-N-[4-f(5-oxo-5H-pvrrolol2,1-cM1,4ļbenzodiazepin-10(11HVvncarbonvllphenvllbenzamide
To a stirred solution of 107 mg of 10,11-dihydro-5H-pyrrolo{2,1-c)[1,4]benzodiazepin-5-one in 3 ml of methylsne chloride containing 0.084 mi of triethylamine is added 165 mg of 4-((2-methylbenzoyl)amino]benzoyl chloride and stirring continued for 6 hours. The volatiles are removed in vacuo to a residue vvhich is purified on thick layer chromatography plates vvith 7:3 hexane-ethyi acetate to afford the desired product as a foam.
Example 41
N-f4-(3-Chtoro-5H-pvrrolo[2,1-cļf1,4ļbenzodiazeptne-10(11H)vlcarbonvnphenvU-2-methvlbenzamids
To an lce-water cooled suspension of 211 mg of 2-methyl-N-[4-(5H-pyrrolo[2,1-c](1,4]-benzodiazepin-10(11H)ylcarbonyl)-phenyl]benzamide in 5 ml of tetrahydrofuran is added 67 mg of N-chlorosuccinimide followed by continued stirring in the cold for 10 minūtes. The bath is removed and stirring continued for 2.25 hours. The reaction mixture is added to ice-water and extracted vvith ether. The organic layer is dried and concentrated in vacuo to give a foam which is crystallized from ethyl acetate-hexane to give 157 mg ol the desired product as an orange-pink solid, m.p. 185-187*C.
Examole 42
2-Methvl-N-f4-(1-chtoropvrrolof1,2-a1quinoxalin-5(4H1-vlcarbonvltohenyl1benzamide
To an ice-water cooled suspension of 5 mmol of 2-methyl-N-(4-(pyrrolo(1,2-a]quinoxalin-5(4H)-ylcarbonyt)-phenyl] benzamide in 5 ml of tetrahydropyran is added 5.5 mmol of N-chlorosuccinimide follovved by continued stirring in the cold for 10 minūtes. The bath is removed and stirring continued for 2.25 hours. The reaction mixture is added to icevvater and extracted vvith ether. The organic layer is dried and concentrated in vacuo to give the desired product as a soiid.
Table II
The follovving Examples are prepared using the conditions of Example 42.
Example No. Compound
43 2-chloro-N-[4-(1 -chloropyrrolo-(1,2-a]quinoxalin-5 (4H)-ylcarbonyl)phenyl]benzamide
44 2,4-dichloro-N-[4-(1 -chloropyrrolo-[1,2-a]quinoxalin-5 (4H)-ylcarbonyl)phenyl]benzamide
45 2,5-dichloro-N-[4-(1 -chloropyrrolo-(1,2-a]quinoxalin-5 (4H)-ylcarbonyl)phenyl]benzamide
46 2,3-dimethyl-N-[4-(1 -chloropyrrolo-[1,2-aļquinoxalin-5 (4H)-ylcarbonyl)phenyl]benzamide
47 2,4-dimethyl-N-[4-(1 -chtoropyrrolo-[1,2-aļquinoxalin-5 (4H)-ylcarbonyl)phenyl]benzamide
48 2,5-dimethyl-N-[4-(1 -chloropyrrolo-[1,2-alquinoxalin-5 (4H)-ylcarbonyl)phenyl]benzamide
Example 49
3-Chloro-10,11 -dihvdro-lO-(4-nitrobenzovi-5H-pvf rolof2,1 -clf 1,41-benzodiazepine
To an ice-water cooled solution of 250 mg ot l0,ll-dihydro-10(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodlazepine in 6 ml of tetrahydrofuran is added 100 mg of N-chlorosuccinimide. The reaction mixture Is stirred in the cold for 30 minūtes and at room temperature for 2 hours. The reaction mixture is poured into ice vvater, stirred for 5 minūtes and extracted vvith ether. The organic layer is dried and concentrated in vacuo to give 0.2 g of a yellow foam. Trituration vvith ethyl alcohol gives 66 mg of the desired product as a yellow solid, m.p. 119-125°C.
s Example 50
3-Chloro-10,11 -dihvdro-10-(4-aminobenzoyl)-5H-pyrrolol2.1 -cļ[1,4ļbenzodiazepine
A mixture of 1 mmol of 3-chloro-10,11-dihydro-10-(4-nitroaminobenzoyl) -5H-pyrrolo[2,1-cļ[1,4)benzodiazepine, to 2.5 mmol of anhydrous hydrazine, 50 mg of palladium on carbon and 10 ml of ethyl alcohol is refluxed for 1.5 hours. The mixture is filtered through diatomaceous earth and the filtrate concentrated to dryness to give the desired product as a solid.
Example 51 15
N-[4-(3-Chloro-5H-pyrrolo(2,1 -clf 1,4ļbenzodiazepin-10(11 H)vlcarbonvl)phenvn-2-methylbenzamide
A mixture of 1 mmol of 3-chloro-10,11 -dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1 -cj[1,4]benzodiazepine, 2 mmol of triethylamine, and 1.1 mmol of 2-methylbenzoylchloride in 8 ml of dichloromethane is stirred at room temperature ovemight. The mixture is vvashed vvith vvater, and 1M NaHCO3 and dried(Na2SO4). The solvent is removed in vacuo to give a solid vvhich is recrystallized from dichloromethane-hexane to give crystals, 185-187· C.
Table III
25 The follovving Examples are prepared using the conditions ol Example 51 vvith the appropriateiy substituted aroyl chloride
Example No. Compound
52 N-[4-(3-Chloro-5H-pyrrolo[2,1 -c][1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]2-chlorobenzam id e
30 53 N-[4-(3-Chloro-5H-pyrrolo(2,1 -c][ 1,4]benzodiazepin-10(11 H)ylcarbonyi)phenyl]2,5-dichlorobenzamide
35 54 N-[4-(3-Chloro-5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin -10( 11 H)ylcarbonyl)phenyl]2,4-dichlorobenzamide (solid foam), Anal. Calc'd for C26H18CI3N3O2; C,61.1; H.3.6; N,8.2; Cl, 20.8; Found: C.60.0; H,3.5; N.7.7; Cf, 20,3
55 N-[4-(3-Chloro-5H-pyrrolo[2,1-c](l,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]- 2-fluorobenzamide
56 N-(4-(3-Chlora-5H-pyrrolo[2,1-c][1,4]benzodiazepin-l0(11H)ylcarbonyl)phenyl]-2-chloro- 4-methylbenzamide
40 57 N-[4-(3-Chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(1lH)ylcarbonyl)phenyl]-2-methyl- 4-chlorobenzamide
58 N-[4-(3-Chloro-5H-pyrrolo[2,1 -c][1,4ļbenzodiazepin-10(11 H)ylcarbonyl)phenyl]2,4-dimethylbenzamide
59 N-[4-(3-Chloro-5H-pyrrolo[2,1 -c][1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]-
45 60 2,3-dimethylbenzamide N-(4-(3-Chloro-5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]2-methoxybenzamide
61 N-(4-(3-Chloro-5H-pyrrolo[2,1 -c]{ 1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]2-trifiuoromethoxybenzamide
50 62 N-[4-(3-Chloro-5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10(11 H)ylcarbonyl)phenylJ2,4-dimethoxybenzamide
63 N-(4-(3-Chloro-5H-pyrrolo(2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenylJ- 2,6-dimethoxybenzamide
55 64 N-(4-(3-Chloro-5H-pyrrolo[2,1 -cļ(1,4]benzodiazepin-10(11 H)ylcarbonyl)pheny Iļbenzamide
65 N-(4-(3-Chloro-5H-pyrrolo[2,1 -cļ(1,4]benzodiazepin-l 0(11 H)ylcarbonyl)phenylļ2,6-dichlorobenzamide
Table III (continued)
The follovving Examples are prepared using the conditions of Example 51 vvith the appropriately substituted aroyi chloride
s Example No. Compound
66 N-[4-(3-Chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]- 2,6-dimethylbenzamide
10 67 N-[4-(3-Chloro-5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10( 11 H)ylcarbonyl)phenyl]2-methylthiobenzamide
68 N-[4-(3-Chloro-5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]-2-methyl3-thtophenecatboxamide
69 N-[4-(3-Chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-3-methyl- 2-thiophenecaiboxamide
15 70 N-[4-(3-Chloro-5H-py rrolo[2,1 -c][ 1,4]benzodiazepin-10( 11 H)ylcarbonyl)phenyl]-2-methyl3-furanecarboxamide
71 N-{4-(3-Chloro-5H-pyrrolo[2,1 -c][ 1,4Jbenzodiazepin-10(11 H)ylcarbonyl)phenyl]-3-methyl2-furanecarboxamide
72 N-(4-(3-Chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]phenylacetamide
10 73 N-(4-(3-Chk>ro-5H-pyrrolo(2,1 -c][1,4]benzodiazepin-l 0(11 H)ylcarbonyl)phenyl]2-ch lorophenylacetamide
74 N-(4-(3-Chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]- 2-methylbenzeneacetamide
75 N-[4-(3-Chloro-5H-pyrrolo[2,1 -c][1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]-2-methyl-
15 3-thiopheneacetamide
76 N-{4-(3-Chloro-5H-pyrrolo{2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-2-methyl- 3-furanacetamide
30 Example 77
1-(2-Nitrobenzvl)-2-pyrrolecarboxaldehvde
To 5.56 g of 60% sodium hydride in mineral oil, vvashed three times vvith hexane, is added 300 ml of N,N-dimethylformamide under argon. The reaction mixture is cooled in an ice-bath and 13.2 g of pyrrole-2-carboxaldehyde is added slowly. The reaction mixture becomes a complete solution and is stirred for an additional 10 minūtes. While stirring, 30.0 g of 2 - nitrobenzyl bromide is added slowly. After complete addition, the reaction mixture is stirred for 30 minūtes, the ice bath is removed and the reaction mixture stirred at room temperature for 24 hours. The N.N-dimethylformamide is concentrated in vacuo to give a residue vzhich is stirred vvith ice vvater for 1 hour. The resulting solid is collected, air dried, then vacuum dried to give 30.64 g of the desired product as a tan solid, m.p. 128-132’C. Example 76
10,11 -dihvdro-5H-pyrrolof2,1 -cļf 1,41benzodiazepine 45
A mixture of 30.6 g of 1 -(2-nitrobenzyl)-2-pyrrolecarboxaldehyde and 3.06 g of 10% Pd/C in 400 ml of ethyl acetate and 400 ml of ethyl aicohol is hydrogenated over 18 hours. The reaction mixture is filtered through diatomaceous earth and the filtrate is treated vvith activated carbon and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to give a residue vvhich is dissoived in methylene chloride containing ethyl aicohol. The solution is passed through so a pad of silica gel and the pad vvashed vvith a 7:1 hexane-ethyl acetate solution to give 16.31 g ot the desired product as solid, m.p. 145-148’C.
Example 79 κ 10,11 -Dihvdro-10(4-nitrobenzovl)-5H-pvrrolo(2·1 -cli 1,41benzodiazepine
To a solution of 3.3 g o, 10,11-dihydro-5H-yrrolo[2.1-c][1,4]benzodiazepine in 50 ml of methylene chloride under argon is added 5.0 ml of triethylamine followed by ice bath cooling. A solution of 4.0 g of 4-nitrobenzoyl chloride in 20 ml of methylene chloride is added dropvvise. Follovving complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue vvhich is dissolved in ethyl acetate. The solution is vvashed vvith vvater, 1N HCI, NaHCO3, brine, dried vvith Na2SO4 and filtered. The filtrate is concentrated jņ vacuo to a solid vvhich is dissolved in methylene chloride, passed through silica gel and the pad vvashed vvith ethyl acetate. The combined filtrate is concentrated in vacuo to give 5.3 g of the desired product as a yellow solid, m.p. 188-190’C.
Example SO
10,11 -Dihvdro-10-(4-aminobenzovO-5H-pyrrolof2. t -cļf 1,4ļbanzodiazepine
A mixture of 2.00g of 10,11 -dihydro-10(4-itrobenzoyl)-5H-pyrrolo[2,1 -c][ 1,4]benzodiazepine in 15 ml of ethyl alcohol and 15 ml of ethyI acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo lo a solid vvhich is dissolved in methylene chloride, passed through silica gel and the pad vvashed vvith 3:1 ethyl acetate-hexane. The filtrate is concentrated jņ vacuo to give 1.5 g of the desired product as a yellow solid, m.p. 166-168’C.
Example 81
10,11 -Dihvdro-10-(4-aminobenzovl)-5H-pyrrolof2,1 -cļf 1,4ļbenzodiazepine
To a solution of 21.58 g of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 325 ml of ethyl alcohol is added 2.15 g of 10% Pd/C and 5.16 g of hydrazine follovved by stirring and heating under reflux tor 15 hours. The room temperature reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated jn vacuo to a solid vvhich is dissolved in methylens chloride and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated jņ vacuo to give 19.2 g of the desired product as a tan solid. The solid is purified by flash chromatography using 7:1 ethyl acetate-hexane to give 17.97 g of the desired product, m.p. 166-168C.
Example 82
N-f4-(5H-Pyrrolof2,1 -cļf t ,4ļbenzodiazepin-t 0(11 H)-vlcarbonvl)phenyl|-3-chlorobenzofblthiophene-2-carboxamide
To a stirred solution of 0.440 g of 3-chlorobenzo(b]thiophen-2-carbonyl chloride in 10 ml of methylene chloride is added 0.33 ml of triethylamine. After stirring for 15 minūtes, 0.485 gof 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo [2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours. The reaction mixture is vvashed vvith vvater, 1N HCI, NaHCO3, and brine. The reaction mixture is dried vvith Na2SO4, filtered and evaporated in vacuo to give a solid vvhich is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.49 g of solid, m.p. 220-222’C.
Example 83
N-[4-(5H-Pyrrolo[2,1 -cļf 1,4ļbenzodiazepin-10(11 H)ylcarbonyl)phenvH-2,3-dimethvlbenzamide
To a stirred solution ot 0.320 g ot 2,3-dimethylbenzoyl chloride in 10 ml of methylene chloride is added 0.33 ml of triethylamine. After stirring for 15 minūtes, 0.485 gof 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 5 hours. The reaction mixture is vvashed vvith vvater, 1N HCI, NaHCO3, and brine. The reaction mixture is dried vvith Na2SO4, filtered and evaporated in vacuo to give a solid vvhich is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.39 g of solid, m.p. 168’-170’C.
Example 84
N-f4-(5H-Pyrrolo[2,1 -clf 1,4ļbenzodiazepin-10(11 H)-ylcarbonvllphenvll-2-ethoxybenzamide
To a stirred solution of 0.362 g of 2-ethoxybenzoyl chloride 5 ml ol mathyiane chloride is added 0.346 g of triathylamine at O’C. After stirring for 3 minūtes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo(2,1-c][1,4]banzodiazepine is added and stirring continued tor 72 hours at room temperatūra. Tha raaction mixtura is diluted with 45 ml of methylene chloride and vvashed vvith vvater, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried vvith Na2SO4, filtered and evaporated in vacuo to give a solid vvhich is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.890 g ot solid vvhich is crystallized from ethyI acetate to give 0.540 g of the desired product as a vvhite solid, m.p. 160-176’C.
Example 85 s N-f4-f5H-Pyrrolo[2,1 -clf1,4ļbenzodiazepin-10(11 H)-vlcarbonyl)phenyl]-2-(methylthio)benzamide
To a stirred solution of 0.364 g of 2-(methylthio)benzoyl chloride 5 ml ot methylene chloride is added 0.346 g ot triethylamine at 0° C. After stirring for 3 minūtes, 0.500 g o, 10,11 -dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1 -c][ 1,4] benzodiazepine is added and stirring continued for 72 hours at room temperatūra. The reaction mixture is diluted vvith io 45 ml of methylene chloride and washed vvith vvater, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried vvith NajSO4, filtered and evaporated in vacuo to give a solid vvhich is purified by flash chromatography using 1 ;1 ethyl acetate-hexane to give a solid vvhich is crystaliized from ethyl aicohol to give 0.460 g of the desired product as a white solid, m.p. 171-174’C.
is Example 66
3- Methylbenzofb1thiophene-2-acetyl chloride
A mixture of 2.0 g of 3-methylbenzo(b]thiophene-2-acetic acid and 19.4 ml of thionyl chloride is heated at rsfiux 20 for 1 hour, The volatiles are evaporated in vacuo to give a residue vvhich is concentrated trom toluene three times and dried under vacuum to give 2.25 g of the desired product as a residue.
Example 67
N44-(5H-Pyrrolof2.1 -cļf 1,4|benzodiazepin-10(11 H)-vlcarbonvl)phenvll-3-methylbenzofblthionhene-2-acetamide
To a stirred solution of 0.445 g of 3-methylbenzo(b]thiophene-2-acetyl chloride in 5 ml of methylene chloride is added 0.346 g of triethylamine at 0* C. After stirring for 3 minūtes, 0.500 gof 10,11-dihydro-10-(4-aminobenzoyl)-5Hpyrrolo[2,1 -c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. An additional 0.445 so g of 3-methylbenzo(b]thiophene-2-acetyl chloride, 0.346 g of triethylamine and 30 mg of dimethylaminopyridine is added and stirring continued for an additional 16 hours. The reaction mixture is diluted with 45 ml of methylene chloride and vvashed vvith vvater, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried vvith Na2SO4, filtered and evaporated in vacuo to give a solid vvhich is purified by flash chromatography using 1:1 ethyi acetate-hexane to give
0.320 g of the desired product as a yellow foam.
Example 88
4- Chloro-2-methoxybenzoyl chloride
A solution of 2.0 g of 4-chloro-o-anisic acid in 22 ml ot thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue vvhich is is concentrated from toluene three times and dried under vacuum to give 2.0 g of the desired product as a residue.
Example 89
N-f4-f5H-Pyrrolo[2.1 -cļ[ 1,4ļ-benzodiazepin 10( 11 H)ylcarbonvhphenyH-4-chloro-2-methoxvbenzamida
To a stirred solution ot 0.406 g of 4-chloro-2-methoxybenzoyl chloride in 5 ml of methylene chloride is added 0.346 g of triethylamine at 0’C. After stirring for 3 minūtes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c] [1,4]benzodiazepine is added and stirring continued for 18 hours at room temperature. An additional 0.406 g of 4-chloro2-methoxybenzoyl chloride and 0.346 g of triethylamine is added and stirring is continued for 2 hours. The reaction mixture is diluted vvith 45 ml of methylene chloride and vvashed vvith vvater, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried vvith Na2SO4, filtered and evaporated jn vacuo to give a residue vvhich is purified by flash chromatography using 1:1 ethyl acetate-hexane to give a solid vvhich is crystallized from ethyl acetate to give 0.320 g ot the desired product as a vvhite crystals, m.p. 222-224’C.
Exampla 90
2-(Trifluoromethyl)benzoyl chloride
A solution of 2.0 g of o-trifluoromsthylbenzoic acid in 21 ml of thionyI chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue vvhich is concentrated from loluene three times and dried under vacuum to give 2.1 g of the desired product as a residue.
Example 91
N-f4-(5H-Pyrrolof2,1 -cļf 1,41benzodiazepin-l0(11 H)vlcarbonyl)phenyll-2-(trifluoromethyl)benzamide
To a stirred solution of 0.413 g of 2-trifluoromethylbenzoyl chloride In 5 ml of methylene chloride is added 0.346 g of triethylamine at 0’ C. After stirring for 3 minūtes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c] (1,4]benzodiazepine is added and stirring continued for 18 hours at room temperature. The reaction mixture is diluted vvith 50 ml ot ethyl acetate and vvashed vvith water, 2N citric acid, NaHCO3, and brine. Tha reaction mixture is dried vvith Na2SO4, filtered and evaporated in vacuo to give a solid vvhich is crystallized from ethyl acetate to afford 0.5 g of a solid vvhich is dissolved in methylene chloride and passed through a pad of hydrous magnesium siiicate. The filtrate is evaporated in vacuo to give a solid vvhich is crystallized from sthyl acetate to afford 0.210 g of the desired product as a vvhite crystals, m.p. 226-228’C.
Example 92
2-Methylphenylacetyl chloride
A solution of 2.0 g of o-tolylacetic acid in 27 ml of thionyl chloride is heated at reflux for 1 hour. The volatifes are evaporated in vacuo to give a residue vvhich is concentrated from toluene three times and dried under vacuum to give 2.1 g of the desired product as a light brovvn oil.
Example 93
N-f4(5H-Pvrrolof2,1-cli1,41benzodiazepin10(11H)-vlcarbonvl')phsnvl1-2-malhvlbenz6neacetamide
To a stirred solution of 0.334 g of 2-methylphenylacetyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at O’C. After stirring for 3 minūtes, 0.500 g of 10,l1-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4] benzodiazepine is added and stirring continued for 72 hours at room temperature. The reaction mixture is diluted vvith 45 ml ot methylene chloride and vvashed vvith vvater, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered through a pad of hydrous magnesium siiicate and evaporated in vacuo to give a solid vvhich is purified by flash chromatography using 1:1 ethyl acetate-hexane to give a solid vvhich is crystallized from athyl acetate to give 0.385 g of the desired product as vvhite crystals, m.p. 198-200’C.
Example 94
10,11 -Dihvdro-10-(3-methvl-4-nitro-benzoyl)-5H-pyrrolo[2,1 -cļļ 1,4ļbanzodiazepine
A mixture of 1.81 g of 3-methyl-4-nitrobenzoic acid and 1.25 g of thionyl chloride in 75 ml of chloroform is heated at reflux under argon for 48 hours. The volatiles are removed in vacuo to a residue vvhich is evaporated vvith toluene several times in vacuo. The residue is partially dissolved in methylene chloride and filtered free of solids and ths filtrate evaporated jņ vacuo to give 1.47 g of the desired acid chloride. A 1.36 g sample of the acid chloride, 0.90 g of N,Ndiisopropylethylamine and 1.25 g of 10,11 -dihydro-5H-pyrrolo[2,1 -c][ 1,4]benzodiazepine in 25 ml of methylene chloride is allovved to stand at room temperature for 8 hours. Water is added to the reaction mixture, the organic layer is separated and dried over Na2SO4, filtered and hexane added to the filtrate at the boil to give 1.4 g of the desired product as crystals, m.p. 246-248’C.
Example 95
10,11 -Dihvdro-10-(4-amino-3-methvlbenzovn-5H-pyrrolof2.1 -cļ[ 1,4ļbenzodiazepine
A mixtura of 1.22 g 10,11-dihydro-10-(3-methyl-4-nitro-benzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.2 g of 10% Pd/C and 0.35 g of anhydrous hydrazine in 50 ml of absolute ethyl alcohol is heated on a steam bath tor 1 houc The reaction mixture is filtered hot through diatomaceous earth and evaporated in vacuo to a residue. The residue is crystallized from methylene chtoride-hexane to give 0.95 g ot the desired product as crystals, m.p. 232-234’C.
Example 96
N-f4-(5H-Pyrrolof2,1-cK1.41benzodiazepin-10(11HMcarbonvO-2-methvlphenyfl-2-methvlbenzamide
A solution of 0.83 g of 10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.5 g of N,N-diisopropylethylamine and 0.6 g of 2-methylbenzoyl chloride In 50 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is vvashed vvith vvater, the organic layer dried wlth Na2SO4 and passed through a pad of hydrous magnesium silicate. Hexane is added at the boil to give 0.75 g of a solid vvhich is crystallized from methylene chloride-hexane to give 0.61 g of the desired product, m.p. 125-130*C.
Table IV
The follovving Examples are prepared using the conditions of Example 96 vvith the appropriateiy substituted aroyl
chloride
Example No. Compound
97 N-[4-(5H-pyrralo[2,1 -c][1,4]benzodiazepin-10(11 H)-ylcarbonyl)-2-methylphenyi]2-chlo(obenzamide
96 N-(4-(5H-pyrrolo(2,1 -c][1,4]benzodiazepin-l 0(11 H)-ylcarbonyl)-2-methylphenyl]2,5-dichlorobenzamide
99 Nļ4-(5H-pyrrolo[2,1-c][1l4]benzodiazepin-10(11H)-yl-carbonyl)-2-methylphenyl]2,4-dichlorobenzamide, m.p. 213°-215’C
100 N-[4-(5H-pyrrolo{2,1 -c][1,4]benzodiazepin-10(11 H)-ylcarbony l)-2-methylpheny l]2-chloro4-methylbenzamide
101 N-(4-(5H-pyrrolo{2,1-c][1,4]benzodiazepin-10(11H)-yl-carbonyl)-2-methylphenyl]2-methyl- 4-chlorobenzamide
102 N-[4-(5H-pyrrolo(2,1-c][1,4ļbenzodtazepin-10(11H)-ylcartJonyl)-2-methylphenyl]2,3-dimethylbenzamide
103 N-[4-(5H-pyrrolo[2,1 -c][1,4]benzodiazepin-10(11 H)-ylcarbonyl)-2-methylphenyl]2-methoxybenzamide
104 N-(4-(5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10(11 H)-ylcarbonyl)-2-methy lpheny I]2-trifluoromethoxybenzamide
105 N-[4-(5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10(11 H)-ylcarbonyl)-2-methylphenyl]2,4-dimethoxybenzamide
106 N-[4-(5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10( 11 H)-ylcarbonyl)-2-methylphenyl]benzamide
107 N-[4-(5H-pyrrolo(2,1 -c][1,4]benzodiazepin-10(11 H)-ylcarbonyl)-2-methylphenyl]2-methylthiobenzamide
106 N-{4-(5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10( 11 H)-ylcarbonyl)-2-methylphenyl]2,6-dichlorobenzamide
109 N-[4-(5H-pyrrolo[2,1 -c][1,4]benzodiazepin-10(11 H)-ylcarbonyl)-2-methylphenylJ-2-methyl3-thlophenecarboxamide
110 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-methylphenyl]-2-methyl- 3-thiophenecarboxamide
111 N-[4-(5H-pyrrolo(2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-methylphenyl]-2-methyl- 3-furancarboxamide
112 N-(4-(5H-pyrrolo(2,1 -c][1,4ļbenzodiazepin-10(11 H)-ylcarbonyl)-2-methylphenyl]3-methyl2-furancarboxamide
Table IV (continued)
The foilowing Examples are prepared using the conditions of Example 96 vvith the appropriately substituted aroyl
chloride
Example No. Compound
113 N-[4-(5H-pyrrolo[2,1 -c][1,4]benzodiazepin-10(11 H)-ylcarbonyl)-2-methylphenyl]phenylacetamide
114 N-(4-(5H-pyrrolo[2,l-c][1,4]benzodiazepin-10(1lH)-ylcarbonyl)-2-methylphenyl]- 2-chlorophenylacetamide
115 N-[4-(5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10( 11 H)-ylcarbonyl)-2-methylphenyl]2-methylphenylacetamide
Example 116
10,11-Dihvdro-10-f4-fff(2-methvlphenvHaminolcarbonvllamino1benzovn-5H-pyrrolof2,1-clf1,4lbenzodiazepine
A mixture of 0.93 g 10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.37 g of o-tolyl isocyanate in 50 ml of tetrahydrofuran is heated at reffux under argon for 24 hours. The volatiles are evaporated jņ vacuo to a residue vvhich is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.68 g of the desired product as crystals, m.p. 155-158’C.
Example 117
N-f4-(5H-pyrrolof2,1 -cļfļ ,41benzodiazepin-10(11 H)-ylcarbonyl)phenvn-1 H-indole-5-carboxamide
To a solution of 319 mg of indole-5-carboxylic acid in 5 ml of tetrahydrofuran is added 418.4 mg of 1,T-carbonyldiimidazole under argon vvith ice-bath cooling. The cooling bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are evaporated in vacuo to a residue vvhich is dissolved in 3 ml of xylene follovved by 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and heating at 120’ C for 18 hours. The volatiles are evaporated in vacuo to a residue vvhich is partitioned betvveen 40 ml of ethyl acetate and water. The organic layer is dried over NagSC^ and the volatiles evaporated in vacuo to a residue vvhich is purified by chromatography on preparative plates by elution vvith 1:1 ethyl acetate-hexane to give 140 mg of the desired product as an orange solid, m.p. 130-170°C.
Example 118
1-(o-Nitrobenzyl)-imidazole-2-carboxaldehyde
A 2.0 g portion of sodium hydride (60% in oil) is vvashed vvith pentane tvvo times. To the residue is added 110 ml of N,N-dimethylformamide under argon. With stirring and extemal cooling, 4.80 g of 2-imidazolecarboxaldehyde is added and the cooling bath removed. Slight external heating results in a yellow solution. The reaction mixture is chilled in ice and 10.8 g of 2-nitrobenzyl bromide is added. The reaction mixture is stirred at O° C for 18 hours. The volatiles are removed jņ vacuo to a residue vvhich is stirred vvith ice vvater, filtered and the cake vvashed vvell vvith water and suction dried to give 10.9 g ot the desired product as a solid, m.p. 141-144° C. MH+ 232.
Example 119
10,11 -Dihydro-5H-imidazof2,1 -cļf 1,4ļbenzodiazepine
A 5.0 g sample of 1 -(o-nitrobenzyl)-imidazole-2-carboxaldehyde is dissolved in 150 ml of hot ethyI alcohol, cooled to room temperature and filtered. To the filtrate is added 0.5 g of 10% Pd/C and the mixture hydrogenated at 48 psi tor 4 hours. An additional 0.5 g of 10% Pd/C is added and hydrogenation continued tor 25 hours at 65 psi. The mixture is filtered through diatomaceous earth and the cake vvashed vvith ethyl acetate. The filtrate is evaporated in vacuo to a residue vvhich is dissolved in methylene chloride, treated vvith activated carbon, filtered through diatomaceous earth and hexanes added to the filtrate at the boil to give 1.86 g of the desired product as a crystalline solid, m.p. 164-170’C.
i
Example 120
10,11 -Dihydro-5H-imidazof2,1 -clf 1.41benzodiazepine s To a suspension of 4 mmol of lithium aluminum hydride in 20 ml of anhydrous tetrahydrofuran is added a 1 mmol solution of 10,11-dihydro-11-oxo-5H-imidazo[2,1-c][1,4]benzodiazepine and the mixture is refluxed for 24 hours and cooled at 0° C. To the mixture is added dropvvise 0.12 ml of vvater and 6 ml of 1N sodium hydroxide. The mixture is extracted vvith 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.
Example 121
N-f4-(5H-lmidazof2.1-clf1.4lbenzodlazepin-10(11H)-ylcarbonyltohenyl1-2-methvlbenzamide
To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C is added 1.5 ml of triethylamine. After stirring tor 3 minūtes, 5 mmol of 10,11 -dihydro-5H-imidazo(2,1 -c] [1,4]benzodiazepine in 5 ml of methylene chloride is added. The cooling bath is removed and after about 30 minūtes a complete solution is obtained. The reaction mixture is allowed to stir at room temperature for 1 hour and the volatiles are concentrated in vacuo. The residue is dissolved in 100 ml of ethyi acetate and vvashed vvith vvater, 2N citric acid, and brine. The solution is dried vvith Na2SO4 and the volatiles concentrated ļņ vacuo to give the desired product as a solid.
Example 122
10, f f -Dihvdro-10-(4-nitrobenzovl)-5H-imidazof2,1 -clf 1,4ļbenzodiazepine
To a solution of 10 mmol of 10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine in 50 ml of methylene chloride under argon is added 15 mmol of triethylamine follovved by ice bath cooling. A solution of 10 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropvvise. Follovving complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue vvhich is dissolved in ethyi acetate. The solution is washed vvith vvater, and brine. The organic layer is dried with NajSO* filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give desired product as a solid.
Example 123
10,11 -Dihvdro-10-(4-aminobenzoyl)-5H-imidazof2,1 -clf f ,4ļbenzodiazepine
A mixture of 5 mmol of 10,11-dihydro-10(4-nitrobenzoyl)-5H-imidazo(2,l-c][1,4]benzodiazepine in 10 ml of ethyl aicohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours in a Parr hydrogenator at 35 psi of hydrogen. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid vvhich is purified by flash chromatography to give the desired product.
Example 124
10,11 -Dihvdro-10-(4-aminobenzoyl)-5H-imidazof2.1 -clf 1,4ļbenzodiazepine
To a solution ol 5 mmol of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo|2,1-c][l,4]benzod'iazepine in 100 ml of ethyl aicohol is added 0.5 g of 10% Pd/C and 10 mmol of hydrazine follovved by stirring and heating under reflux for 3 hours. The reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated jņ vacuo to a residue vvhich is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product vvhich is purified by flash chromatography to give the desired product as a solid.
Example 125
N-f4-(5H-lmidazo[2,1-clf1,4lbenzodiazepin-10(11H)vlcarbonvl)phenvl1-2-methylbenzamide
To a stirred solution of 1 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 1.5 mmol of triethylamine. After stirring for 15 minūtes, 1 mmol of 10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][l,4]benzodiazepins is added and the mixture stirred for 5 hours. The reaction mixture is vvashed vvith vvater, and brine. The reaction mixture is dried vvith Na2SC>4, filtered and evaporated jņ vacuo to give a solid vvhich is purified by flash chromatographv to give the desired product as a solid.
Table V
The follovving Examples are prepared using the conditions of Example 125 vvith the appropriately substituted aroyl chloride
Example No. Compound
126 N-[4-(5H-imidazo[2,1 -c][ 1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]-2-chlorobenzamide
127 N-[4-(5H-imidazo[2,1 -c]( 1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]-2,5-dichlorobenzamide
120 N-[4-(5H-imidazo[2,1 -c][ 1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]-2,4-dichlorobenzamide
129 N-[4-(5H-imidazo[2,1 -c]( 1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]-2-fluorobenzamide
130 N-[4-(5H-imidazo[2,1 -c][ 1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]2-chloro4-methylbenzamide
131 N-(4-(5H-imidazo[2,1 -c][ 1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]2-methyl4-chlorobenzamide
132 N-[4-(5H-imidazo(2,1 -cļ[ 1,4]benzodiazepin-10( 11H )ylcarbonyl)phenyl]-2,4-dimethylbenzamide
133 N-[4-(5H-imidazo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-2,3-dimethylbenzamide
134 N-[4-(5H-imidazo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-2-methoxybenzamide
135 N-[4-(5H-imidazo[2,1 -c](1,4]benzodiazepin-10(11 H)-ylcarbonyl)phenyl]2-trifluoromethoxybenzamide
136 N-(4-(5H-imidazo[2,1 -c][1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]-2,4-dimethoxybenzamide
137 N-[4-(5H-imidazo[2,1 -c][ 1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]-2,6-dimethoxybenzamide
138 N-[4-(5H-imidazo{2,1 -c]( 1,4]benzodiazepin-10( 11 H)ylcarbonyl)phenyl]benzamide
139 N-[4-(5H-imidazo(2,1 -c](1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]-2,6-dichlorobenzamide
140 N-[4-(5H-imidazo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-2,6-dimethylbenzamide
141 N-[4-(5H-imidazo[2,1 -c][ 1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]-2,methylthiobenzamide
142 N-[4-(5H-imidazo[2,1-cJ[1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]-2,methyl3-thiophenecarboxamide
143 N-[4-(5H-imidazo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-3,methyl- 2-thiophenecarboxamide
144 N-[4-(5H-imidazo[2,1 -c][1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]-2,-methyl3-furanecarboxamide
145 N-[4-(5H-imidazo[2,1 -c][ 1,4]benzodiazepin-10( 11 H)ylcarbonyl)phenyl]-3,-methyl2-furanecarboxamide
146 N-[4-(5H-imidazo[2,1-c][1,4]benzodiazepin-lO(11H)ylcarbonyl)phenyl]phenyl acetamide
147 N-[4-(5H-imidazo[2,1 -c][1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]-2-chlorophenylacetamide
140 N-[4-(5H-imidazo[2,1 -c][ 1,4]benzodiazepin-10(11 H)ylcarbonyl)phenyl]-2-methylphenylacetamide
149 N-[4-(5H-imidazo[2,1 -c](1,4]benzodiazepin-i 0(11 H)ylcarbonyl)phenyl]-2-methyl3-thiopheneacetamide
150 N-[4-(5H-imidazo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]2-methyl-3-furanacetamide
Example 151
N-[4-(7-Chloro-5H-imidazo[2,1 -cļf 1,4ļbenzodiazepin-10(11 H)-ylcarbonvHphenyH-2-methylbenzamide
As described for Example 125 a mixture of 1 mmol of 7-chloro-10,l1-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine, 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mmol of triethylamine in 10 ml of dichlo75 romethane is stirred at room temperature for 3 hours and vvorked up to give the desired product as a solid.
Example 152
N-f4-(7-Methoxv-5H-imidazof2, t -cļf 1,4ļbenzodiazepin-10(11 H)-ylcarbonyl1phenvll-2-methvlbenzamide
As described for Example 125 a mixture of 1.0 mmol of 7-methoxy-10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine, 1.1 mmol of 4-{(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mmol of trlethylamine in 10 ml of dichloromethane is stirred for 3 hours at room temperature and worked up to give the product as a solid.
w
Example 153
N-[4-(7.8-Methvlenedioxv-5H-imidazof2.1-clf1.41benzodiazepin-l0(l1H)-vlcarfaonvllphenvn-2-methylbenzamide is As described for Example 125 a mixture of 1.0 mmol of 7,8-methylenedioxy-10,11 -dihydro-5H-imidazo-[2,1 -c][ 1,4] benzodiazepine, 1.1 mmol of 4-{(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mmol of triethylamine in 10 ml of dichloromethane is stirred at room temperature for 3 hours and vvorked up to give the desired product as a solid.
Example 154
4.5- Dihvdro-5-(4-nitrobenzovl)pyrrolof1,2-alquinoxalina
To a solution of 5 mmol of 4,5-dihydropyrrolo-[1,2-a]quinoxaline in 50 ml of methylene chloride under argon is added 10 mmol of triethylamine follovved by ice bath cooling. A solution of 5 mmol ol 4-nitrobenzoyl chloride in 10 ml
2s of methylene chloride is added dropwise. Follovving complete addition, the ice bath is removed and the reaction mixture stirred at room temperature tor 2 hours. The volatiles are removed jņ vacuo to give a residue vvhich is dissolved in ethyl acetate. The solution is washed vvith vvater, 1N HCI, NaHCO3, and brine. The reaction mixture is dried vvith Na^O^ filtered and evaporated in vacuo to give a solid vvhich is purified by flash chromatography to give the desired product (from ethyl acetate) as a solid, m.p. 174-178°C.
Example 155
4.5- Dihvdro-5f4-aminobenzovltovrrolof 1.2-a1auinoxaline
3S A mixture of 1 mmol o, 4,5-dihydro-5-(4-nitrobenzoyl)pyrrolo[1,2-a]quinoxaline in 10 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated jņ vacuo to a solid vvhich is purified by flash chromatography to give the desired product, m.p. 225-228°C.
Example 156
4.5- Oihvdro-5(4-aminobenzoyl)pyrrolof 1,2-alquinoxaline
To a solution of 1 mmol of 4,5-dihydro-5-(4-nitrobenzoyl)pyrrolo[1,2-a]quinoxaline in 20 ml of ethyl alcohol is added
4S 0.2 g of 10% Pd/C and 2.5 mmol of hydrazine follovved by stirring and heating under reflux for 2 hours. The hot reaction mixture is filtered through diatomaceous earth and the filter cake vvashed vvith hot chloroform and the filtrate concentrated iņ vacuo. The residue is triturated vvith ethyI acetate and the mixture filtered to give the desired product as crystals, m.p. 225°-228°C.
so Example 157
N-f4-(pvrrolof1,2-alquinoxalin-5(4H)-ylcarbonvl)phenvll-2-methvlbenzamide
To a stirred solution of 1.5 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 3 mmol of triethylamine. After stirring for 15 minūtes, 1.5 mmol of 4,5-dihydro-5-(4-aminobenzoyl)pyrrolo[1,2-aļquinoxaline is added and the mixture stirred for 5 hours. The reaction mixture is vvashed vvith vvater, 1N HCI, NaHCOa, and brine. The reaction mixture is dried vvith Na2SO4, filtered and evaporated jņ vacuo to give a solid vvhich is purified by flash chromatography to give the desired product as a solid, m.p. 206-207'C.
Table VI
The follovving Examples are prepared using the conditions ot Example 157 vvith the appropriately substituted aroyl
chloride
Example No. Compound
158 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-chlorobenzamide
159 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyllphenyl-2,5-dichlorobenzamide
160 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide, m.p. 200·202°C
161 N-[4-(pyrrolo[1,2-aļquinoxalin-5(4H)-ylcarbonyl)phenyl]-2-chloro-4-methylbenzamide
162 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-methyl-4-chlorobenzamide
163 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenylJ-2.4-dimethylbenzamide
164 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2,3-dimethylbenzamide, m.p. 216·· 220’C
165 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-methoxybenzamide
166 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-trifluoromethoxybenzamide
167 N-[4-(pyrrolo(1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2,4-dimethoxybenzamide
168 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2,6-dimethoxybenzamide
169 N-[4-(pyrrolo[1,2-aJquinoxalin-5(4H)-yicarbonyl)phenylJbenzamide
170 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2,6-dichlorobenzamide
171 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2,6-dimethylbenzamide
172 N-[4-(pyrrolo[1,2-a)quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-(methylthio)benzamide
173 N-[4-(pyrrolo[1,2-aJquinoxalin-5(4H)-ylcarbonyl)phenyll-2-methyl-3-thiophenecarboxamide
174 N-[4-(pyiTolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-3-methyl-2-thiophenecarboxamide
175 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-methyl-3-1uranecarboxamide
176 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenylļ-3-methyl-2-furanecarboxamide
177 N-[4-(pyrrolo{1>2-a]quinoxalin-5(4H)-ylcarbonyl)phenyi]benzeneacetamide
178 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyt]-2-chlorobenzene acetamide
179 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-methylbenzene acetamide, yellow foam
180 N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyll-2-methyl-3-thiopheneacetamide
Example 181
9.10- Dihvdro-4H-furoi2.3-e1pvrrolo[ 1,2-al i 1,4ļdiazepine
To a suspension of 4 mmol ol lithium aluminum hydride in 25 ml ol anhydrous tetrahydrofuran is added 1 mmol ol
9.10- dihydro-4H-furo[2,3-eļpyrrolo[1,2-a][ 1,4]diazepin-9-one. The mixture is refluxed lor 12 hours and allovved to stand overnight. To the mixture is added dropwise 0.12 ml of vvater and then 6 ml of 1N sodium hydroxide. The mixture is extracted vvith ethyl acetate and the extract dried(Na2SO4). The volatiles are removed jņ vacuo to give the desired product as a solid.
Example 182
9.10- Dihvdro-4H-(uro[2,3-elpyrrolof 1,2-aļ f 1,4ļdiazepine
A solution of 1 mmol ol 4H-furo[2,3-e]pyrrolo[1,2-a)[1,4]diazepine and 0.2 g of 10% Pd/C in 10 ml ol 10 ml of ethanol is hydrogenatad for 18 hours. The reaction mixture is filtered through diatomaceous earth and the fiitrate is evaporated in vacuo to give the desired product as a solid.
Example 183
N-f4-(4H-Furof2,3-elPvrrolof1,2-aff1,4ldiazepin-10(9H)-vlcarbonyl)phenvn-2-methvlbenzamide 5 To a mixture of 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 10 ml of methylene chloride, cooled to
0° C is added 1.5 mmol of triethylamine. To the mixture is added 1 mmol of 9,10-dihydro-4H-furo{2t3-e]pyrrol0(1,2-a] [1,4]diazepine and the mixture stirred at toom temperature for 2 hours. The reaction mixture is concentrated in vacuo and the residue is dissolved in 100 ml of ethyl acetate and vvashed vvith vvater, 2N citric acid, aqueous NaHCOj and brine. The solution is dried vvith Na2SO4 and the volatiles concentrated ļn vacuo to give a solid vvhich is purified by īo flash chromatography to give the desired product.
Example 184
9.10- Dihvdro-10-(4-nitrobenzoyl)-4H-furof2,3-el pvrrolof 1,2-alf 1,41diazepine is
To a solution of 1.0 mmol of 9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][ 1,4]diazepine in 10 ml of methylene chloride under argon is added 1.5 mmol of triethylamine follovved by ice bath cooling. A solution of 1.1 mmol of 4-nitrobenzoyl chloride in 5 ml of methylene chloride is added dropvvise. Follovving complete addition, the ice bath is removed and the reaction mixture is stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue 20 vvhich is dissolved in ethyl acetate. The solution is vvashed vvith vvater, 1N HCl, NaHCO3, and brine. The reaction mixture is dried vvith Na2SO4, filtered and evaporated ļņ vacuo to give a solid vvhich is purified by flash chromatography on silica gel to give desired product as a solid.
Example 185
9.10- Dihvdro-10-f4-aminobenzov0-4H-furof2.3-e1 pyrrolof1,2-a1f1,41diazepine
A mixture of 1 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-aJ[1,4]diazepine in 10 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is oo filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid vvhich is purified by flash chromatography on silica gel to give the desired product.
Example 186
9,10-Dihvdro-10-f4-aminobenzoyl)-4H-turof2.3-el pvrrolofl ,2-alf 1,4fdiazepine
To a solution of 1 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e]pyrroio(1,2-a][1,4]diazepine in 20 ml of ethyl alcohol is added 0.2 g of 10% Pd/C and 2.5 mmol of hydrazine follovved by stirring and heating under reflux for 3 hours. The room temperature reaction mixture is filtered through diatomaceous earth and the filtrate concentrated jņ vacuo. The residue is dissolved in methylene chloride and passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product vvhich is purified by flash chromatography on silica gel to give the desired product as a solid.
Example 187
N-f4-(4H-Furof2,3-efpvrrolof1,2-a1f1,41diazepin-10(9H)-vlcarbonvl)phenvll-2-mathyl benzamide
To a stirred solution of 1.1 mmol of 2-methylbenzoyl chloride in 10 ml of methy!ene chloride is added 1.5 mmol ol triethylamine. To the mixture is added 1.1 mmol of 9.10-dihydro-10-(4-aminobenzoyl)-4H-furo{2,3-e]pyrrolo(1,2-a][1,4] so diazepine and tha mixture is stirred for 5 hours. The reaction mixture is vvashed vvith vvater, 1N citric acid, NaHCO3, and brine. The reaction mixture is dried vvith Na2SO4, filtered and evaporated in vacuo to give a solid vvhich is purified by flash chromatography on silica gel vvith ethyl acetate-hexane as soivent to give the desired product as a solid.
Table VII
The follovving Examples are prepared using the conditions of Example 187 vvith the approphately substituted aroyl chloride.
Example No. Compound
188 189 190 191 N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)-ylcarbonyl)phenyl]-2-chlorobenzamide N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)-ybarbonyl)phenyl]-2,5-dfchlorobenzamide N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)-ylcarbonyl)phenyl]-2-chloro4-methylbenzamide
192 N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)-ylcarbonyl)phenyl]-2-methyl4-ch brobenzam ide
193 N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)-ytearbonyl)phenyl]2,4-dimethylbenzamide
194 N-[4-(4H-Furo[2,3-eJpyrralo[1,2-aj[1,4jdiazepin-10(9H)-ylcarbonyl)phenylJ2,3-dim ethy Ibenzam ide
195 196 N-[4-(4H-Furo{2,3-e]pyrrolo(l, 2-a][1,4]diazepin-10(9H)-ybarbonyl)phenyl]-2-methoxybenzamide N-[4-(4H-Furol2,3-e]pyrrolo[1,2-all1,4]diazepin-10(9H)-ylcarbonyl)phenyl]- 2-trifluoromethoxybenzamide
197 N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)-ylcarbonyl)phenyl]2,4-dimethoxy ben zamide
198 N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)-ylcarbonyl)phenyl]-2-methoxy4-ch brobenzam id e
199 200 N-(4-(4H-Furo[2,3-e]pyrrolo(1,2-a][1,4]diazepln-10(9H)-ylcarbonyl)phenyl]-2,6-dbh!orobenzamide N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)-ytearbonyl)phenylJ2-methy Ith iobenzam ide
201 N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)-ylcarbonyl)phenyl]-2-methyl- 3-thbphenecarboxamide
202 N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4]diazspin-10(9H)-ylcarbonyl)phenyl]-3-methyl- 2-thbphenecarboxamide
203 N-(4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4Jdiazepin-10(9H)-ylcarbonyl)phenylJ-2-methyl-3-furanecarboxamide
204 N-[4-(4H-Furo[2,3-e]pyrrolo(1,2-a][1,4]diazepin-10(9H)-ytearbonyl)phenyl]-3-methyl2-furanecarboxamide
205 N-[4-(4H-Furo{2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)-ybarbonyl)phenyl]- 2-chbrobenzeneacetamide
206 N-f4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)-ylcarbonyl)phenyl]- 2-methylbenzeneacetamide
207 N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)-ylcarbonyl)phenyl]-2-methyl- 3-thiopheneacetamide
208 N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-l0(9H)-ylcarbonyl)phenyl]- cyclohexanecarboxamide
209 N-[4-(4H-Furo[2,3-e]pyrrolo[1.2-a][1,4]diazepin-10(9H)-ylcarbonyl)phenyl]-cyclohexylacetamide
Example 210
N-f4-(4H-Pyrazolof5,1 -clf 1,4fbenzodiazeoin-5f 10m-vlcarbonvl)phenvll-2-methylbenzamide
To a mixture of 1.37 g of 4-{(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C is added 1.5 ml of triethylamine. To the mixture is added 5 mmol of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4Jbenzodiazepine. The reaction mixture is allovved to stir at room temperature for 48 hours and the volatiles are removed jņ vacuo to give a residue. The residue is dissolved in 100 ml of ethyl acetate and vvashed vvith vvater, 2N citric acid, aqueous NaHCOj and brine. The solution is dried vvith NajSO4 and the solvent removed jņ vacuo. The residue is purified by flash chromatography on silica gel vvith ethyl acetate-hexane to give the desired product, m.p. 142°-146°C.
Example 211
5.10- Dihvdro-5-(4-nitrobenzoyl)-4H-pyrazolo-[5,1 -cļ[1,4ļbenzodiazepine s To a solution ol 10 mmol of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine in 50 ml of methylene chloride under argon is added 15 mmol of triethylamine follovved by ice bath cooling. A solution of 11 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropvvise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue vvhich is dissolved in ethyl acetate. The solution is vvashed vvith vvater, NaHCO3, and brine. The reaction mixture is dried vvith
Na2SO4, filtered and evaporated in vacuo to give a solid vvhich is purified by flash chromatography on silica gel to give desired product as a solid, m.p. 227’-219eC.
Example 212 is 5,10-Dihvdro-5-(4-aminobenzoyl)-4H-pyrazolo-f5,1 -clf 1,41benzodiazepine
A mixture of 5 mmol of 5,10-dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine in 25 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid vvhich is purified by flash chromatography on silica gel to give the desired product as a tan solid.
Example213
5.10- Dihvdro-5-(4-aminobenzovl)-4H-pyrazolo-f5,1 -cļ[1,4ļbenzodiazepine
To a solution of 5 mmol of 5,10-dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo-(5,1 -c)[1,4]benzodiazepine in 25 ml of ethyl alcohol is added 0.3 gof 10% Pd/C and 15 mmolof hydrazine. The mixture is heated under reflux for 3 hours, and the mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in methylene chloride and passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product vvhich is purified by flash chromatography on silica gel to give the desired product as a solid, exact mass by mass spectrometry: 305.1402(M+H).
Example 214
N-f4-(4H-Pyrazolof5,1-cl[1,4lbenzodiazepin5ff0H)-vlcarbonvl)phenyll-2-methvlbenzamide
To a stirred solution of 3 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 5 mmol of triethylamine and 3 mmol of 5,10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo-[5,1 -c][1,4]benzodiazepine. The mixture is stirred at room temperature for 5 hours and is then vvashed with vvater, NaHCO3, and brine. The organic layer is dried vvith Na2SO4, filtered and evaporated in vacuo to give a solid vvhich is purified by flash chromatography on silica gel to give the desired product as a solid, m.p. 142’-146’C.
Table VIII
45 The follovving Examples are prepared using the conditions of Example 214 vvith the appropriately substituted aroyl
chloride.
Example No. Compound
215 N-[4-(4H-Pyrazolo(5,1 -c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]2-methoxybenzeneacetamide
50 216 N-[4-(4H-Pyrazolo{5,1 -cļ[ 1,4]benzodiazepin-5(10H)-ylcart>onyl)phenyl]-2,5-dichlorobenzamide
217 N-(4-(4H-Pyrazolo(5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide, colorless foam; exact mass by mass spectrametry:479.0896 (M+H)
55 218 N-[4-(4H-Pyrazolo(5,1 -c][1,4]benzodiazapin-5(10H)-ylcarbonyl)phenyl]-2-chloro4-methylbenzamide
219 N-[4-(4H-Pyrazolo[5,1 -c][ 1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2-methyl4-chlorobenzamide
220 N-[4-(4H-Pyrazolo(5,1 -c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2,4-dimethylbenzamide
Table VIII (continued)
The follovving Examples are prepared using the conditions of Example 214 vvith the appropriately substituted aroyl
chloride.
Example No. Compound
221 N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2,3-dimethylbenzamide
222 N-[4-(4H-Pyrazolo[5,1 -c][ 1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2-methoxybenzamide
223 N-[4-(4H-Pyrazolo(5,1 -c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyi]2-trifluoromethoxybenzamide
224 N-(4-(4H-Pyrazolo[5,1 -c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2,4-dimethoxybenzamide
225 N-[4-(4H-Pyrazolo(5,1 -c][ 1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2,6-dimethoxybenzamide
226 N-[4-(4H-Pyrazolo(5,1-c](l,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]benzamide
227 N-[4-(4H-Pyrazolo[5,1 -c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2,6-dichlorobenzamide
228 N-[4-(4H-Pyrazolo[5,1 -c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2,6-dimethylbenzamide
229 N-[4-(4H-Pyrazolo[5,1 -c][ 1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2-methylthiobenzamide
230 N-[4-(4H-Pyrazolo(5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2-methyl- 3-thiophenecarboxamide
231 N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]3-methyl- 2-thiophenecarboxamide
232 N-(4-(4H-Pyrazolo[5,1 -c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2-methyl3-furanecarboxamide
233 N-[4-(4H-Pyrazolo[5,1 -c][ 1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]3-methyl2-furanecarboxamide
234 N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]- 3-cyclohexenecarboxamide
235 N-[4-(4H-Pyrazolo[5,1 -c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyi]2-chlorobenzeneacetamide
236 N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]- 2-methylbenzeneacetamide
237 N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2-methyl- 3-thiopheneacetamide
Example 238
9,10-Dihvdro-4H-pyrroloH,2-althienoi2,3-elf1,4l diazepine
To a mixture of 7.0 g of 9-oxo-9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin in 25 ml of anhydrous tetrahvdrofuran is added 9 ml of 10 molar boron-dimethyisuifide in tetrahydrofuran. The mixture is refluxed for 6 hours. The solution is cooled to room temperature and 25 ml of mēthanol added dropvvise. The volatiles are removed under vacuum. To the residue is added 100 ml of 2 N NaOH. The mixture is refiuxad 5 hours and filtered. The solid is extracted vvith dichloromethane and the extract is vvashed vvith 2 N citric acid, vvater and dried (Na2SO4). The solvent is removed in vacuo to give the desired product as a solid.
Example 239
N4ļh(4H-.Pvrazolof1,2-althi9rtof2.3-alf1,4]diazepin-10(9H)-vlcarbonvl)ph9nvll-2-mgthvlb9nzamide
To a mixture of 1.37 g (5mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C is added 1.5 ml of triethylamine. To the mixturs is added 5 mmol of 9,10-dihydro-4H-pyrazolo[1,2-aļ thieno[2,3-e][1,4]diazepine. The cooling bath is removed and the reaction mixture is allovved to stir at room temperature for 48 hours. The volatiles are removed in vacuo to give a residue. The residue is dissolved in 100 ml of ethyl acetate and vvashed vvith vvater, 2N citric acid, aqueous NaHCO3 and brine. The solution is dried vvith Na2SO4 and the solvent removed in vacuo to give a solid. The solid is purified by flash chromatography on silica gel to give the desired product.
Example 240
9.10- Dihvdfo-10-(4-nitrobenzovl)-4H-pvrroloH.2-althienof2.3-9lff .4ļdiazepine s To a solution of 10 mmol of 9,10-dihydro-4H-pyrrolo(1,2-a]thieno[2,3-e][1,4]diazspine in 50 ml of methylene chloride under argon is added 15 mmol of triethylamine followed by ice bath cooling. A solution of 11 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropvvise. Follovving complete addition, the ice bath is removed and the reaction mixture stined at room temperatūra for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyI acetate. The solution is vvashed vvith vvater, 1N HCI, NaHCO3, and brine. The organic layer is dried īo vvith Na2SO4, filtered and evaporated jņ vacuo to give a solid vvhich is purified by flash chromatography on silica gel to give desired product as a solid.
Example 241 fs 9,10-Dihvdro-10-(4-aminobenzoyl)-4H-py rrolof 1,2-althieno[2,3-elf 1,4ļdiazepine
A mixture of 2 g of 9,10-dihydro-l0-(4-nitrobenzoyl)-4H-pyrroio-[1,2-a]thieno(2,3-e][1,4]-diazepine in 20 ml of elhyl alcohol and 20 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The fiitrate is concentrated in vacuo to a solid vvhich is purified by flash chromatography to give the desired product.
Example 242
9.10- Dihvdro-10-(4-aminobenzovl)-4H-pyrrolo-n ,2-althienof2,3-eļ[ 1,41diazepine
To a solution of 5 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-pyrrolo-[1,2-a]thienol2,3-e][1,4]diazepine in 25 ml of ethyl alcohol is added 0.13 g of 10% Pd/C and 15 mmol of hydrazine follovved by stirring and heating under reflux for 3 hours. The cooled reaction mixture is filtered through diatomaceous earth. The fiitrate is concentrated in vacuo to a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The so fiitrate is concentrated jņ vacuo to give the desired product vvhich is purified by flash chromatography on silica gel to give the desired product as a solid.
Example 243
N-f4-(4H-Pyrrolof1.2-althienof2.3-elf1,4ldiazepin-10(9H)-vlcarbonvDphenyH-2-methylbenzamide
To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml ot methylene chloride is added 7 mmol of triethylamine and 5 mmol of 9,10-dihydro-10-(4-aminobenzoyl)-4H-pyrrolo-[1,2-aJthieno{2>3-e][1,4Jdiazepine and the mixture stirred for 5 hours. The reaction mixture is washed vvith water, 2N citric acid, NaHCOj, and brine. The organic iayer is dried vvith NajSOļ, filtered and evaporated jņ vacuo to give a solid vvhich is purified by flash chromatography on silica gel to give the desired product as a solid.
Table IX
45 The follovving Examples are prepared using the conditions of Example 243 vvith the appropriateiy substituted aroyl chloride.
Example No. Compound
244 N-[4-(4H-pyrrolo[1,2-a]thieno[2,3-ej[1,4]diazepin-10(9H)-yl carbonyl)phenyl]-2-chlorobenzamide
50 245 N-[4-(4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-yl carbonyl)phenyl]2,5-dichlorobenzamide
246 N-{4-(4H-py rrolof 1,2-a]thieno{2,3-eJ[1,4]diazepin-10(9H)-yl carbonyl)phenyl]2,4-dichlorobenzamida
55 247 N-[4-(4H-py rrolof 1,2-a]thieno[2,3-e)[1,4]diazepin-10(9H)-yl carbonyl)phenyl]-2-chloro4-methylbenzamide
248 N-[4-(4H-pyrrolo{1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-yl carbonyl)phenyl]-2-methyl4-chlorobenzamide
Table IX (continued)
The follovving Examples are prepared using the conditions of Example 243 vvith the appropriately substituted aroyi chloride.
s Examp!e No. Compound
249 N-[4-(4H-pyrrolo[1,2-a]thieno[2,3-e][ 1,4]diazepin-10(9H)-y I carbonyl)phenylj2,4-dimethylbenzamide
10 250 N-(4-(4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-yl carbonyl)phenyl]2,3-dimethylbenzamide
251 N-[4-(4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-yl carbonyl)phenyl]2-methoxybenzamide
252 N-(4-(4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-yl carbonyl)phenyl]2-trifiuoromethoxybenzamide
1S 253 N-[4-(4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-yl carbonyl)phenylļ2,4-dimethoxybenzamide
254 N-[4-(4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-yl carbonyl)phenyl]2,6-dimethoxybenzamide
255 N-[4-(4H-pyrrolo(1,2-a]thieno[2,3-e][ 1,4]diazepin-10(9H)-yl carbonyl)phenyl]-
20 256 2.6- dichlorobenzamide N-[4-(4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-yl carbonyl)phenyl]- 2.6- dimethylbenzamide
257 N-[4-(4H-pyrrolo{1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-yl carbonyl)phenyl]-2-methoxy4-chlorobenzamide
25 25S N-[4-(4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-yl carbonyl)phenyl]2-methoxybenzeneacetamide
259 N-{4-(4H-pyrrolo[1,2-a]thieno[2,3-e](1,4]diazepin-10(9H)-yl carbonyl)phenyl]-2-(methylthio) benzamide
30 260 N-[4-(4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-yl carbonyl)phenyl]-2-methyl3-thiophenecarboxamide
261 N-[4-(4H-pyrrolo{1,2-a]thieno[2r3-e][1,4]diazepin-10(9H)-yl carbonyl)phenyl]-3-methyl2-thiophenecaiboxamide
35 262 N-(4-(4H-pyrrolo(1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-yl carbonyl)phenyl]-3-methyl· 2-furancarboxamide
263 N-[4-(4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-yI carbonyl)phenylj3-chlorophenylacetamide
264 N-[4-(4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-yl carbonyl)phenyl]2-methylbenzeneacetamide
40 265 N-[4-(4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-yl carbonyl)phenyl]-2-methyl3-thiopheneacetamide
Example 266 45 4,10-Dihvdro-5H-pyrrolo[ 1,2-aļth ienof3,2-eļf 1,41 diazepin e
To a suspension of 7.0 g ol 5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine in 25 ml of anhydrous tetrahydrofuran is added 9 ml of 10 M borane-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6 hours. The solution is cooled to room temperature and 25 ml of methanol added dropvvise. The volatiles are removed under vac50 uum. To the residue is added 100 ml of 2 N NaOH. The mixture is refluxed 5 hours and filtered. The solid is extracted vvith dichloromethane and the extract is vvashed vvith 2 N citric acid, vvater and dried (Na2SO4). The solvent is removed to give a solid.
Example 267
N-f4-(5H-Pyrazolof1 ,2-althianof3,2-el[1,41-diazepin-4(10H)-ylcarbonyl)phenvll-2-methylbenzamide s To a mixture of 5.5 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 20 ml of methylene chloride, cooled to 0’ C is added 7.5 mmol of triethylamine and 5 mmol of 4,10-dihydro-5H-pyrazolo-[1,2-a]thieno{3,2-s][1,4]diazspine. The cooling bath is removed and the reaction mixture is allovved to stir at room temperature for 48 hours. The voiatiies are removed in vacuo to give a residue. The residue is dissolved in 100 ml of ethyl acetate and the soiution vvashed vvith vvater, 2N citric acid, aqueous NaHCOj and brine. The soiution is dried vvith NagSC^ and the solvent concentrated īo jņ vacuo to give a solid. The solid is purified by fiash chromatography on siiica gel to give the desired product as a solid and foam, m.p. 162’-188“C, Anal. Calc'd for C25H21N3O2S: C.70.2; H.5.0 N.9.8; S.7.5 Found: C,69.5, H.5.2 N,
9.6; S.7.0.
Example 268
IS
4.10- Dihvdro-4-(4-nitrobenzovl)-5H-pyrrolo-f 1,2-althienof3,2-elf 1,41diazepine
To a soiution of 3 mmol of 4,10-dihydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine in 10 ml of methylene chloride under argon is added 5 mmol of triethylamine follovved by ice bath cooling. A soiution of 3.3 mmol of 4-nitrobenzoyl 20 chloride in 3 ml of methylene chloride is added dropvvise. Follovving complete addition, the ice bath is removed and the reaction mixture stined at room temperature for 2 hours. The voiatiies are removed in vacuo to give a residue vvhich is dissolved in ethyl acetate. The soiution is vvashed vvith vvater, 2 N citric acid, NaHCO3, and brine. The reaction mixture is dried vvith NagSO^ filtered and evaporated jņ vacuo to give a solid vvhich is purified by fiash chromatography on siiica gel to give desired product as a solid.
ss
Example 269
4.10- 0ihydro-4-(4-am inotoenzovl)-5H-py rrolo-f 1.2-alth ienof 3,2-elf 1,4)diazepine
A mixture of 5 mmol of 4,10-dihydro-4-(4-nitrobenzoyi)-5H-pyrrolo-[1,2-a]thieno[3,2-e][1,4ļ-diazepine in 25 ml of ethyl alcohol and 25 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid vvhich is purified by fiash chromatography on siiica gel to give the desired product.
3S Example 270
4.f0-Dihvdro-4-(4-aminobenzovl)-5H-pyrrolo-f1.2-althienof3,2-elf1.4ldiazepina
To a mixture of 5 mmol of 4,10-dihydro-4-(4-nitrobenzoyl)-5H-pyrrolo-[1,2-aļthieno{3,2-eļ[1,4ļ-diazepine in 25 ml of ethyl alcohol is added 0.3 g of 10% Pd/C and 15 mmol of hydrazine follovved by stirring and heating under reflux for 3 hours. The cooled reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate ls concentrated In vacuo to give the desired product vvhich is purified by fiash chromatography on siiica gel to give the desired product as a solid.
Example 271
N-f4-(5H-Pvrrolof 1,2-althieno[3,2-elf 1,4ļdiazepin-4( 10H)-ylcarbonyl)phenyn-2-methvlbenzamide
To a stirred soiution of 3 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 5 mmol of triethylamine and 3 mmol of 4,10-dihydro-4-(4-aminobenzoyl)-5H-pyrrolo-[1,2-a]lhieno[3,2-e][1,4jdiazepine. The mixture is stirred for 5 hours. The reaction mutture is vvashed vvith water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried vvith Na2SO4, filtered and evaporated in vacuo to give a solid vvhich is purified by fiash chromatography on siiica gel to give the desired product as a solid, m.p. 162°-188°C (amorphous) ss
Table X
s The follovving Examples are prepared using the conditions ot Example 271 vvith the appropriately substituted aroyl chloride.
Example No. Compound
272 N-(4-(5H-pyrrolo[1,2-a)thieno[3,2-eļ[1,4]diazepin-4(10H)-yl carbonyl)phenyl]-2-chlorobenzamide
273 N-(4-(5H-pyrrolo(1,2-a]thieno[3,2-e][1,4]diazepin-4(10H)-yi carbonyl)phenyl]2,5-dichlorobenzamide
10 274 N-[4-(5H-pyrrolo[1,2-a]thieno[3,2-eJ[1,4]diazepin-4(10H)-yl carbonyl)phenylļ2,4-dichlorobenzamide (solid foam), m.p. 105-190’C; Anal Calc'd for C24H17N3 CI^S: C.59.8; H, 3.6; N,8.7; S,6.6, CI, 14.7 Found: C.59.6; H.3.8; N.8.1; S,5.5; Cl.14.0
15 275 N-[4-(5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-4(10H)-yl carbonyl)phenyl]-2-chloro4-methylbenzamide
276 N-(4-(5H-pyrrolo[1,2-a]thieno(3,2-e][1,4]diazepin-4(10H)-yl carbonyl)phenyl]-2-methyl4-chlorobenzamide
277 N-[4-(5H-pyrrolo(1,2-aJthieno(3,2-eJ[1,4]diazepin-4(1 OH )-y I carbonyl)phenylj2,4-dimethylbenzamide
20 278 N-(4-(5H-pyrrolo[ 1,2-a]thieno[3,2-eJ[ 1,4]diazepin-4(10H)-yl carbonyl)phenyl]2,3-dimethylbenzamide
279 N-(4-(5H-pyrrolo[1,2-a]thieno[3,2-e]{1,4]diazepin-4(10H)-yl carbonyl)phenyl]2-methoxybenzamide
280 N-[4-(5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-4(10H)-yl carbonyl)phenylļ-
25 281 2-trifluoromethoxybenzamide N-[4-(5H-pyrrolo(1,2-a]thieno[3,2-e][1,4]diazepin-4(10H)-yl carbonyl)phenyl]2,4-dimethoxybenzamide
30 282 N-[4-(5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-4(10H)-yl carbonyl)phenyl]2,6-dimethoxybenzamide
283 N-(4-(5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-4(10H)-yl carbonyl)phenyl]2,6-dichlorobenzamide
284 N-[4-(5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-4(10H)-yl carbonyl)phenylļ2,6-dimethylbenzamide
35 285 N-[4-(5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-4(10H)-yl carbonyl)phenyl]2-methy Ith iobenzam ide
286 N-[4-(5H-pyrrolo(1,2-a]thieno[3,2-eļ[1,4]diazepin-4(10H)-yl carbonyl)phenylJ-2-methyl3-thiophenecarboxamide
287 N-[4-(5H-pyrroto[1,2-a]thieno(3,2-eJ(1,4]diazepin-4(10H)-yl carbonyl)phenyiJ-3-methyl-
40 288 2-thiophenecarboxamide N-[4-(5H-pyrroio[1,2-a]thieno[3,2-e](1,4]diazepin-4(10H)-yl carbonyl)phenyl]-3-methyl2-furancarboxamide
289 N-[4-(5H-pyrrolo[1,2-a]thieno[3,2-e][l,4]diazepin-4(10H)-yl carbonyl)phenyl]3-chlorobenzeneacetamide
45 290 N-[4-(5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-4(1 OH)-yI carbonyl)phenyl]2-methoxybenzeneacetamide
291 N-[4-(5H-pyrrolo( 1,2-a]thieno[3,2-eļ[ 1,4]diazepin-4(1 OH )-yI carbonyl)phenyl]-2-methoxy4-chlorobenzamide
292 N-(4-(5H-pyrrolo[1,2-a]thieno[3,2-e][l,4]diazepin-4(10H)-yl carbonyl)phenyl]-
50 293 2- methylbenzeneacetamide N-[4-(5H-pyrrolo(1,2-a]thieno(3,2-e][1,4]diazepin-4(10H)-yl carbonyl)phenyl]-2-methyl- 3- thiopheneacetamide
ss
Example 294
6.7- Dihvdro-5-(4-nitrobenzovl)-5H-pyrrolof1.2-aff1.51benzodiazepine
To a solution of 10 mmol of 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine in 30 ml of methylsns chloride under argon is added 15 mmol ol triethyiamine follovved by ice bath cooling. A solution of 11 mmol of 4-nitrobenzoyl chloride in 10 mi of methy lene chloride is added dropvvise. Follovving complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue vvhich is dissolved in ethyl acetate. The solution is vvashed vvith vvater, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried >o wilh Na2SO4, filtered and evaporated jņ vacuo to give a solid vvhich is purified by flash chromatography on silica gel to give the desired product as a solid.
Example 295 ,s 6.7-Dihvdro-5-(4-aminobenzovl)-5H-pyrrolo[ 1,2-alH ,51benzodiazepine
A mixture of 2.0 g of 6,7-dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo(1,2-aļ(1,5Jbenzodiazepine, 20 ml of ethyi alcohol and 20 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture ie filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid vvhich is purified by flash chroma20 tography on silica gel to give the desired product.
Example 295
6.7- Dihydro-5-(4-aminobenzoyl)-5H-pvrrolof1.2-alf1,5fbenzodiazepin9
To a solution of 5 mmol of 6,7-dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo{1,2-a][1,5]benzodiazepine in 25 ml of ethyl alcohol is added 0.3 g of 10% Pd/C and 15 mmol of hydrazine follovved by stirring and heating under reflux for 3 hours. The reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue vvhich is dissolved in methylene chloride and passed through a pad ot hydrous magnesium siiicate. The filtrate is concentrated in vacuo to give the desired product vvhich is purified by flash chromatography on silica gel to give the desired product as a solid.
Example 297
N-(4-f(6,7-0ihvdro-5H-pvffoiof1,2-ali1,51benzodiazepin-5-vl)carbonvHphenvil-2-methylbenzamide
To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)aminojbenzoyl chloride in 10 ml of methylene chloride, cooled to 0“ C is added 7 mmol of triethylamine and 5 mmol of 6,7-dihydro-5H-pyrrolo-[1,2-a][1,5]benzodiazepine. The cooling bath is removed and the reaction mixture is allovved to stir at room temperature for 48 hours. The volatiles are removed in vacuo to give a residue. The residue is dissolved in 100 ml of ethyl acetate and vvashed vvith vvater, 2N citric acid, aquaous NaHCO3 and brine. The solution is dried with NagSO, and the solvent removed in vacuo to give a solid. The solid is triturated vvith ether-hexane to give the desired product, mass spectrum (CI);422(M+H).
Exampie 298
N-f4-ff6,7-Dihydro-5H-pyiTOlof1,2-alf1,51benzodiazepin-5-vl)carbonvl)phenvn-2-methvl-benzamida
To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 7 mmol of triethylamine and 5 mmol of 6,7-dihydro-5-(4-aminobenzoyl)-5H-pyrrolo(1,2-aļ[1,5]benzodiazepine. The reaction mixso tūre is vvashed vvith vvater, 2M citric acid, NaHCO3, and brine. The organic layer is dried vvith Na2SO4, filtered and evaporated in vacuo to giva a solid vvhich is purified by flash chromatography on silica gel to give the desired product as a solid; mass spectrum (Cl) :422 (M+H).
Table XI
The follovving Examples are prepared using the conditions of Example 298 vvith the appropriately substituted aroyl chloride.
Example No. Compound
299 300 N-[4-[(6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenyl]-2-chlorobenzamide N-[4-((6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenyl]2,5-dichlorobenzamide
301 N-[4-[(6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenyl]2,4-dichlorobenzamide
302 N-(4-[(6,7-dihydra-5H-pyrrolo [1,2-aJ[1,5]benzodiazepin-5-yl) carbonyljphenyl]-2chloro4-methylbenzamide
303 N-[4-[(6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyljphenyl]-2methyl4-chlorobenzamide
304 N-[4-[(6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenylļ2,4-dimethylbenzamide
305 N-[4-[(6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenyl]2,3-dimethylbenzamide
306 N-[4-[(6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenyl]2-methoxybenzamīde
307 N-(4-[(6.7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenyl]2-trifluoromethoxybenzamide
308 N-{4-[(6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenyl]2,4-dimethoxybenzamide
309 N-[4-[(6,7-dihydro-5H-pyrrolo [1,2-a][l ,5]benzodiazepin-5-yl) carbonyl]phenyl]2,6-dimethoxybenzamide
310 N-(4-[(6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenyl]2,6-dichlorobenzamide
311 N-[4-[(6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenyl]2.6-dimethylbenzamide
312 N-[4-[(6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenylļ- 2-methylthiobenzamide
313 N-[4-[(6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenyl]-2-methyl3-thiophenecarboxamide
314 N-[4-[(6,7-dihydro-5H-pyrrolo (1,2-a](1,5]benzodiazepin-5-yl) carbonyl]phenyl]-3-methyl2-thiophenecarboxamide
315 N-[4-[(6.7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenyl]-2-methyl3-furanecarboxamide
316 N-[4-[(6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyJ]phenyl]-3-methyl2-furanecarboxamide
317 318 N-[4-((6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenylļbenzeneacetamide N-[4-[(6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenylļ2-chlorobenzeneacetamide
319 N-[4-[(6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenyl]2-methylbenzeneacetamide
320 N-[4-[(6,7-dihydro-5H-pyrrolo [1,2-a][1,5]benzodiazepin-5-yl) carbonyl]phenyl]-2-methyl3-thiopheneacetamide
Example 321
i,6-Dihydro-4H-f1,2,4|triazolo[4.3-al[1,5ļbenzodiazepine
A mixture of 7.0 g of 5,6-dihydro-4H-[1,2,4]-triazolo-[4,3-a][1,5]benzodiazepin-5-one in 25 ml of tetrahydrofuran is idded 9 ml of 10 M borane-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6 hours, cooled lo room temperature and 25 ml of methanol added dropvvise. The volatiles are removed under vacuum and to the residue is added 100 ml of 2N sodium hydroxide. The mixture is refluxed for 5 hours, chilled and extracted vvith dichloromethane. The extract is washed vvith 2N citric acid, vvater and dried (Na2SO4). The solvent is removed under vacuum to give a solid. The solid is purified by chromatography on silica gel to give the desired product.
Example 322
N-t4-(4H-t1,2,4ltriazolof4,3-alf1,5lbenzodia zepin-6(5H)-ylcart)onvl)phenyn-2-methvl benzamide
To a mixture ot 5 mmol of 5,6-dihydro-4H-[1 ,2,4]triazolo{4,3-a][1,5]benzodiazepine in 20 ml of dichioromethane is added 5.5 mmoi of 4-[(2-methylbenzoyl)amino]benzoyl chloride and then 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 hours and then vvashed vvith vvater, agueous NaHCOg and brine. The solution is dried (Na2SO4) and the solvent removed iņ vacuo to give a solid. The solid is purified by chromatography on silica gel with ethyl acetate-hexane as solvent to give the desired product as a glass.
Example 323
5.6- Dihydro-6-(4-nitrobenzovh-4t-t-(1,2,41triazolof4,3-aif1,5lb8nzodiazepine
To a mixture of 3 mmol of 5,6-dihydro-4H-[1,2,4]-triazolo[4,3-a][1,5]benzodiazepine in 10 ml of dichloromethane under argon is added 5 mmol of triethylamine. To the mixture is added dropvvise 3.3 mmol of 4-nitrobenzoyl chloride in 3 ml of dichloromethane. The mixture is stirred at room temperature 3 hours and then washed vvith vvater, aqueous NaHCOg and brine. The organic layer is dried (Na2SO4) and the solvent removed under vacuum. The residue is purified by chromatography on silica gel to give the desired product as a solid.
Example 324
5.6- Dihvdro-6-(aminobenzoyl)-4H-f1.2.4itriazolo-f4,3-ali1,4lbenzodiazepine
To a mixture of 5 mmol of 5,6-dihydro-6-(4-nitrobenzoyl)-4H-[1,2,4]triazolo(4,3-a][1,4]benzodiazepine in 25 ml of ethanol is added 0.3 g of 10% Pd/C and 15 mmol of hydrazine. The mixture is refluxed for 3 hours, cooled and filtered through diatomaceous earth. The filtrate is concentrated in vacuo and the residue purified by chromatography on silica gel to give the desired product as a solid.
35 Table XII
The follovving Examples are prepared using the conditions of Example 322 vvith the appropriately substituted aroyl chloride
Example No. Compound
40 325 N-(4-(4H-[1,2,4]triazolo[4,3-aļ[1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2-chlorobenzamide
326 N-{4-(4H-[1,2,4]triazolo[4,3-a][1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2,5-dichlorobenzamide
45 327 N-(4-(4H-[1,2,4]triazolo(4,3-a][1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2,4-dichlorobenzamide
328 N-[4-(4H-[1,2,4Jtriazolo[4,3-a][1,5]benzodiazepin-6(5H)-ylcarbonyl)phenyi]2,3-difluorobenzamide
329 N-{4-(4H-[1,2,4]triazolo[4,3-a][1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2-chloro4-methylbenzamide
50 330 N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2-methyl4-chlorobenzamide
331 N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2,4-dimethylbenzamide
332 Ν·14·(4Η-[1,2,4]triazolo[4t3-aļ(1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl]
ss 2,3-dimethylbenzamide
333 N-ļ4-(4H-[1,2,4]triazoto(4,3-a][1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl) 2-methoxybenzamide
Table XII (continued)
The follovving Examples are prepared using Ihe conditions of Example 322 vvith the appropriately substituted aroyl chloride
5 Example No. Compound
334 N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2-trifluoromethoxybenzamide
10 335 N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2,3-dichlorobenzamide
336 N-f 4-(4H-[ 1,2,4]triazolo[4,3-a][ 1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2,4-dimethoxybenzamide
337 N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5] benzodiazapin-6(5H)-ylcarbonyl)phenyl] 2,6-dimethoxybenzamide
is 336 N-(4-(4H-{1,2,4Jlriazolo(4,3-aļ[1,5] benzodiazepin-6(5H)-ylcarbonyl)phenylļ 2-methoxy4-chlorobenzamide
339 N-[4-(4H-[1,2,4]triazolo[4,3-a)[1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2-trifluoromethylbenzamide
340 N-[4-(4H-[1,2,4]triazolo(4,3-a][1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl]
20 341 2.6- dichlorobenzamide N-[4-(4H-(1 t2,4]friazolo[4,3-aJ(1,5] benzodiazepin-6(5H)-ylcarbonyl)phenylJ 2.6- dimethylbenzamide
342 N-[4-(4H-(1,2,4]triazolo[4,3-a][1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2-methylthiobenzamide
25 343 N-{4-(4H-(1,2,4]triazolo[4,3-a][1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2-methyl3-thiophenecarboxamide
344 N-[4-(4H-[1,2,4)triazolo[4,3-a][1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl) 3-methyl2-thiophenecarboxamide
30 345 N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2-methyl3-f uranecarboxam ide
346 N-[4-(4H-[1,2,4]triazolo{4,3-aJ[1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2-methyl3-t u ranecarboxam ide
35 347 N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 3-methyl2-furanecarboxamide
348 N-(4-(4H-[1,2,4]triazolo{4,3-a](1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2-methoxybenzeneacetamide
349 N-[4-(4H-[1,2,4]triazolo[4,3-aļ[1,5ļ benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2-methylbenzeneacetamide
40 350 N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2-chlorobenzeneacetamide
351 N-f4-(4H-[1,2,4]triazolo[4,3-aļ[1,5] benzodiazepin-6(5H)-ylcarbonyl)phenyl] 2-methyl3-thiopheneacetamide
45 Example 352
N-f4-( 1 -Methyl-4H-ft ,2.4ļtriazolof4,3-alf 1,51 benzodiazepin-6(5H)-ylcarbonyl)phenvH-2-methyl benzamide
To a mixture of 5 mmol of 5,6-dihydro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20 ml of dichlo50 romethane is added 5.5 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 7.5 mmol o, triethylamine. The mixfure is stirred at room temperature for S hours and then vvashed vvith vvater, aqueous NaHCO3 and brine. The organic layer is dried (Na2SO4) and the solvent removed in vacuo to give a solid. The solid is purified by chromatography on silica gel vvith ethyl acetate-hexane as solvent to give the desired product.
Example 353
N-f4-(1-Methvl-4H-f1,2.4ltriazolof4,3-a1f1,5ļ benzodiazepin-6(5Hf-vlcarbonylļphenyll-2.4 dichlorobenzamide s To a mixture of 5 mmol of 5,6-dihydro-1-methyl-4H-(1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20 ml of dichloromethane ie added 5.5 mmol of 4-[(2,4-dichlorobenzoyl)amino]benzoyl chtoride and 7.5 mmol of triethylamihe. The mixture is stirred at room temperature for 8 hours and then vvashed vvith vvater, aqueous NaHCO3 and brine. The organic layer is dried (Na2SO4) and the solvent removed in vacuo to give a solid. The solid is purified by chromatography on silica gel to give the desired product as a solid.
Example 354
N-f4-(5H-Pvrrolof2.1 -cļfļ ,4lbenzodiazepin-10fl 1 )-vlcarfaonvl)phenvll-3-cyclohexenecarboxamide ts A mixture of 0.50 g of 10,11-dihydro-10{4-aminobenzoyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.286 g o, 3-cyclohexenecarbonyl chloride and 346 pl of triethylamine in 5 ml of dichloromethane is stirred at room temperature 16 hours. The mixture is diluted with 50 ml of dichloromethane and the solution washed with 20 ml of water, 2N citric acid, 1N NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated in vacuo. The residue is chromatographed on thick layer silica gel plates to give a solid vvhich is crystallized from ethyl acetate to give 0.34 g of crystals, m.p. 216-21S°C.
Example 355
N-f4-(5H-Pyrrolof2,1 -cļf 1,4lbenzodiazepin-1 Of 11) vlcarbonvl)phenyll-5-methyl-2-thiophenecarboxamide
To a solution of 0.318 g of 5-methyl-2-thiophenecarbonyl chloride in 5 ml of dichloromethane cooled to O° C is added 0.50 g of l0,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 346 pl of triathylamine. The mixture is stirred at room temperature 16 hours and diluted vvith 50 ml of dichloromethane. The solution is vvashed vvith 20 ml each of vvater, 2N citric acid. 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated in vacuo to give a solid. The soiid is crystallized from ethyl acetate to give 0.53 g of crystals, m.p. 235-236°C.
Example 356
3S N-f4-(5H-Pyrrolof2,1 -cļf 1,4|benzodiazepin-10( 11) ylcarbonyl)phenyll-cyclohexylacetamide
To a solution of 0.318 g of cyclohexylacetyl chloride in 5 ml of dichloromethane cooled to O° G is added 0.50 g of
10,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo[2,1-cJ[l,4]benzodiazepine and 346 pl of triethylamine. The mixture is stirred at room temperature 16 hours and diluted vvith 50 ml of dichloromethane. The solution is washed with 20 mi « each of vvater, 2N citric acid. 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrou8 magnesium silicate and the filtrate evaporated Jņ vacuo to give a solid. The solid is crystallizad from ethyl acetata to give 0.52 g of crystals, m.p. 231-234°C.
Example 357
N-|4-(5H-Pyrroloi2.1-c1f1,41benzodiazepin-l0f1f) vtcarbonvDphenvll-2-fluorobenzeneacetamide
To a solution of 0.342 g of 2-fluorophenylacetyl chloride in 5 ml of dichloromethane cooled to O°C is added 0.50 g of l0,11-d'iiydro-10-(4-aminobanzoyl-5H-pyrrolo[2,1 -c][1,4]benzodiazepine and 346 pl of triethylamine. The mixture so is stirred at room temperatūra 16 hours and diluted vvith 50 ml of dichloromethane. The solution is washed vvith 20 ml each of watar, 2N citric acid. 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrou8 magnesium silicate and the filtrate evaporated jņ vacuo to give a solid. The solid is crystallizad from athyl acetate to give 0.43 g of crystals, m.p. 204-207°C.
Exampla 359
N-f4-(5H-Pyrrolof2,1 -clf 1,41benzodiazepin-10(11) ylcarbonvl)pher)vl1-cyclohexanecarboxamide
To a solution of 0.342 g of cyclohexanecarbonyl chloride in 5 ml of dichloromethane cooled to O° C is added 0.50 g of 10,11 -dihydro-10-(4-aminobenzoyl-5H-pyrrolo[2,1 -c][1,4]benzodiazepine and 346 μΙ ot triethylamine. The mixture is stirred at room temperature 16 hours and diluted vvith 50 ml of dichloromethane. The solution is vvashed vvith 20 ml each ot vvater, 2N citric acid. 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated ļņ vacuo to give a solid. The solid is crystailized from ethyl ra acetate to give 0.54 g of crystals, m.p. 202-204°C.
Example 359
4-fN-Methyl-N-(2-methvlbenzovlamino1benzoyl chloride
A solution ot 6.72 g of 4-(N-methyl-N-(2-methylbenzoyl)amino]benzoic acid in 20 ml of thionyl chloride is refluxed for one hour. The volatiles are removed iņ vacuo. Toluene is added to the residue and then the toluene removed iņ vacuo (repeated several times) to give the 7.3 g of product as a brovvn oii.
Example 360
4-fN-Methvl-N-(2-methvlbenzovl)amino1benzoic acid
A sample of 1.51 g of sodium hydride (60% in oii) is vvashed vvith hexane under argon to remove the oii. To the 25 vvashed sodium hydride is added 5 ml of N,N-dimethylformamide. To this mixture is added dropvvise a solution of Θ.69 g of ethyl 4-[(2-methylbenzoyl)amino]benzoate in 20 ml of N,N-dimethylformamide The mixture is stirred at room temperature for 0.5 hour and then 5.23 g of methyl iodide is added. The mixture is stirred at room temperature for 16 hours. The mixture is diluted vvith vvater and extracted vvith dichloromethane. The extract is dried (NajSC^), concentrated to reduce the volume and the solution filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated jņ vacuo to give 11 gof an oii (1:1 mixtureof product and N,N-dimethylformamide). The preceding product, ethyl4-{Nmethyl-N-(2-methylbenzoyl)amino]benzoate, (11 g) is dissolved in 30 ml of methanol and 25 ml of 2N NaOH added. The mixture is refluxed for 2 hours and the soivent removed. The residue is extracted vvith ether (discard) and the remaining residue dissolved in 50 ml of vvater. The basie solution is acidified vvith 2N citric acid and the solid filtered off and vvashed vvith vvater. The product is air dried to give 6.72 g of crystals, m.p. 1S7-190°C.
As described for Example 360 but substituting the appropriate ethyl 4-[(N-aroyl)aminoļbenzoate, the follovving compounds are prepared.
Example 361
4-fN-Methvl-N-(2-chlorobanzovnaminolbenzoic acid s Example 362
4-fN-Methvl-N-(2,5-dichlorobsnzoyl)aminolbenzoic acid
Exampla 363 īo
4-fN-Methvl-N-(2.4-dichlorobenzovOaminolbenzoic acid
Exarople 364
4-fN-Mathvl-N-(2-chloro-4-methvlbenzovl)aminolbenzoic acid
Exampla 365
4-fN-Methvl-N-(2-methvl-4-chlorobenzovl)aminolbenzoic acid
Exampla 366
4-[N-Methvl-N-(2,4-dimethvlbenzoyOaminoļb8nzoic acid
Exampla 367
4-[N-Methvi-N-(2,3-dimethvlbenzovhamino1benzoic acid
Exampla 366
4-(N-Mathvl-N-(2-methoxvbenzoyOaminoļbenzoic acid
Example 369
4-tN-Methvl-N-(2-tri(luoromethoxvbenzoyl)aminoļbenzoic acid
Exampla 370
4-[N-Methyl-N-(2.4-dimethoxybenzoyl)amino1benzoic acid
Example 371
44N-Methvl-N-(2-methoxv-4-chtorobenzoyl)arninolbenzoic acid
4S Exampla 372
4-[N-Methvl-N-(2-methytthiobenzovl)aminoļbenzoic acid
Example 373
4-iN-Melhyl-N-(2-methylthiophan-3-vlcarbonvl)aminolbenzoic acid
Example 374
4-fN-Mothvl-N-(3-methylthiophene-2-ylcarbonvl)amino1benzoic acid
Example 375
4-fN-Methvl-N-(2-melhvlfuran-3-vlcarbonyl)aminolbenzoic acid
Example 376
4-(N-Methyl-N-(3-methylfuran-2-ylcarbonyl)amino1benzoic acid
Example 377
4-fN-Methvl-N-(phenylacetvl)aminoi banzoic acid
Example 378
4-fN-Methyl-N-(2-chlorophenylacetvl)amino]benzoic acid
Example 379
4-[N-M9thyl-N-(2-m8thoxyphenvlacBtvl)aminolbenzoic acid
Example 380
4-fN-Methvl-N-(2-methvlphenylacetvl)aminolbenzoic acid
Example 381
4-fN-Methvl-N-(cyclohexvlcarbonyl)aminolbenzoic acid
Exarrtple 382
4-[N-Methvl-N-(3-cvclohexenecarbonyl)aminolbenzoic acid
Example 383
4-fN-Methyl-N-(cvclohexvlacetvnamino|benzoicacid
Example 384
N-(4-(5H-Pyrrolof2,1 -clf 1,4lbenzodiazepin-10(11hļ)-vlcarbonvl)phenvl|-N-methyl-2-methylbenzamide
A mixture of 0.27 g of 10,11 -dihydro-5ļļ-pyrrolo[2,l-c][1,4]benzodiazapine, 0.518 g of 4-[N-methyl-N-(2-melhyl40 benzoyl)aminojbenzoyl chloride, 0.182 g of triethylamine and 7 ml of tetrahydrofuran is stirred at room temperature for 3 hours. To the mixture is added 0.29 g of 4-[N-methyl-N-(2-methylbenzoyl) amino]benzoyl chloride and 0.10 g of triethylamine in 2 ml of dichloromethane and the mixture stirred for 2 days. The mixture is poured into vvater and extracted vvith dichloromethane. The extract is vvashed vvith vvater, 1N HCI, 1N NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo and the residue crystallized trom dichloromethane-hexane to give 0.38 g ol crystals, m.p. 168-170°C.
As described for Example 384, but substituting the appropriate aroyl chloride, the follovving compounds are prepared.
Example 385
N-[4-(5H-Pyrrolof2,1-cll1,4lbenzodiaz9ūin-10(ntļ)-vlcarbonvl)phenvll-B-methvl-2-chlorobenzamide
Example 386
N-f4-(5H-Pyrrotof2,1 -clf 1,41benzodiazapin-10(11Hf-vlcarbonvl)phenvll-AI-tnathvl-2,5-dichlorobertzamida
Example 387
N-i4-(5H-Pyrrolof2,1 -clf 1,4ļbenzodiazepin-10(1 lū)-ylcarbonvl)phenyll-N-methvl-2-chloro-4-methylbenzamide
Exampla 388
N-f4-(5H-Pyrrolof2,1 -clf 1,4ļbenzodiazepin-10( 11U)vlcarbonyl)phanyn-N-nriethvl-2-methvl-4-chlorobanzamida
Example 389
N-[4-(5H-Pyrrolo[2,1 -cl( 1,4lbenzodiazepin-10( 11 mvlcarbonvllphanvll-N-m9thyl-2,4-dimethvlbenzamida
Example 390
N-[4-(5H-Pyrrolof2,1-elfl,4lbanzodiazepin-10(11hi)-ylcarbonvllph9nyll-JJ-malhvl-2,3-dimelhvlb9nzanriid9
Example 391
N-f4-(5H-Pvrrotof2,l-clf1,4lbenzodiazepin-l0(11idl-vlcarbonvllphanyll-ļsl-methvl-2-mathoxvbenzaniide
Example 392
N-i4-(5H-Pvrrolof2,1-clU,4lbanzodtazepin-W(11lri')-vlcarbonv0phanvll-N-mathvl-2-lnfluoromelhoxvbenzamida
Example 393
N-f4-(5H-Pvrroloi2,1-clf1,4lbenzodiazepin-10(11H)-ylcarbonvl)phenyl|-B-methyl-2,4-dimethoxvbsnzamide
Example 394
N-f4-(5H-Pyrrolof2.1 -clf 1,4ļbenzodiazepin-10(1 1b)ylcarbonyl)phenvll-N-m8thvl-2-methoxv-4-chlorobenzamide
Example 395
N-[4-(5H-Pvrroloi2.1 -clf 1,4lbenzcxjiazepln-10(11hH-ylearbonyllphanvll-M-methvl-2-m9thvlthiobanzamide
Example 396
N-(4-(5H-Pyrrolo[2,1-cl(1,4lbenzodiazepin-10(imi-vlcarbonvnphenvll-N-methvl-2-m9thyl-3-thiophenecarboxamida
Example 397
N-(4-(5H-Pyrrolof2,1-clf1,4lbgnzodiazflpin-10(11ū)-vlcarbonyl)phenvll-M-nnethvl-3-methyl-2-thiophenecarboxamida
Exanriple 398
N-f4-(5H-Pvrrolof2.1-clf1,4lbenzodiazepin-10(11Id)-ylcarbonvl)phenvll-N-methv[-2-methvl-3-(uranecarboxamidB
Example 399
N-f4-(5H-Pyrrolof2,l7Clf1,4lbenzodiazepin-10f11hļ)-ylcarbonyl)phenvH-Jī|-melhylb9nz9neac9famide
Example 400
N-[4-(5H-Py rrolo[2,1 -cļf 1,4ļbenzodiazepin-10(11 Jj)-ylcarbonvl)phenvlļ-M-methvl-2-chlorobenzeneacetamide
Example 401
N-f4-(5H-Pyrrolo[2,1 -clf 1,4ļb9nzodiazepin-1 Of 11 tļ)-vlcarbonyl)phenvll-h-me1hvl-2-methoxybonz8neac8tannide
Example 402
N-f4-(5H-Pyrrolof2,1-clf1,4lbenzodiazepin-10(11tļ)-ylcafbonvl)pbanvll-N-methyl-2-methylbanzaneacatamide
Exampla 403
N-f4-(5H-Pyrrolo[2,1 -clf 1,41benzodiazepin-10(11H)-vlcarbonyl)phenvll-h-methvl-2-m9thyl-3-thīopheneacetamida
Example 404
N-i4-(5H-Pvrrolo(2,1-cl[1,4lbenzodiazepin-10(im)-vlcarbonvnphenvll-Jsl-mathvlcvclohexanecarboxamide
Example 405
N-f4-(5H-Pvrrolof2,1-clf1,4lbenzodiazepin-10(im)vlcarbonvl)phenvll-N-mathvlcvclohexvlacetamida
Example 406
N-f4-(5H-Pvrroloi2,1-cl(1,4]bsnzodiazepin-10(niJ)-ylcarbonvl)phenvll-B-m9thvl-3-cvelohexenecarboxaniide
Example 407
N-f4-(5H-Pyrrolof2.1-clf1.4lbenzodiazepin-10(im)-vlcarbonvl)-2-methvlphenvll-2,4-dichlorobenzamide
A mixture of 0.40 g of 1ū,11-dfhydro-10-(3-methyl-4-aminobenzoyl)-5H-pyrrolo[2,1-c]{1,4]benzodiazepine, 0.40 g of 2,4-dichlorobenzoyl chlorida and 0.75 g of diisopropylathylamina in 50 ml of dichloromethane is stirred at room temperature for 16 hours. The mixfure is vvashed vvith vvater, dried (MgSO4) and the solution passed through a thin pad ot hydrous magnesium silicate. The filtrate is concentrated and hexane added to give crystals. Hecrystallization from dichloromethane-hexane gives 0.52 g of crystals, m.p. 213-2154C.
Example 408
-(2-NitrophenvO-1 H-pyrrole-2-carboxaldehyde
A sample of 4.7 g of sodium hydride (60% in oil) is vvashed vvith hexane (under argon). To the sodium hydride is added 200 ml of dry N,N-dlmethylformamide and the mixture is chilled to 0°C. To the mixture is added 10.11 g of pyrrole-2-carboxaldehyde in smail portions. The mixture is stirred 10 minūtes and 15.0 g of 1-fluoro-2-nitrobenzene added dropvvise. After the addition, the mixture is stirred at room temperatūra 16 hours and the mixture concentrated (65’C) under high vacuum. To the residue is added 400 ml of dichloromethane and the mixture vvashed vvith 150 ml each of H2O, brine and dried (Na2SO4). The solvent is removed jņ vacuo to give a yellow solid. Crystailization from elhyl acelate-hexane (9:1) gives 17.0 g of light yeilow crystals, m.p. 119°-122°C.
Example 409
4,10-Dihydro-5H-pyrrolo[l ,2-althienof3,2-eļf1,41-diazepine
To an ice cooled mixture of 2.1 g of pyrrole-2-carboxylic acid and 3.2 g of methyl 3-aminothiophene-2-carboxylate in 40 ml of dry dichloromethane is added 4 g ol N,N-dicyclohexylcarbodiimide. Tha mixture is stirred at room temper95 ature for 3 hours and filtered. The filter cake is vvashed vvith dichloromethane and then extracted tvvice vvith 60 ml of acetone. The acetone extract is concentrated to dryness to give 0.8 g of solid, m.p. 214-218°C. To a suspension of the preceding compound (1.19 g) in 20 ml ol dry tetrahydrofuran is added 0.2 g of sodium hydride (60% in oil). Aiter the hydrogen evolution, the mixture is stirred and refluxed for 4.5 hours, cooled and poured into ice-water. The precips itated solid is filtered and the solid triturated vvith petroleum ether (bp 30-60°C) to give 0.75 g of 4,10-dihydro-4,10-dioxoSH^rrolofl^-aJthienop^-eļļl ,4]diazepine as a solid, m.p. 280-290’C. The preceding compound (0.362 g) is added to an ice-water cooled solution of 1 M diborane in tetrahydrofuran. The mixture is stirred at room temperature for 65 hours. The solution is concentrated to dryness and ice-water added to the residue. The mixture is acidified with dilute HCI, stirred and then basified vvith solid NaHCO3. The mixture is filtered to give 0.223 g of a solid (foam) m.p. 80-85°C.
Example 410
10,11-Dihydro-5B-1,2,4-triazolof3,4-£lf1,4lbenzodiazepine w A mixture of 2.2 g of 2-cyanoaniline, 2.0 g of methyl bromoacetate and 1.3 g of potassium carbonate in 12 ml of dry N,N-dimethylformamide is heated at 15O-155°C for 40 minūtes. The cooled mixture is poured into ice-water and the mixture filtered to give 2 g of methyl (N-(2-cyanophenyl)amino]acetate as a yellow solid, m.p. 70-78°C. The preceding compound (2.0 g) is added to a solution of 0.5 g of sodium methoxide in 50 ml of mēthanol. The mixture is shaken under an atmosphere of hydrogen vvith the catalyst Raney-Ni for 19 hours. The mixture is filtered through 20 diatomaceous earth and the fiitrate evaporated. Water is added to the residue and the mixture filtered to give 2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-3-one as a yellow solid, m.p. 167-170’C.
A mixture of the preceding compound (1.6 g) and 0.84 g of phosphorus pentasulfide in 10 ml of dry (dried over KOH) pyridine is stirred and heated at 80-85°C for 15 minūtes. The mixture is poured into vvater and stirred for 30 minūtes. Filtration gives 1.0 g ol 1,2,4,5-tetrahydro-3H-l ,4-benzodiazepin-3-thione as yellow solid, m.p. 150-153°C.
2S The preceding compound (0.5 g) and 0.5 g of N-formylhydrazine in 6 ml of dry n-butanol is refluxed for 16 hours and the soivent removed. The gummy residue is triturated vvith cold vvater and the mixture filtered. The solid is triturated vvith acetone to give 0.19 g of yellow solid, m.p. 232-237’C.
Example 411
4.5- Dihvdro-6H-f 1,2.41triazolo[4,3-alf 1,5ļbenzodiazepine
A mixture of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-thione (0.8 g) and 0.80 g of N-formylhydrazine in 8 ml of n-butanol is stirred and refluxed for 18 hours and the soivent removed under vacuum. Ice vvater is added to the residual os solid and the mixture filtered to give 0.312 g of a gray solid, m.p. 162-165’C.
Example 412
4.5- Dihvdro-6B-imidazof 1,2-alf 1,51benzodiazepine
A mixture of 30 g of acrylic acid, 33 g of o-phenylenediamine is heated on a steam bath for 1.5 hours and the cooled black mixture triturated vvith ice-water. The aqueous phase is decanted and ice and aqueous ammonium hydroxide added to the residue. The mixture is extracted vvith dichloromethane and the extract concentrated to dryness. The residue is triturated vvith carbon tetrachloride and filtered. The oily solid is triturated vvith a smail amount of ethanol 45 to give 9.7 g of a solid. Trituration of the solid vvith ethyl acetate gives 2,3,4,5-tetrahydro-1 H-1,5-benzodiazepin-2-one as an impure solid, m.p. 75-107’C.
A mixture of the preceding compound (11.3 g) and 5.9 g of phosphorus pentasulfide in 70 ml of dry pyridine is stirred and heated at approximately 80’C for 20 minūtes. The mixture is poured into vvater and the mixture stirred for 30 minūtes. Filtration gives 8.6 g of 2,3,4,5-tetrahydro-1 H-1,5-benzodiazepin-2-thione as a solid, m.p. 154-157’C.
so 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 is refluxed for 4 hours and the soivent removed under vacuum. The residue is heated (refluxed) vvith 10 ml ol 3 Ņ hydrochloric acid for 55 minūtes. Ice is added to the cooled mixture and the mixture made basie vvith solid NaHCO3. The mixture is extracted vvith dichloromethane and the exlract dried (NajSO4). The soivent is removed to give an orange syrup vvhich solidified on standing. The oily solid is triturated
SS with acetone to give a light yellow solid (0.185 g) m.p. 119-122°C.
Example 413
1-(2-Nitrophenvl)-2-pvrroleacetic acid, ethvl aster s To a stirred mixture of 1.38 g ot 1 -(2-nitrophenyl)pyrroie, 4.30 g of ethy I iodoacetate and 2.22 g of FeSO4.7H2O in ml of dimethyl suifoxide is added dropvvise 10 ml ot 30% hydrogen peroxide vvhile keeping the reaction mixture at room temperature vvith a cold vvater bath. The mixture is stirred at room temperature for one day. An additional 2.4 g of ethyl iodoacetate, 1.1 gof FeSO4.7H2O and 5 ml of 30% hydrogen peroxide is added and the mixture stirred at room temperature for 1 day. The mixture is diluted vvith vvater and extracted vvith diethyl ether. The organic extract is vvashed vvith vvater, brine and dried (Na2SO4). The soivent is removed and the residue (2.12 g) chromatographed on silica gel vvith ethyl acetate-hexane (1:4) as soivent to give 0.30 g of product as a brovvn gum.
Example 414 is 6,7-Dihvdro-5U-pyrrotof1,2-fllf1,5Ibenzodiazepin-6-one
To a solution of 0.3 mmol of 1 -(2-nitrophenyl)-2-pyrroleacetic acid, ethyl ester in 3 ml of ethanol is added stannus chloride dihydrate (SnCI2.2H2O) in 2 ml of concentrated hydrochloric acid (vvith cooling in vvater bath). The mixture is stirred at room temperature for 5 hours and chilled in an ice bath. To the mixture is added slowly saturated sodium so carbonate solution. The solid vvhich precipitates is filtered and the solid vvashed vvith vvater and then extracted vvith ethyl acetate. The ethyl acetate extract is dried (Na2SO4) and the soivent removed to give 0.16 g of solid vvhich is triturated vvith ether to give 0.11 g of product as an off-vvhite solid.
Example 415
6,7-Dihvdro-5iJ-pyrrolof 1,2-aff 1,51benzodiazepine
To a solution of 0.070 g ot 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-6-one in 2 ml ot tetrahydrofuran is added 0.45 ml of a 2.0 M solution ot diborane-dimethylsulfide in tetrahydrofuran. The mixture is refluxed tor 3 hours, poured into vvater and make basie vvith 2 N NaOH. The tetrahydrofuran is removed under vacuum and the residual aqueous mixture extracted vvith diethyI ether. The extract is vvashed vvith brine, dried (Na2SO4) and the soivent removed to give 0.065 g of a colorless oii; one spot by thin layer chromatography (silica gel) vvith ethyl acetate-hexane (1:2) as soivent (Rf 0.81).
Example416
10,11 -Oihvdro-10-(2-chloro-4-aminobenzoyl)-5i=L-pvrrolofzl 1 -clf 1,41benzodiazepine
A mixture of 5.0 g of 10,11 -dihydro-10-(2-chloronitrobenzoyi)-5H-pyrrolo(2,1 -c][ 1,4]benzodiazepine, 15.4 g of stan^o pus chloride and 170 ml of ethanol is heated at 70-30’C for 1 hour. The mixture is chiSlied (ice bath) and made basie vvith 1 M NaHCO3 solution (350 ml) and then stirred at room temperature for 1 hour. The mixture is brought to pH 5 vvith acetic acid and extracted vvith 500 ml of ethyl acetate and vvith 300 ml of ethyl acetate. The combined extract is vvashed vvith 250 ml of brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter pad vvashed vvith ethyl acetate. The filtrate is concentrated to dryness and the residue dissolved in 200 ml of hot chloroform-methanol (1:1) and the solution filtered Ihrough a thin pad of hydrous magnesium silicate. The filtrate is concentrated under vacuum to give 4.36 g (after drying under vacuum at 60°C overnight) of product as a vvhite solid. A sample is recr/staūized from chlcrcfcrm-methanol to give white cr/stals, m.p. 210-212°C.
Example 417 so
4-f(5-Fluoro-2-methylbenzoyl)amino1benzoic acid
A mixture of 0.60 g of ethyl 4-[(5-fluoro-2-methylbenzoyl)aminojbenzoate 0.60 ml of 10 N NaOH, 25 ml of vvater and 50 ml of absolute ethyl alcohol is heated on a steam bath for 1 hour, cooled and acidified vvith acetic acid. The resulting solid is filtered and dried in vacuo at 60-80°C to give 0.47 g of the desired product as a solid, m.p. 272-275°C. The follovving Examples are prepared using the conditions of Example 417.
Example No. Compound
418 4-[(3-fluoro-2-methylbenzoyl)amino]benzoicacid, m.p. 309-311’C
419 4-[(5-fluoro-2-methylbenzoyl)amino]-2-chlorobenzoic acid, m.p. 247-249’C
420 4-[3-fluoro-2-methylbenzoyl)aminoļ-2-chlorobenzoic acid, m.p. 260-263’C
421 4-[[4-fluoro-3-(trifluoromethyl)]benzoyl]amino]-2-chlorobenzoic acid
422 4-[[2-fluoro-3-(trifluoromethyl)]benzoyl]aminoļ-2-chlorobenzoic acid
423 4-((2,5-difluorobenzoyl)amino]-2-chlorobenzoic acid
424 4-((2,5-dichlorobenzoyi)amino]-2-chlorobenzoic acid
425 4-((2,3-dimethylbenzoyl)aminoJ-2-chlorobenzoic acid
426 4-((2,3-dichlorobenzoyl)amino]-2-chlorobenzoic acid
427 4-((2,5-dimethylbenzoyl)amino]-2-chlorobenzoic acid
428 4-(2,3-difluorobenzoyl)amino]-2-chlorobenzoicacid
Example 429
4-f(2,4-Dichlorobenzoyl)aminol-2-chlorobenzoic acid
To a stirred mixtura of 5.19 g of 2-chloro-4-aminobenzoic acid in 150 ml of mathyiena chloride is added 7.86 g of N,N-diisopropyfethylamine and 12.67 g of 2,4-dichlorobenzylchloride and stirring continued for 18 hours. Water is added to the filtrate and the organic layer dried vvith Na2SO4 and concentrated in vacuo to give 13.68 g of Ihe desired product, m.p. 171-175’C.
The following Examples are prepared using the conditions of Example 429.
Example No. Compound
430 4-[(2-methylbenzoyl)aminoļ-2-chlorobenzoicacid, m.p. 196-199° C
431 4-((2-methylbenzoyl)amino]-3,5-dimethylbenzoic acid, m.p. 286-289’C
432 4-((2,4-dichlorobenzoyl)amino]-3,5-dimethylbenzoic acid, m.p. 2O9-212“C
433 4-[(2-methylbenzoyl)amino]-3-chlorobenzoicacid, m.p. 199-202’C
434 4-((2,5-dichlorobenzoyl)amino]-2-chlorobenzoic acid
435 4-[(3-fluoro-2-methy lbenzoy l)amino]-3-chlorobenzoic acid, m.p. 225-227’C
436 4-((5-fluoro-2-methy lbenzoyl)aminoļ-3-chlorobenzoic acid, m.p. 182-185’C
437 4-((2,3-dima1hylbenzoyl)amino]-3-chlorobenzoic acid
438 4-((2,3-d ichlorobenzoyl)aminoļ-3-chlorobenzoic acid
439 4-((2,5-dimethylbenzoyl)amino]-3-chlorobenzoic acid
440 4-([4-fluoro-2-(trifluoromethyl)benzoyl]amino]-3-chlorobenzoic acid
441 4-[(3-fluorobenzoyl]amino]-2-chlorobenzoic acid, m.p. 249-252’C
442 4-[[2-(trifluoromethyl)benzoyllaminoļ-3-chlorobenzoic acid
Example 443
Ethvl 10,11-dihvdro-10-(2-chloro-4-nitrobenzovi)-5H-pvrrolof2,1-clf1,4lbenzodiazeoine-3-carboxvlate
To 25 ml ol absolute ethanol is added 0.12 g of sodium matal vvith stirring follovved by 0.68 g of 10,11 -dihydro-10(2-chioro-4-nitrobenzoyl)-(3-(trichloroacetyl)]-5H-pyrrolo[2,1 -cj[ 1,4]benzodiazepine.
Stirring is continued for 18 hours. The volatiles are removed in vacuo to a residue vvhich is partitioned betvveen methylene chloride and vvater. The organic layer is separated, dried vvith Na2SO4 and filtrate heated on a steam bath vvhile hexane is added to give 0.45 g ot the desired product as a solid, m.p. 165-166’C.
The following Examples are prepared using the conditions of Exampie 443.
Example No. Compound
444 ethyl 10,11 -dihydro-10-(3-methyl-4-nitrobenzoyl)-5H-pyrrolo[2,1 -c][ 1,4ļbenzodiazepine3-carboxylate, m.p. 200-202’C
(continued)
Example No. Compound
445 ethy 110,11 -dihydro-10-(2-methyl-4-nitrobenzoyl)-5H-pyrrolo[2,1 -c][1,4]benzodiazepine3-carboxylate
446 ethyl 10,11-dihydro-10-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine3-carboxylate
447 ethyl 10,11 -dihydro-lO-(3-chloro-4-nitrobenzoyl)-5H-pyrro1o(2,1 -c][1,4]benzodiazepine3-carboxylate
Example 448
10,11 -Dihydro-10-(3-methyl-4-nitrobenzovl)-(3-trichloroacetyl)|-5Jd-pyrrolof2, t -fifff ,4ļbenzodiazepine
Toa stirred solution of 3.47 9 of 10,11-dihydro-10(4-nitro-3-methylbenzoyl)-5H-pyrrolo[2,t-c][1,4]benzodiazapine in 50 ml of methylene chloride is added 3.40 g of trichloroacetic anhydride and stirring continued for 18 hours. Water is added and ihe separated organic layer vvashed vvith saturated sodium bicarbonate, dried vvith NagSC^ and passed through a short pad of hydrous magnēsium silicate. Hexane is added to the filtrate at the boīl to give 4.07 g of the desired product as a solid. MASS SPEC (Cl) 491 (MH+).
The follovving Examples are prepared using the conditions of Example 448.
Example No. Compound
449 10,11-dihydro-10-(4-nitrobenzoyl)-[3-(trichloroacetyl)]-5H-pyrazolo[2,1-c][1,4]benzodiazepine, m. p.122-123’C
450 10,11 -dihydro-10-(2-chloro-4-nitrobenzoyl)-[3-(trichloroacetyl)]-5H-pyrrolo[2,1 -c][1,4] benzodiazepine, m.p. 149-151’C
Example 451
10,11 -Dihvdro-10-(4-nitrobenzovl)-f3-(trifluoroacetyl)1-5h-pyrrolof2.1 -clf 1,4)benzodiazepine
A mixture of 0.50 g of 10,11-dihydro-10(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 10 ml of methvlene chloride is cooled in an ice bath and 2.0 g of trifluoroacetic anhydride added. The bath is removed and the reactants stirred for 18 hrs, partitioned vvith saturated sodium bicarbonate and the separated organic layer dried vvith NajSO4 then passed through a short pad of hydrous magnēsium silicate. The filtrate is heated at the boil vvhile hexane is added to give 0.40 g of the desired product, m.p. 169-17O°C.
The follovving Examples are prepared using the conditions of Example 451.
Example No. Compound
452 10,11 -dihydro-10-(2-chloro-4-nitrobenzoyl)[3-(trifluoroacetyl)]-5H-pyrrolo[2,1 -c][1,4] benzodiazepine, m.p. 151-153’C
453 10,11 -dihydro-10-(3-chloro-4-nitrobenzoyl)[3-(trifluoroacetyl)]-5H-pyrrolo[2,1 -c][1,4] benzodiazepine
454 10,11-dihydro-10-(2-methyl-4-nitrobenzoyl)[3-(trifluoroacetyl)]-5H-pyrrolo(2,1-c][1,4] benzodiazepine
Example 455
10,11 -Dihvdro-10-(3-methoxv-4-nitrobenzoyl)-5ļl-pvrroloļ2,1 -clfļ ,4lbenzodiazepine
A mixture of 5.0 g of 3-methoxy-4-nitrobenzoic acid and 5.0 g of thionyI chloride is heated under argon for 1 hour. The volatiles are removed in vacuo to give 2.85 g of a 3-methoxy-4-nitrobenzoyl chloride as a residue vvhich is dissolved in 50 ml of methylene chloride. To the preceding solution is added vvith stirring 1.75 g of N,N-diisopropylethylamine follovved by 1.84 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine. The reaction mixture is stirred under argon for 18 hours and diluted vvith saturated sodium bicarbonate. The organic layer is dried vvith NeķSO4 and passed through a short pad ot hydrous magnesium silicate. While boiling, hexane is added to the fiitrate to give, upon cooling, 3.39 g of the desired product as a solid, m.p. 191-192’C.
The follovving Examples are prepared using the conditions of Example 455.
Example No. Compound
456 10,11 -dihydro-10-(2-methoxy-4-nitrobenzoyl)-5H-pyrrolo[2,1 -cj[ 1,4]benzodiazepine
457 10,11 -dihydro-10-(2-methyl-4-nitrobenzoyl)-5H-pyrrolo[2,1 -c][ 1,4]benzodiazepine
458 10,11 -dihydro-10-{3-methoxy-6-chloro-4-nitrobenzoyl)-5H-pyrrolo[2,1 -c][1,4]benzodiazepine
459 10,11 -dihydro-10-(3-methoxy-6-methyl-4-nitrobenzoy l)-5H-pyrrolo[2,1 -c][ 1,4]benzodiazepine
Example 460 f 0,11 -Dihvdro-10-(4-amino-3-methoxybenzovl)-5}-l-pyrrnlnfP. 1 -£ļf 1,4ļbenzodiazepine
A mixture of 3.24 g of 1Q,11-dihydro-10-(4-nitro-3-m8thoxybsnzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.35 g of 10% Pd/c and 0.60 g of anhydrous hydrazine in 100 ml of absolute ethyl alcohol and heated on a steam bath for 1 hour. The hot reaction mixture is filtered through diatomaceous earth and the fiitrate evaporated in vacuo to a residue vvhich is partitioned betvveen methylene chloride and vvater. The organic layer is dried vvith Na2SO4 and passed through a short pad of hydrous magnesium silicate. Hexane is added to the fiitrate vvhile heating on a steam bath to give 2 g of crystals, m.p. 184-185’C.
The follovving Examples are prepared using the conditions of Example 460.
Example No. Compound
461 10,11 -dihydro-10-(4-amino-2-chlorobenzoyl)-5H-pyrrolo(2,1 -c][ 1,4]benzodiazepine, m.p. 197-199’C
462 10.11 -dihydro-10-(4-aminobenzoyl)[3-(lrifluoroacetyl)]-5H-pyrrolo[2,1 -c][ 1,4]benzodiazepine, m.p. 200-206’C
463 ethyl 10,11-dihydro-l0-(4-amino-3-methylbanzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine3-carboxylate, m.p. 210-211’C
464 elhyl 10,11 -dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1 -c][ 1,4]benzodiazepine-3-carboxylate, m. p. 174-175’C
Example 465
N-f4-f5iJ-Pyrrolof2. t -clf 1,4lbenzodiazepin-10( 1 m)vlcarbonyl)phenvl1-5-fluoro-2-methvlbenzamide
To a stirred solution of 500 mg of 10.11 -dihvdro-10-(4-aminobenzovl)-5H-pyrrolof2.1 -clH ,41-benzodiazepine in 3 ml of methylene chloride, cooled to 0°C, under argon, is added 346 pl of triethylamine follovved by the addition of 340 mg of 2-methyl-5-fluorobenzoyl chloride in 2 ml of methylene chloride. The cooling bath is removed and stirring continued for 18 hours. After cooling to O’C, an additional 342 mg of 2-methyl-5-fluorobenzoyl chloride in 2 ml of methylene chloride is added. The cooling bath is removed and stirring continued for 18 hours. The volatiles are removed in vacuo to a residue vvhich is dissolved in 50 mi of methylene chloride and vvashed vvith 20 ml each of vvater, 2 N citric acid, 1 M sodium bicarbonate and brine. The organic layer is dried over Na2SO4 and passed through a pad of hydrous magnesium silicate. The fiitrate is evaporated in vacuo to a residue vvhich is crystallized from ethyl acetate-hexane to give 295 mg of the desired product as a vvhite solid, m.p. 17O-1'8O’C.
The follovving Examples are prepared using the conditions of Example 465 vvith the appropriately substituted aroyl chloride.
Example No. Compound
466 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-3-fluoro2-methylbenzamide, m.p. 194-208’C
467 N-[4-(5H-pyrrolo{2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,3-dimethylbenzamide, m.p. 168-170’C
100 (continued)
Example No. Compound
468 N-[4-(5H-pyrrolo(2,1 -c][ 1,4]benzodiazepin-10( 11 H)-ylcarbonyl)phenyl]-2,3-dichlorobenzamide, m. p. 219-222’C ” ~
469 N-[4-(5H-pyrrolo(2,1 -c][1,4]benzodiazepin-10(11 H)-ylcarbonyl)phenyl)-2,6-dichlorobenzamide, m. p. 174-182°C
470 N-[4-(5H-pyrrolo[2,1-c)[1,4]benzodiazepin-10(11H)-ylcarbonyl-3-chlorophenyl]2-methylbenzamids, m.p. 190-195’C
471 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yicarbonyl-3-chlorophenyl]2,4-dichlorobenzamide, m.p. 144-16O°C
472 N-[4-(5H-pyrrolo(2,1-c][1,4]benzodiazepin-lO(11H)-ylcarbonyl-2,6-dimethyl phenyl]2-methylbenzamide, amorphous solid
473 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl-2,6-dimethyl phenylļ2,4-dichlorobsnzamide, amorphous solid
474 N-(4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-3-(trifluoromethyl) benzamide, amorphous solid
475 N-(4-(5H-pyrrolo(2,1-c][1,4Jbenzodiazepin-lO(11H)-ylcarbonyl)-2-chlorophenylJ- 3-methylthiophene-2-carboxamide
476 N-[4-(5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10( 11 H)-y lcarbonyl)phenyl]-3-chlorothiophene2-carboxamide, solid; MASS SPEC (Cl): 448(M+H)
477 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-methoxyphenylJ2-methyibenzamide, m.p. 184-186° C
478 N-[4-(5H-pyrrolo[2,1 -c][1,4]benzodiazepin-10(11 H)-ylcarbonyl)-2-methoxyphenyl]2,4-dichlorobenzamide, m.p. 192-194°C
479 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-methoxyphenyl]-3-fluoro2-methylbenzamide m.p. 203-204°C
480 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-chloro5-nitrobenzamide, m.p. 110-160’C (amorphous solid)
267 N-(5H-pyrrolo[1,2-a]thisno[3,2-e][1 P4]diazepin-4(10H)-ylcarbonyl)phenyl]-2-methylbenzamide, m. p. 162-188°C (amorphous solid)
274 N-[4-(5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]-diazepin-4(10H)-ylcarbonyl)phenyl]2,4-dichlorobenzamide, m.p. 105-190’C
Example 481
N-f4-(5fc|-pvrrolof2,1 -clf 1,4ļbenzodiazepin-10(11 H)-ylcarbonyl)-3-chlorophenylļ-3-fluoro-2-methylbenzamido
To a solution of 1.50 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 25 ml of methylene chloride is added 1.23 g of N.N-diisopropylethylamine. While cooling in an ice bath, a solution of 3.08 g of [4-[(2-methyl-5-fluorobenzoyl)amino)-2-chlorobenzoyl chloride in 50 ml of methylene chloride is added. The reaction mixture becomes homogeneous and is stirred at room temperature for 18 hours. Water is added and the separated organic layer vvashed vvith saturated sodium bicarbonate, dried vvith Na2SO4 and passed through a short pad of hydrous magnesium siiicate tvvo times. The methylene chloride is removed in vacuo to give 3.81 g of a glass. A sample is crystallized from ethyl acetate to give crystalline solid, m.p. 200-205’C.
Example 482
N-i4-(5tl-pyrrolof2,1 -clf 1,4ļbenzodiazepin-1 Of 11 H)-ylcarbonyl)-3-chlorophenvl)-5fluoro-2-melhylbenzamide
To a solution ot 1.84 g of 10,11-dihydro-5H-pyrrolo(2,1-cļ[1,4]benzodiazepine in 25 ml ot methylene chloride is added 1.30 g of N,N-diisopropylethylamine. While cooling in an ica bath, a solution of 3.45 g of (4-{(2-methyl-5-fluorobenzoyl)amino]-2-chlorobenzoyl chloride in 50 ml of methylene chloride is added. The reaction mixture becomes homogeneous after 5 minūtes and is stirred at room temperature for 18 hours. VVater is added and the separated organic fayer vvashed vvith saturated sodium bicarbonate, dried vvith Na2SO4 and passed through a short pad of hydrous magnesium siiicate. The methylene chloride is removed jn vacuo to give 4.60 g of the desired product as a glass. A
101 sampie is crystallized from ethyl acetate to give crystalline solid, m.p. 191-195°C.
Example 483
4-(5tJ-Pyrrolof2,1 -jclf 1,4ļbenzodiazepin-10(11b )-ylcarbonyl)benzoic acid
A solution of 0.92 g of 10,11-dihydro-5H-pyrrolo(2,1-c][1,4]benzodiazepine, 1.19 g of monomethyl terephthaloyl chloride in 20 ml of pyridine is refluxed for 2 hours. The mixture is chilled and 1 N HCl added until the pH is 5. The mixture is filtered and vvashed vvith vvater to give 1.53 g of solid. Recrystaltization from dichloromethane-hexane gives to crystais, m.p. 186-188°C of methyl 4-(5H-pyrrolo-[2,1-c][l,4]benzodiazepin-lO(11H)-yl-carbonyl)benzoate.
A mixture of 1.83 g of the preceding compound, 8 ml of 2 N NaOH and 14 ml of methanol is refluxed for 0.5 hour and then concentrated under vacuum. The residue is extracted with ether and the aqueous layer acifidied vvith 2 N citric acid. The mixture is filtered and the solid vvashed vvith vvater and dried (60’C under vacuum) to give 1.61 g of crystals, m.p. 210-214’C.
Example 484
N-(2-Methvlphenvl)-4-(5h-pyrrolof2,1 -clf 1,4ļbenzodiazepin-10( 11 U)-ylcarbonyl)benzamide a mixture of0.332 g of 4-(5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10(11 H)-ylcarbonyl)benzoic acid, 0.111 g of triethylamine, 0.107 g of o-toluidine, and 0.15 ml of diethylphosphoryl cyanide in 20 ml of dichloromethane is heated on a steam bath overnight. The mfcture is vvashed vvith vvater, 1 M NaHCO3,1 N HCl, brine and dried (Na2SO4). The dichloromethane solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is crystallized from dichloromethane-hexane to give 0.23 g of vvhite crystals, m.p. 228-231’C.
Example 485
N-(2,3-Dimethvlphenyl)-4-f51d-Pvrrolof2,1 -clf 1,4ļbenzodiaz9pin-10( 11W-ylcarbonyl)benzamide
A mixture of 0.332 g of 4-(5H-pyrrolo(2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoic acid, 0.222 g of triethylamine, 0.157 g of 2,3-dimethylaniline hydrochloride, 0.15 ml of diethylphosphotyl cyanide in 20 ml of dichtoromelhane is heated on a steam bath for 3 hours. The mixture is vvashed vvith H2O, 1 M NaHCO3, H2O, 1 N HCl, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter cake vvashed vvith dichloromethane. The filtrate is concentrated to dryness under vacuum and the residue crystallized from dichlo35 romethane-hexane to give 0.11 g of crystals, m.p. 239-240’C.
Example 486
N-f4-f(4.5-DihvdiO-6hl-H,2,4ltriazolof4,3-alf1,51benzodiazepin-6-vl)carbonvl)phenvll-2-methvibenzoata
A mixture of 0.246 g of (4-(2-methylbenzoyl)aminoļbenzoyl chloride, 0.14 g of 4,5-dihydro-6H-[1,2,4]triazolo[4,3-aJ [1,5]benzodiazepine and 2 ml of pyridine is heated on a steam bath for 4.5 hours and heated (oil bath) at 110’C overnight. The mixture is chilled and poured into vvater. The mixture is neutralized vvith 1 N HCl and filtered. The solid is vvashed vvith dichloromethane and the dichloromethane filtrate evaporated under vacuum to give 0.151 g of product, *5 MASS SPEC (FAB) 424.2(M+H).
Example 487
N-i4-(Pvrrolof1,2-alquinoxalin-5(4hl)-vlcarbonyl)phenvH-2,3-dichlorobenzamide so
As described for Example 157, 0.47 g of 4,5-dihydro-5-(4-aminobenzoyi)pyrrolo[1,2-a]quinoxaline, 346 μΙ of triethylamine and 5 ml of dichloromethane are chilled (ice bath) and 0.415 g ot 2,3-dichlorobenzoyl chloride in 2 ml of dichloromethane added. After stirring overnight, an additional 346 μΐ ot triethylamina is added and an additional 0.415 g of 2,3-dichlorobenzoyl chloride added. The mixture is stirred for 2 hours, diiuted vvith 50 ml of dichloromethane and the solution vvashed vvith 20 ml each of H2O, 2 N citric acid, 1 M NaHCO3 and brine. The organic layer is dried (Na^SO*) and filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is chromatographed on thick layer siiica gel plates vvith ethyl acetate-hexane (1:1) as solvent to give 0.100 g oi vvhite solid, m.p. 230-240’C.
102
Example 488
10-f4-ff(2-Chlorophenvl)sulfonvHaminolbenzoyH-10,11 -dihydro-5iJ-pyrrolof2.1 -clf 1,4ļbenzodiazepine
To a solution of 0.418 g of 2-chlorobsnzenesulfonyl chloride in 5 ml of dichloromethane, cooled to 0’C is added
0.50 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.346 μΙ ot triethylamine. The mixture is stirred at room temperature overnight and diluted vvith 50 ml of dichloromethane. The mixture is vvashed vvith 20 ml each of H2O, 2 N citric acid, 1 M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium siiicate and the filtrate concentrated to dryness. The residue is chromatographed on thick layer īo silica gel plates (4) vvith the solvent ethyl acetate-hexane (1:1) to give a solid. Crystallization from ethyl acetate gives
0.165 g of vvhite crystals, m.p. 206-210’C.
Example 489
Methvl 4-(5hf-Pvrrolo[2,1-c1[1,41benzodiazepin-10(11H)-vlcarbonyl)benzoate
To a cooled solution of 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-cJ[1,4]benzodiazepine and 346 μΙ of triethylamine in 5 ml of dichloromethane is added 0,394 g of mono methyl terephthaloyl chloride. The mixture is stirred overnight under argon and diluted vvith 50 ml of dichloromethane. The mixture is vvashed vvith 20 ml each of
H2O, 2 N citric acid, 1 M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium siiicate and the filter cake vvashed vvith dichloromethane. The filtrate is concentrated to dryness and the residue crystallized from ethyl acetate to give 0.50 g of vvhite crystals, m.p. 224-228’C.
Example 490
N-ffDimethylamino)methvl1-hl-f4-fB-pyrrolof2,1 -clf 1,41benzodiazepin-l0( 11B)-ylcarbonyl)phenyH2,4-dichlorobenzamide
To a suspension under argon of 0.072 g of sodium hydride (60% in oil) in 10 ml of tetrahydrofuran is added 0.71 g of Ņ-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,4-dičhlorobenzamide and the mixture stirred at room temperature for 1 hour. To the mixture is added N,N-dimethylmethyleneammonium iodide and the mixture stirred 20 hours. The mixture is diluted vvith diethy I ether (30 ml), filtered and the filtrate concentrated under vacuum. The residue is triturated vvith hexane to give 0.76 g of vvhite solid, m.p. 126-129’C.
Example 491
10-f4-i(Diphenvlphosphinyl)amino1benzoyl]-10,11 -dihydro-5fct-pyrrolo-f2,1 -clf 1,4ļbenzodiazepine
A mixture of 0.10 g of 10,11 -dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1 -c][ 1,4]benzodiazepine 0.060 g of t riethy I40 amine and 0.12 g of diphenylphosphinyl chloride in 2 ml of dichloromethane is stirred at room temperature for 2 hours and then 1 NaOH is added. The mixture is extracted vvith ethyl acetate and the extract vvashed wilh brine and dried (NagSO^. The solvent is removed and the residue triturated vvith ether-hexane to give 0.16 g of a vvhite solid.
Example 492
10-f4-fDiphenoxyphosphinyl)aminolbenzoyll-10,11 -dihydro-5hi-pyrrolof2,1 -clf 1,4tbenzodiazepine
To a solution of 0.10 g of l0,11-dihydro-l0-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.060 g of triethylamine in 2 ml of dichloromethane is added 0.14 g of diphenoxyphosphinyl chloride. The mixture is stirred at room temperature for 2 hours and 1 N NaOH added. The mixture is extracted vvith ethyl acetate and the extract vvashed vvith brine and dried (Na2SO4). The solvent is removed to give a solid. Trituration vvith ether-hexane gives 0.20 g of product as a vvhite solid.
Example 493 ss
10-f4-ff(2,5-Dichlorophenvl)sulfonvl1aminoļbenzovl]-10,11-dihydro-5lj-pvrrolof2,1-c1f1,4lbenzodiazepine
A mixture of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.050 g of tri103 ethylamine and 0.0Θ3 g of 2,5-dichlorobenzenesulfonyl chloride in 2 ml of dichloromathana is stirred at room temperatūra for 1 hour and than 4 mg of 4-(N,N-dimethylamino)pyridine is added. Aftar another hour, 93 mg of 2,5-dichlo· robenzenesulfonyl chloride is added along with 50 mg ot triethylamina. The mixture is stirred at room temperatūra tor 2 days and 1 N NaOH added. The mixture is extracted vvith ethyl acetate and the extract vvashed vvith 50% ammonium chloride solution, brine and dried (Na2SO4). The solvent is removed to give 0.30 g of solid. Trituration vvith ether-hexane gives 0.26 g of solid. This solid is dissoived in a mixture of 5 ml of tetrahydrofuran, 1 ml of methanol, 1 ml of i N NaOH and the mixture stirred for 18 hours at room temperature. The organic solvents are removed and the mixture extracted vvith ether acetate. The extract is vvashed vvith NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue (0.16 g) triturated vvith ether to give 0.14 g of yellow solid.
Example 494
10-[4-K(Phenvlmethvl)sulfonvl1amino1benzovl1-10,11-dihvdro-5B-pvrrolo[2,1-£U1.41benzodiazepine
To a solution of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.060 g of triethylamine in 2 ml of dichloromethane is added 0.10 g of a-toluenesulfonyl chloride. The mixture is stirred at room temperature for 2 hours and 1 N NaOH is added. The mixture is extracted vvith ethyl acetate and the extract vvashed vvith brine and dried (NagSO,,). The solvent is removed and the residue (0,20 g) is chromatographed on silica gel vvith the solvent ethyl acetate-hexane (3:2) to give 0.080 g of product as a vvhite solid and 0.080 g of 10-{4-[(bis(phenylmethyl) sulfonyl]amino]benzoyl]10,11-dihydro-5H-pyrrolo(2,1-cJ[1,4]benzodiazepine as a vvhite solid. The preceding compound in methanol, 2N NaOH is heated on a steam bath, the solvent removed and the basie aqueous residue extracted vvith ethyl acetate to give an additional amount of the product.
Example 495
Ethvl 4-((2-methvlbenzovl)aminol-3-chlorobenzoate
A mixture of 8.26 g ot ethyl 4-aminobenzoate, 8.26 g ot N-chlorosuccinimide in 50 ml of dichloromethane is refluxed overnight. The mixture is vvashed vzith saturated NaHCO3 solution and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filter cake vvashed vvith dichloromethane. The filtrate is concentrated and hexane added. Chilling gives 7.38 g of ethyl 3-chloro-4-aminobenzoate, m.p. 82-83°C.
To the preceding compound (3.66 g), 3.0 g of diisopropylethylamine in 50 ml of dichloromethane is added 3.55 g of 2-methyibenzoyl chloride in 10 ml of dichloromethane. The mixture is stirred at room temperature overnight, vvashed with H2O, NaHCO3 and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filter cake vvashed vzith dichloromethane. The filtrate is concentrated and diluted vzith hexane. Chilling gives 4.71 g of the product as crystals, 129-130°C.
The follovzing Examples are prepared using the conditions of Example 495.
Example No. Compound
496 Ethyl 4-[(2-chlorobenzoyl)amino]-3-chlorobenzoate
497 Ethyl 4-((2,5-dichlorobenzoyl)amino]-3-chlorobenzoate
498 Ethyl 4-((2,4-dichlorobenzoyl)amino]-3-chlorobenzoate
499 Ethyi 4-((3,5-dichlorobenzoyl)aminoļ-3-chlorobenzoate
500 Ethyl 4-[(2-methyl-4-chlorobenzoyl)amino]-3-chlorobenzoate
501 Ethyl 4-[(2,3-dimethylbenzoyl)amino]-3-chlorobenzoate
502 Ethyl 4-[(2-methoxybenzoyl)amino]-3-chiorobenzoale
503 Ethyl 4-[(2-(trifluoromethoxy)benzoylļamino]-3-chlorobenzoate
504 Ethyl 4-[(2-methoxy-4-chlorobenzoyl)amino]-3-chlorobenzoate
505 Ethyl 4-[[2-(methylthio)benzoyl]amino]-3-chlorobenzoate
506 Ethyl 4-[(2-methylbenzeneacetyl]amino]-3-chlorobenzoate
507 Ethyl 4-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-3-chlorobenzoate
508 Ethyl 4-[(4-fluoro-3-(trifluoromethyl)benzoyl]amino]-3-chlorobenzoate
509 Ethyl 4-[[2-fluoro-3-(trifluoromethyl)benzoyl]amino]-3-chlorobenzoate
510 Ethyl 4-((3-fluoro-2-methyibenzoyl)amino]-3-chlorobenzoate
511 Ethyl 4-((2,3-dichlorobenzoyl)amino]-3-chlorobenzoate
104 (continued)
Example No. Compound
512 Ethyl 4-[(4-fluoro-2-methylbenzoyl)amino)-3-chlorobenzoate
513 Ethyl 4-[(5-fluoro-2-methylbenzoyl)amino]-3-chlorobenzoate
514 Ethyl 4-[[2-fluoro-5-(trifluoromethyl)benzoylJaminoļ-3-chlorobenzoate
515 Ethyl 4-[[2-(trifluoromethyl)benzoyl]aminoJ-3-chlorobenzoate
516 Ethyi 4-[[3-(trifluoromethyl)benzoyl]aminoJ-3-chlorobenzoate
Example 517
N-(4-(4H-Pyrazolof5,1-cļf 1,4]benzodiazepin-5(10h))vlcarbonyl)phenyl1-3-fluoro-2-melhylbenzamide /5 A solution of 2.Θ7 g of 3-fluoro-2-methylbenzoic acid in 25 ml of thionyl chloride is refluxed for 1.75 hour and ths excess thionyl chloride removed under vacuum. To the residue is added toluene (several times) and the toluene removed under vacuum after each addition to give 3-fluoro-2-methylbenzoyl chloride.
To a solution ot 0.25 g of 5.10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo[5,1-c][1,4]benzodiazepine and 0.0914 g of triethylamine in 6 ml of dichloromethane under argon is added a solution of 0.156 g of 3-fluoro-2-methylbenzoyl chloride in 1.5 ml ot dichloromethane. The mixture is stirred overnight at room temperature and is vvashed vvith H2O and saturated NaHCO3. The organic layer is treated vvith activated carbon and filtered through magnesium sulfate. The filtrate is evaporated, ethyl acetate added and the solvent removed to give 0.38 g of vvhite crystals, m.p. 245-250°C: Exact mass by mass spectrometry~44l.1720(M+H).
Example 518
N-[4-(4U-Pyrazolof5,1-clf1,41benzodiazepin-5(10ti)-vlcarbonvl)-3-chlorophenvl1-5-lluoro-2-methvlbenzamid9
A mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo[5, V-c][],4ļbgnzodiazepine, 0.391 g of 4-{(5-fluoro-2-methylben30 zoyl)amino]-2-chlorobenzoyl chloride and 0.158 g of cJiisoprog^lethVtamine in 10 ml of dichloromethane is stirred at room temperature overnight. The mixture is vvashed vvith H2O,1 N HCl. H20,1 M NaHCO3, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filter cake vvashed vvith dichloromethane. The filtrate is again passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and the solid crystallized from ethyl acetate to give crystals, m.p. 137-140°C.
Example 519
N-f4-(4tJ-Pyrazolof5,1-c1f1,41benzodiazepin-5(10tl)-ylcarbonvl)-3-chlorophenvl1-2-methylbenzamide
As described for Example 518, a mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo[5,1 -c]f 1,4Jbenzodiazepine, 0.369 g of 4-[(2-methylbenzoyl)amino]-2-chlorobenzoyl chloride and 0.158 g of diisopropylethylamine in 10 mi ol dichloromethane is stirred at room temperalure to give crystals (from elhyl acetate) m.p. 241-244’C.
Example 520
N-f4-(4tļ-Pvrazolof5,1-c1f1,41benzodiazepin-5(10tļ)-vlcarbonvl)-3-chlorophenyl1-2,4-dichlorobenzamide
As described for Example 518, a mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo[5,1-c](1,4]benzodiazepine, 0.472 g of 4-[(2,4-dichlorobenzoyl)aminoļbenzoyl chloride and 0.158 g of diisopropylathylamine in 10 ml of dichloromethane so is stirred at room temperature overnight to give the product (0.27 g) as a pale yellow glass; anal. calc'd: C, 58.7; H,
3.4; N, 11.0; Cl, 20.8 Found C, 57.3; H, 3.3; N, 9.5; Cl, 21.3.
Example 521
5,10-Dihvdro-5-(4-nitro-2-chlorobenzovl)-4B)pyrazolof5,1-Pl[1,41benzodiazepine
To a solution of 1.85 g of 5,10-dihydro-4H-pyrazolo[5,1 -c][1,4]benzodiazepine and 1.60 g of diisopropylethylamine in 50 ml of dichloromethane, cooled in an ice bath, is added dropvvise a solution ot 2.64 g of 4-nitro-2-chlorobenzoyl
105 chloride in 25 ml of dichloromethane. The mixture is stirred at room temperature overnight and poured into vvater. The organic layer is separated and vvashed vvith H2O, saturated NaHCO3, H2O and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filtrate evaporated. The residue is crystallized from dichloromethane-hexane to give 3.0 g of crystals, m.p. 197-199’C.
Example 522
5,10-Dihvdro-5-(4-amino-2-chlorobenzovt)-4H-pvrazolo|5,1-clH,41benzodiazepine
A mixture of 0.553 g of 5,10-dihydro-5-(4-nitro-2-chlorobenzoyl)-4H-pyrazolo[5,1 -c][ 1,4]benzodiazepine, 1.70 g of stannous chloride dihydrate in 20 ml of ethanol is heated at 70-80’C for 1 hour. The mixture is chilled, made basie vvith 1 M NaHCO3 and then stirred at room temperature for 0.5 hour. The mixture is brought to pH 5 vvith acetic acid and extracted (several times) vvith ethyl acetate. The combined extracts are dried (Na2SO4) and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated and the residue dissolved in dichloromethane and the solution passed through a thin pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give 0.40 g of a giass, m.p. 9B-117’C; Anal. Calc'd: C, 62.9; H, 4.7; N, 16.3; Cl, 11.6. Found: C, 62.4; H, 4.3; N, 15.6; Cl, 11.7.
The follovzing examples are prepared using the conditions of Example 465.
Example No. Compound
523 N-[4-(5H-pyrrolo[2,1 -c J[ 1,4]benzodiazepin-10( 11 H)-ylcarbonyl)-3-chloropheny I]2-fluorobenzamide, m.p. 223-226°C
524 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]-2(thiomethylbenzamide), vvhite foam
525 N-[4-(5H-pyrrolo(2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl]-3-chlorophenyl]2,3-dimethylbenzamide, m.p. 189-192’C
526 N-[4-(5H-pyrrolo{2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl]-3-chlorophenyl]2-chlorobenzamide, m.p. 198-203’C
527 N-[4-(5H-pyrrolo(2,1 -c][1,4]benzodiazepin-10( 11 H)-ylcarbonyl]-3-chlorophenyl]-4-fluoro2-chlorobenzamide, m.p. 139-141 ’C
528 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-l0(11H)-ylcarbonyl]-3-chlorophenyl]-2-(trifluoromethyl) benzamide, vvhite foam
529 N-[4-(5H-pyrrolo(2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonylJ-3-chlorophenyl]2,6-dichlorobenzamide, m.p. 246-248’C
Example 530
N-f4-(5iJ-Pvrrolof2,1-clf1,4]benzodi3zepin-10(11hl)vlcarbonyl)-2-chlorophenyll-2-methylbenzamide
Toamixtureof 1.38 gof 10,11-dihydro-5H-pyrrolo[2,1-c](1,4]benzodiazepine, 1.11 gof N,N-diisopropylethylamine in 50 ml of dichloromethane is added 2.61 g of 4-((2-methylbenzoyl)amino]-3-chlorobenzoyl chloride in 25 ml of dichloromethane. The mixture is stirred at room temperature overnight and then vvashed vvith HgO and saturated NaHCO3. The organic layer is dried (Na2SO4) and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated, the residue (4.0 g) dissolved in dichloromethane and again filtered through a pad of hydrous magnesium silicate. The filtrate is evaporated to give the product as a giass (3.62 g). A 1.8 g sample of the giass is crystallized from ethyl acetate to give 1.4 gof crystals, m.p. 176-178’C.
The follovzing Examples are prepared using the conditions of Example 530.
Example No. Compound
531 N-[4-(5H-pyrrolo[2,1-c][1,4ļbenzodiazepin-1Q(11H)-ylcarbonyl)-2-chloraphenylļ2,3-dimethylbenzamide
532 N-[4-(5H-pyrrolo[2,1 -c][1,4]benzodiazepin-10(11 H)-ylcarbonyl)-2-chlorophenyl]2,5-dimethylbenzamide
533 N-{4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-chlorophenyl]- 2,6-dimathylbenzamide
106 (continued)
Exampla No. Compound
534 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazapin-10(11H)-ylcarbonyl)-2-chlorophenyl]- 2-chlorobanzamida
535 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-chlorophenyl]- 2,4-dichlorobanzamida
536 N-[4-(5H-pyrrolo[2,1 -c][1,4ļbenzodiazepin-10( 11 H)-ylcarbonyl)-2-chlorophenyl]2,5-dichlorobenzamida
537 N-[4-(5H-pyrrolo(2,1 -c][1,4]banzodiazepin-10(11 H)-ylcarbonyl)-2-chlorophanyl]3,5-dichlorobenzamide
53Θ N-(4-(5H-pyrrolo[2,1 -cj[1,4]banzodiazapin-l 0(11 H)-ylcarbonyl)-3-chlorophanylļ3-fluorobenzamide, amorphous solid
539 N-(4-(5H-pyrrolo[2,1 -c][1,4]banzodiazapin-10( 11 H)-ylcarbonyl)-2-chlorophanylJ-2-chloro4-fluorobanzamida
540 N-[4-(5H-pyrrolo[2,1-c][1,4]banzodiazapin-10(11H)-ylcarbonyi)-2-chlorophanyl]-2-mathyl- 4-chlorobanzamida
541 N-[4-(5H-pyrrolo(2,1-c][1,4jbenzodiazepin-10(11H)-ylcarbonyl)-2-chlorophanylJ-2-(methylthio) banzamida
542 N-[4-(5H-pyrrolo(2,1 -c][1,4Jbenzodiazepin-10(11 H)-ylcarbonyl)-2-chlorophenyl]2-ch lorobanzanaacatam ida
543 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-chlorophenyl]- 2-methylbanzaneacetamida
544 N-[4-(5H-pyrrolo(2,1-c][1,4]banzodiazepin-10(11H)-ylcarbonyl)-2-chlorophanyl]- 2-mathyithiophane-3-carboxyamida
545 N-[4-(5H-pyrrolo[2,1-c][l,4]banzodiazapin-10(11H)-ylcarbonyl)-2-chlorophanyl]- 3-mathylthiophena-2-carboxamide
546 N-[4-(5H-pyrrolo[2,1-c][1,4]banzodiazapin-10(1lH)-ylcarbonyl)-2-chlorophanyl]-3-ftuoro2-mathylbanzamida, m.p. 230-231 °C
547 N-[4-(5H-pyrrolo[2,1 -c][ 1,4]banzodiazapin-10( 11 H)-ylcarbonyl)-2-chlorophanyl]-5-fluoro2-malhylbanzamida, m.p. 178-180°C
548 N-[4-(5H-pyrrolo[2,1-c][1,4]banzodiazapin-lQ(11H)-ylcarbonyl)-2-chlorophenyl]- 2,3-dichlorobanzamida
549 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-chlorophanyl]2,3-difluorobanzam ide
550 N-(4-(5H-pyrrolo[2,1-c][1,4]banzodiazepin-10(11H)-ylcarbonyl)-2-chlorophanyl]-4-fluoro- 2-mathylbanzamide
551 N-[4-(5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10(11 H)-ylcarbonyl)-2-chlorophanyl]2-methoxybenzamida
552 N-[4-(5H-pyrrolo[2,1-c][1,4]banzodiazepin-10(11H-ylcarbonyt)-2-chlorophenyl]-2- (trifluoromathoxy)banzamide
553 N-(4-(5H-pyrrolo[2,1-c][1,4]banzodiaz8pin-10(11H)-ylcarbonyl)-2-chlorophertyl]-2-ma!hoxy- 4-chlorobanzamida
554 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-chlorophanyl]-2-(trifluoromathyl) banzamida
555 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-chlorophenyl]-3-(trifluoromBthyl) banzamida
556 N-[4-(5H-pyrrolo[2,1-c][1,4]banzodiazepin-10(11H)-ylcarbonyl)-2-ch!orophanyl]- 2,6-dichlorobanzamide
557 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-chlorophanyl]- 2,3,5-trichlorobanzamida
558 N-[4-(5H-pyrrolo[2,1-cļ[1t4]banzodiazapin-10(11H)-ylcarbonyl)-2-chlorophanyl]-2-fluoro-5- (trifluoromathyi)benzamida
559 N-[4-(5H-pyrrolo(2,1 -cJ[1 ,4]banzodiazepin-10(11 H)-ylcarbonyl)-2-chlorophanylļ-4-fluoro-2(trifluoromethyl)benzamide
107 /
(continued)
Example No. Compound
560 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(1lH)-ylcarbonyl)-2-chlorophenyl]-2-fluoro-3- (trifluoromethyl)benzamide
561 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-chlorophenyl]- 2,5-difluorobenzamide
562 N-(4-(5H-pyrrolo[2,1 -c][1,4]benzodiazepin-l0(l 1 H)-ylcarbonyl)-2,3-dichlorophenyl]-5-fluoro2-methylbenzamide
563 N-(4-(5H-pyrrolo[2,1 -c] [ 1,4]benzodiazepin -10( 11H )-y lcarbonyl)-2,3-dichlorophenyl]2,3-dimethylbenzamide
564 N-(4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2,3-dichlorophenyl]-3-fluoro- 2-methylbenzamide
565 N-(4-(5H-pyrrolo(2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2,3-dichlorophenyl]- 2,4-dichlorobenzamide
566 N-[4-(5H-pyrrolo[2,1-cj(1,4]benzodiazepin-l0(1lH)-ylcarbonyl)-2,3-dichlorophenyl]2,3-dichlorobenzamide
567 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2,3-dichlorophenyl]- 2-methylbenzamide
566 N-[4-(5H-pyrrolo[2,1-cJ[1,4]benzodiazepin-10(11H)-ylcarbonyl)-2,5-dichlorophenyl]-5-fluoro- 2-methylbenzamide
569 N-[4-(5H-pyrrolo{2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2,5-dichlorophenyl]2,3-dimethylbenzamide
570 N-[4-(5H-pyrrolo[2,1 -c][1,4]benzodiazepin-10(11 H)-ylcarbonyl)-2,5-dichlorophenyl]-3-fluoro2-methylbenzamide
571 N-(4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyi)-2,5-dichlorophenyll- 2,4-dichlorobenzamide
572 N-(4-(5H-pyrrolo(2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2,5-dichlorophenyl]- 2,3-dichlorobenzamide
573 N-(4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2,5-dichlorophenylJ- 2-methylbenzamide
574 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2,5-dichlorophenyl]2,3-dichlorobenzamide
575 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2,5-dichlorophenyl]- 2,5-dichlorobenzamide
576 N-[4-(5H-pyrrolo[2,1-cļ[1,4]benzodiazepin-10(11H)-ylcarbony!)-2,5-dichlorophenyl]-2-(methylthio) benzamide
577 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11 H)-ylcarbonyl)-2,5-dichlorophenyl]2-chlorobenzamide
578 N-(4-(5H-pyrrolo[2,1-c](1,4]benzodiazepin-10(llH)-ylcarbonyl)-2,5-dichlorophenyl]-2- (trifluoromethyl)benzamide
579 N-[4-(5H-pyrrolo[2,1-c][l,4]benzodiazepin-10(11H)-ylcarbonyl)-2,5-dichlorophenyl]-2- (trifluoromethoxy)benzamide
Example 560
2,4-Dichloro-N-[4-((3-formvl-5hl-pvrrolof2,1-cl[1,4ļbenzodiazepin-10(11hl)-vl)carbonvllphenyllbenzamide
To a soiution of 0.48 g of 2,4-dichloro-N-[4-(5H-pyrrolo[2,1 <][1,4]benzodiazepin-10(11H)-yl)carbonyl)phenyl]benzamide in 2 ml of N,N-dimethylformamide at 0°C is slowly added 0.3 ml of POCI3. The mixture is stirred at 0’C tor 30 minūtes and at room temperature for 1 hour. The final mixture is quenched with ice and made alkaline vvith 2 N NaOH to pH 12. The resulting precipitate is collected, vvashed vvith vvater and dried in vacuo to give 0.55 g ot solid. Further vvashing vvith 1:2 ether-isopropanol gives 0.50 g of vvhite solid. MS(CJ) calculated 503.0774;
found 503.0789.
108
Example 581
2.4- Dichloro-N-|4-ff3-(hvdroxvmethvl)-5ld-pvrrolo-f2,1-£l[1,4lbenzodiazBpin-10(l1hl)-vl1carbonvllphenvl)benzamide
To a suspension of 39 mg of NaBH4 in 1 ml of tetrahydrofuran is added 0.42 g of 2,4-dichioro-N-[4-[(3-formyl-5Hpyrrolo[2,1-aļ(1,4]benzodiazepin-10 (11 H)-yl)carbonyl]phenyl]benzamide and the reaction mixture stirred at room temperature for 18 hours and then quenched vvith vvater. The tetrahydrofuran is evaporated in vacuo and the aqueous residue treated vvith 5 ml of 1 N NaOH and extracted vvith 50 ml ot ethyl acetate. The organic extract is vvashed vvith brine, dried over Na2SO4 and evaporated to give 0.47 g ot a foam. Preparative thiek layer chromatography by eiution īo vvith 2:1 ethyl acetate-hexane gives 0.24 g of vvhite solid. MS(FAB): 488 (MH+-OH).
Example 582
2.4- Dichloro-N-t4-[f3-(1hl-imidazol-1-vlmethvl)-5H-DvriolQ[2..1^;lf1,4lbenzodiazepin-10(11iļ)-vl1-carbonvllPhenvll benzamide
To a suspension of 0.28 g of N,N-dimethylglycine hydrochloride in 5 ml of tetrahydrofuran is added 0.21 g of triethylamine and 0.35 g of carbonyldiimidazole. After stirring at room temperature for 30 minūtes and then heating at reflux for 18 hours, the tetrahydrofuran is evaporated jņ vacuo to a residue vvhich is dissolved in ethyl acetate and vvashed vvith vvater, saturated NaHCO3 and brine and dried over Na2SO4, filtered and evaporated in vacuo to a residue. The residue is vvashed vvith ether-hexanes (1:1) to give 0.17 g of vvhite solid. MS(FAB): 556(M+H).
Example 583 a-Chloro-N-f4-(5ļJ-pvrrolof2.1-c1f1,41benzodiazepin-lO(11iJ)-vlcarbonyl)phenvllbenzeneacetamide
To a solution of 0.61 g of 10,11 -dihydro-l 0-(4-aminobenzoy l)-5H-pyrrolo(2,1 -c][1,4]benzodiazepine in 8 ml of methvlene chloride is added 0.30 g of triethylamine follovved by 0.47 g of (±)-2-chloro-2-phenylacetyl chloride in 2 ml of msthylene chloride. The mixture is stirred at room temperature for 1 hour and then diluted vvith 10 ml of 50% NaHCOg. oo The methylene chloride is evaporated and the residue is extracted vvith ethyl acetate. The separated organic layer is vvashed vvith saturated NaHCOg and brine and then dried vvith Na2SO4 follovved by fiitering through a pad of hydrous magnesium silicate. The filtrate is evaporated to a residue vvhich is stirred vvith ether-hexane to give 0.98 g of pink solid. MS(CI): 456(M+H).
Example 584 a-[t2-(Dimethvlamino)ethvl1thio1-N-[4-(5J-i-ovrrolofP.l-c1f1,4ļbenzodiazepin-10(11ij)-vicarbonvl)phenvll benzeneacetamide
A mixture of 0.14 g of a-chloro-N-[4-(5H-pyrroio[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide, 0.47 g of 2-dimethylaminoethanethiol hydrochloride in 2 ml of methyl aicohol, 0.30 g of triethylamine and 3 ml ot 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is heated at 60°C for 48 hours. The methyl aicohol is evaporated and the residue diluted vvith vvater. The resulting suspension is filtered and the precipitate vvashed vvith vvater. The solid is dissolved in ethyl acetate and vvashed vvith saturated NaHCOg, brine and dried vvith Na2SO4. The mixture is filtered and the filtrate evaporated in vacuo to a residue vvhich is stirred vvith ether-hexane to give 0.15 g of beige solid. MS(Ci): 525(M+H).
Example 585 a-fN-(Acgtamido)amino1-N-f4-(5hi-pvrrolof2,1-c][1,41benzodiazepin-10(1lU)-ylcarbonvl)phenynbenzeneacetamide
A mixture of 0.14 g of a-chloro-N-(4-(5H-pyrrolo(2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenylļbenzeneacetamide,0,17gof glycinamide HCl, 0.15 gof triethylamine, 3mlof l,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 1 ml of methyl aicohol is heated at 75°C for 2 days. The methyl aicohol is evaporated and the residue diluted vvith vvater. The resulting suspension is filtered and the precipitate vvashed vvith vvater. The solid is dissolved in ethyl acetate and vvashed vvith saturated NaHCOg, brine and dried vvith Na2SO4. The mixture is filtered and the filtrate evaporated in vacuo to a residue vvhich is stirred vvith ether-hexanes to give 0.13 g ot tan solid. Ms(CI): 494(M+H).
109
Example 5S6 g-(Dimethylamino)-N-f4-(5hi-Pvrrolo|2,1-c)f1,4l-benzodiazepin-10(11Jd)-vlcarbonvl)phenvl1benzeneacetamide
A partial solution ot ??g of a-chloro-N-[4-(5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10(11 H)-ylcarbonyi)phenyl]benzaneacetamide in 1 ml of methanol is treated vvith 0.5 mi of dimethylamine and 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro2(1 H)-pyrimidinone and stirring continued for 20 hours. The methanol is evaporated and the residue diluted vvith vvater. The resulting solid is vvashed vvith vvater, dissolved in ethyl acetate and the organic layer vvashed vvith saturated NaHCO3, brine and dried vvith Na2SO4. The mixture is filtered and the filtrate evaporated in vacuo to give a residue to vvhich is stirred vvith ethyl acetate-hexane to give 0.15 g of a beige solid. MS(C1): 465(M+H).
Example 5S7 a-(Acetyloxv)-N-f4-(5H-Pvrrolof2,1 -£li 1,4lbenzodiazepin-10(1 1h)-ylcarbonyl)phenvHbenzeneacetamide is
To a solution ot 0.30 g of 10,11 -dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1 -c][ 1,4]benzodiazepine in 5 ml of methylene chloride is added 0.15 g ot triethylamine follovved by 0.27 g of O-acetylmandelic acid chloride. The mixture is stirred at room temperature for 1 hour and then diluted vvith 50% NaHCO3. The methylene chloride is evaporated and the residue is extracted vvith ethyl acetate. The separated organic layer is vvashed vvith saturated NaHCOj and brine 20 and then dried vvith Na2SO4 follovved by filtering through a pad of hydrous magnesium silicate. The filtrate is evaporated to a residue vvhich is stirred vvith ether-hexane to give 0.54 g of beige solid. MS(CI): 480(M+H).
Example 588
2S (±)a-Hvdroxv-N-f4-(5H-pyrrolof2,1 -£11 1,4ļbenzodiazepin-10(11 tl)-vlcarbonvl)phenvllbenzeneacetamida
A solution of 0.34 g of <x-(acetyloxy)-N-[4-(5H-pyrrolo[2,1 <][ 1,4]benzodiazepin-10(11 H)-ylcarbonyl)phenyl]benzeneacetamide in 2 ml of 1 N NaOH and 4 ml of methyl alcohol is stirred at room temperature for 30 minūtes, diluted vvith 2 ml ot vvater and evaporated in vacuo. The aqueous suspension is extracted vvith 30 ml of ethyl acetate and the extract vvashed vvith brine, dried vvith Na2SO4 and filtered through a pad of hydrous magnesium silicate and evaporated jn vacuo to a residue. The residue is stirred vvith ether-hexanes to give 0.26 g of cream colored sotid. MS(CI): 438(M+H).
Example 589
2-Chloro-N-f4-(5ļJ-pvrrolof2,1-clf1,4lbenzodiazepin-10(11lJ)-vlcarbonvl)phenvl1acetamide
To a stirred solution of 0.91 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo(2,1-c][1,4]benzodiazepine in 10 ml of methylene chloride is added 0.46 g ot triethylamine and 36 mg ot dimethylaminopyridine follovved by the slovv addition of 0.42 g of chloroacetyl chloride in 5 ml of methylene chloride. The resulting mixture is stirred at room tem40 perature for 3 hours then partitioned vvith 10 ml of 50% NaHCO3 and the methylene chloride evaporated in vacuo. The remaining suspension is filtered, vvashed vvith 50% NaHCO3, H2O, EtOAc (2x2 ml), ether (2x5 ml) and dried in vacuo to give 1.14 g of beige solid. MS(CI): 380(M+H).
Example 590
N-|4-(5ij-pyrrolof2,1 -clf 1,4lbenzodiazepin-10( 11Jd)ylcarbonvl)phenvH-4-morpholineacetamide
A stirred suspension of 0.19 g of 2-chloro-N-(4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyi)phenyl] acetamide in 1 ml of methylene chloride is added 0.44 g of morpholine follovved by 1 ml of 1,3-di- methyl-3,4,5,6-tetso rahydro-2(1 H)-pyrimidinone and stirring continued for 20 hours. The methylene chloride is evaporated and the residue diluted vvith vvater. The resulting suspension is filtered and the precipitate vvashed vvith vvater. The brovvn solid is dissolved in 15 ml of ethyl acetate and vvashed vvith saturated NaHCO3, brine and dried vvith Na2SO4. The mixture is filtered and the filtrate evaporated in vacuo to give 0.23 g of a colorless gum vvhich is stirred vvith ethyl acetate-hexanes to give 0.21 g of vvhite solid. MS(CI): 431 (M+H).
110
Example 591
N-ff2-Chlorophenvl)methyll-N-f4-f5iJ-pyrrolof2,1 -clf 1,4ļbenzodiazepin-1 Of 11Jd)-Vlcarbonyl)phenvll4-morpholineacetamide
A mixture of 0.11 g of N-[4-(5H-pyrrolo-[2,1 -c][ 1,4]benzodiazepin-10( 11 H)-ylcarbonyl)phenyl]-4-morpholineacetamide, 56 mg of 0-chlorobenzyl bromide and 0.41 g of KaCO3 in 5 ml of acetonitrile is heated at reflux for 18 hours. An additional 30 mg of O-chlorobenzyl bromide and 0.4 mmol of sodium hydride is added follovved by heating for 24 hours. The reaction mixture is diluted vvith vvater and extracted vvith ethyI acetate. The organic layer is dried vvith Na2SO4 and to evaporated to give 0.18 g of a residue vvhich is purified by chromatography on silica gel vvith 1:1 ethyl acetate-methylene chloride to give 80 mg of off vvhite solid. MS(CI): 555(M+H).
Example 592 ’S Ethvl 10-f4-f(2,4-dichlorobenzoyl)aminol-3-methylbenzoyll-10,11 -dihydro-5h-pyrrolof2,1 -clf 1,4ļbenzodiazepine3-carboxylate
To a solution of 0.30 g ot ethyl 10,11 -dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo(2,1 -c][1,4]benzodiazepine3-carboxylate in 20 ml of methylene chloride is added 0.15 g of N,N-diisopropylethylamine and 0.24 g of 2,4-dichlo20 robenzoyl chloride. The reaction mixture is stirred at room temperature for 18 hours and vvashed vvith vvater, saturated NaHCO3 and dried vvith Na2SO4. The organic layer is passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.24 g of solid, m.p. 174-184’C.
Exampls 593
Methvl 10-f4-(2.4-dichlorobenzoyl|amino1benzovll-10,n-dihvdro-5U-pyrrolof2.1-clf1,41benzodiazepine-3-carboxvlate
To 50 ml of absolute methyl alcohol is added 0.15 g of sodium mētai. After complete solution, 1.0 g of Nļ4-[[3(trichloroacetyl)-5H-pyrrolo(2,1-c][1,4]benzodiazepin-10(11hļ)-yl)ļcart)onyl]phenyl]-2,4-dichlorobenzamide is added and the reaction mixture stirred overnight at room temperature. Methylene chloride is added follovved by Na2SO4. The organic layer is filtered through hydrous magnesium silicate. Hexane is added at the boil to the filtrate to give 0.29 g of solid.
Examole 594
N-f4-ff3-(trifluoroacetvl)-5hl-pvrrolof2,1-clf1,4lbenzodiazepin-10(11hl)-vl)lcarbonvllphenvl|-2-(trifluoromethylļ benzamide
To a solution of 1.0 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]2-(trifluoromethyl) benzamide in 10 ml of methylene chloride is added 1.0 ml ol trifluoroacetic anhydride follovved by stirring for 18 hours at room temperature. The reaction mixture is washed vvith saturated NaHCO3, dried vvith Na2SO4, filtered and hexane added at the boil to give a solid vvhich is crystallized from methylene chloride-hexane. to give 0.89 g of solid, m.p. 248-250’C.
Example 595
N-|4-f[3-(Trtfluoroacetyl)-5fd-pvrrolof2,1-clf1,4lbenzodiazepin-10(11hl)-yl1carbonvlļ-3-chlorophenvll2methylbenzamide so Toa solution of 0.30 gof N-[4-(5H-pyrrolo-[2,1-c][1,4]benzodiazepin-lO(llH)-ylcarbonyl)-3-chlorophenyl]-2-methylbenzamide in 25 ml of methylene chloride is added 0.5 ml of trifluoroacetic anhydride follovved by stirring at room temperature for 18 hours. The reaction mixture is vvashed vvith salurated NaHCO3, dried vvith Na2SO4, filtered through hydrous magnesium silicate and hexane added to the filtrate at the boil to give 0.22 g of colorless solid. MS: M+551.
111
Example 596
Ethvl 10-f4-f(2.4-dichlorobenzovhamino1benzovl1l 0,11 -d)hydro-5H-pvrrolof2.1 -pļf 1.41benzodiazepine-3-cafboxyiate
To 50 ml of absolute ethyl alcohol is added 0.30 g of sodium mētai, follovved by the addition of 2.0 g of N-(4-[[3(trichloroacetyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)yl]carbonyl]phenyl]-2,4-dichlorobenzamideand the mixture is stirred for 18 hours at room temperature. The volatiles are evaporated iņ vacuo to a residue vvhich is dissolved in methylene chloride and vvashed vvith H2O. The organic layer is dried vvith Na2SO4 and filtered through hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give a solid vvhich is crystallized from methylene chloride-hexane to give 0.57 g of a solid. MS (M+):548.2.
Example 597
N-f4-ff3-(Trichloroacetyl)-5il-pvrrolof2,1-clf1.4ibenzodiazepin-10iim)-vl1carbonvllPhenvll-2-(trifluoromethvl) benzamide
To a stirred solution of 0.48 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-(trifluoromethyl)benzamide in 20 ml of methylene chloride is added 0.40 g of trichloroacetic anhydride follovved by stirring at room temperature for 18 hours. The reaction mixture is vvashed vvith vvater and saturated NaHCOg, dried over Na2SO4 and passed through a pad of hydrous magnesium silicate. Hexane is added at the boil to give 0.37 g of solid, m.p. 219-221’C.
Example 598
N-|4-f[3-(T richloroacetvl)-5H-pvrrolof2.1 tgH 1,41benzodiazepin-10( 11Jd)-vl|carbonyllphenyll-2.4-dichlorobenzamide
To a stirred solution of 4.76 g of N-[4-(5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10(11 H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide in 150 ml of methylene chloride is added 3.75 g of trichloroacetic anhydride follovved by stirring for 18 hours. The reaction mixture is vvashed vvith vvater and saturated NaHCOg, dried over Na2SO4 and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give 2.91 g of solid.
Example 599
N-f4-(5Jd-Pvrrolof2,1-c1f1.4lbenzodiazepin-l0(11hl)vlcarbonvnphenvl1-2,3.5-trichlorobenzamide
As described for Example 8, 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo(2,1-c][1,4]benzodiazepine is reacted vvith 0.483 g of 2,3,5-trichlorobenzoyl chloride to give a glass vvhich is crystallized from ethyl acetate to give 0.686 g of crystals‘, m.p. 231 -234'C.
Example 600
N-f4-(5ū-Pyrrolof2,1 -clf 1,4ļbenzodiazepin-10(11ļj)vlcarbonvl)phenvl1tetrahvdrolurane-2-carboxamide
As described for Example 8, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo{2,1-cl[1,4ļbenzodiazepine is reacted vvith 0.267 g of tetrahydrofurane-2-carbonyl chloride to give a glass vvhich is crystallized from ethyl acetate to give 0.22 g of crystals, m.p. 208-214C.
The follovving Examples are prepared using conditions of Exampie 297 vvith the appropriately substituted aroyl chloride.
Example No. Compound
601 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2,5-dichlorophenyl]2,3-dimethylbenzamide
602 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5ļbenzodiazepin-5-yl)carbonyl]-2,5-dichlorophenyl]2-ch lorobenzam ide
603 N-[4-[(6,7-Dihydro-5H-pyrrolo(1,2-a](1,5]benzodiazepin-5-yl)carbonylļ-2,5-dichlorophenyll- 2,4-dichlorobenzamide
112 (continued)
Example No. Compound
604 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2,5-dichlorophenyl]- 3,5-dichlorobenzamide
605 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-aļ[1,5]benzodiazepin-5-yl)carbonyl]-2,5-dichlorophenyl]2-methyl-4-chiorobenzamide
606 N-[4-((6,7-Dihydra-5H-pyrrOlo[1,2-aļ[1,5ļbenzodiazepin-5-yl)carbonyl]-3-chlorophenyl]- 2-methoxybenzamide
607 N-[4-[(6,7-Dihydro-5H-pyrrofo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]-2(trifluoromethoxy) benzamide
60Θ N-[4-[(6,7-Dihydro-5H-pyrrolo(1,2-a][1,5Jbenzodiazepin-5-yl)carbonyl]-3-chlorophenyl]-2(trifluoromethyl) benzamide
609 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][l,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]2,4-dichlorobenzamide, amorphous white solid, m.p. 134-137°C
610 N-[4-[(6,7-Dihydro-5H-pyrroio(1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]-2- (methylthio)banzamide
611 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonylJ-3-chlorophenyl]-3-fluoro2-methylbenzamide, amorphous vvhite solid, m.p. 136-138° C
612 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]-5-fluoro2-mathylbenzamide, amorphous solid, m.p. 132-135°C.
613 N-(4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]-4-fluoro2-methylbenzamide
614 N-[4-[(6,7-Dihydro-5H-pyrrolo(1,2-a][1,5]benzodiazepin-5~yl)carbonyl]-3-chlorophenyl]-4-fluoro-2- (trifluoromethyl)benzamide
615 N-[4-((6,7-Dihydro-5H-pyrro1o(1,2-a][1,5]bsnzodiazepin-5-yl)carbonyl]-3-chiorophenyl]2,3-dichlorobenzamide
616 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-aJ[1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]2,3-dif luorobenzam ide
617 N-{4-[(6,7-Dihydra-5H-pyrrolo[1,2-a][1,5lbenzodiazepin-5-yl)carbonyl]-3-chlorophenyl]-2-fluoro-5- (trifluoromethyl)benzamide
618 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]-2-fluoro-3- (trifluoromethyl)benzamide
619 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]-4-fluoro-2- (trifluoromethyl)benzamide
620 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenylJ- 2,5-difluorobenzamide
621 N-(4-[(6,7-Dihydro-5H-pyrrolo[ 1,2-a][ 1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]2,3-difluorobenzamide
622 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]- 2,5-dimethylbenzamide
623 N-(4-[(6,7-Dihydro-5H-pyrrolo[1>2-al[1,Sļbenzodiazepin-5-yl)carbonylļ-3-chlorophenyl]-3-methyl- 2-thiophenecarboxamide
624 N-[4-{(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]-2-methyl- 3-thiophenecarboxamide
625 N-[4-[(6,7-Dihydro-5H-pyrrolo[ 1,2-a][ 1,5Jbenzodiazepin-5-yl)carbonyl]-3-chlorophenyl]-2-methyl3-furanecarboxamide
626 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]-3-methyl- 2-furanecarboxamide
627 N-[4-[(6,7-Dihydro-5H-pyrrolo(1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]2-chlorobenzeneacetamide
628 N-(4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]- 2-methylbenzeneacetamide
629 N-[4-[(6.7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]-4-fluoro-3- (trifluoromethyl)benzamide
113 (continued)
Example No. Compound
630 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-chiorophenyl]-3-fluoro-
5 631 2-methylbenzamide N-(4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-chlorophenyl]2,3-dichlorobenzamida
10 632 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-chlorophenyl]- 2,3-difluorobenzamide
633 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonylļ-2-chlorophenyl]-4-fluoro- 2-methylbenzamide
634 N-[4-((6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-chlorophenyt]-5-fluoro- 2-methylbenzamide
15 635 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-chlorophenyl]-2-fluoro-5- (trifluoromethyl)benzamide
636 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-chlorophenyl]- 2-methylbenzamide
637 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-chlorophenyl]-
20 2-chlorobenzamide
638 N-(4-[(6,7-Dihydro-5H-py rrolo( 1,2-a][ 1,5]benzodiazepin-5-y l)carbonyl]-2-chloropheny 1]2,3-dimethylbenzamide
639 N-[4-[(6,7-Dihydro-5H-pyrrolo(1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-chlorophenyl]- 2,5-dlmethylbenzamide
25 640 N-[4-[(6,7-Dihydro-5H-pyrrolo(1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-chlorophenyll- 2-methoxybenzamide
641 N-[4-[(6,7-Dihydro-5H-pyrrolo(1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-chlorophenyl]-2- (trifluoromethoxy)benzamide
30 642 N-[4-[(6,7-Dihydro-5H-pyrrolo(1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-chlorophenyl]- 2-methoxy-4-chlorobenzamide
643 N-[4-[(6,7-Dihydro-5H-pyrrolo[1-,2-a][1,5Jbenzodiazepin-5-yl)carbonyl]-2-chlorophenyl]- 2,6-dichlorobenzamide
35 644 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-chlorophenyl]-2- (methylthio)benzamide
645 N-(4-((6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-chlorophenyl]-2- (trifluoromethyl)benzamide
646 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-chlorophenyl]-3- (trifluoromethyl)benzamide
40 647 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-chlorophenyl]- 2,3,5-trichlorobenzamide
648 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-methoxyphenyl]-3-fluoro- 2-methyibenzamide
649 N-(4-((6,7-Dihydro-5HI-pyrralo(1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-methoxyphenyl]-5-fluoro-
45 650 2-methylbenzamide N-[4-((6,7-Oihydro-5H-pyrrolo[1,2-aļ[1,5]benzodiazepin-5-yl)carbony!ļ-3-methoxyphenyl]-4-fluoro- 2-methylbenzamide
50 651 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-methoxyphenyl]- 2,4-dichlorobenzamide
652 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-methoxyphenyl]- 2,3-dimethylbenzamide
653 N-[4-[(6,7-Dihydro-5H-pyrroio[1,2-a][1,5]benzodiazepin-5-y1)carbonyl]-3-methoxyphenyl]-3-fltioro- 5-(trifluoromethyl)benzamide
55 654 N-[4-[(6,7-Dihydro-5H-pyrrolo[l,2-a][1,5]benzodiazepin-5-yi)carbonyl]-2-methoxyphenyl]-3-fluoro- 2-methylbenzamide
655 N-[4-[(6,7-Dihydro-5H-pyrrolo(1,2-a][1,5]benzodiazepin-5-y))carbonyl]-2-methoxyphenyl]-5-fluoro- 2-methylbenzamide
114 (continued)
Example No. Compound
656 N-[4-[(6,7-Dihydro-5JH-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-methoxyphenyl]-4-fluoro- 2-methylbenzamide
657 N-[4-[(6,7-Dihydro-5H-pyrrolo[ 1,2-a][ 1,5]benzodiazepin-5-yl)carbonyl]-2-methoxyphenyl]2,4-dichlorobenzamide
658 N-[4-[(6,7-Dihydro-5jļ-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-2-methoxyphenyl]2,3-dimethy Ibenzamide
659 N-[4-[(6,7-Dihydro-5j4-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbony!]-2-methoxyphenyl]-3-fluoro- 5-(trifluoromethyl)benzamide
Example 660
N-f4-f[f3-[-f(Dim9lhvlamino)methyll-5 U-pyrroloi2,1 -clf 1,4ļbenzodiazepin-1 Of 1 IļD-vHcarbonvilphenvIl2-methvlbenzamide
To a stirred solution of 0.842 g of 2-methyl-N-[4-(5H-pyrrolo[2,1-c][l ,4ļbenzodiazepin-10(11H)-ylcarbonyl)phenyl] benzamide in 25 ml of 1:1 methanoltetrahydrofuran is added 10 ml of 35% formaldehyde and 10 ml of 30% N,Ndimethylamine at 0°C. After 2 drops of acetic acid is added, the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated jņ vacuo to a residue vvhich is dissolved in chloroform and vvashed vvith vvater. The organic layer is dried vvith Na2SO4 and evaporated in vacuo to a residue. The residue is chromatographed on silica gel with 10:1 ethyl acetate-methanol as eluent to give 0.800 g of the desired product, M+H:479.
The following products are prepared by using the condition of Example 660 and by using the appropriately substituted benzamide.
Example No. Compound
661 N-[4-[[3-(1-piperidinylmethyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11jd)-yl]carbonyl]phenyl]2-methylbenzamide, solid; mass spectrum (M+H) 518
662 N-[4-[[3-(4-morpholinomethyl)-5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10(11 H)-yl]carbonyl]phenylj2-methylbenzamide, solid; mass spectrum (M+H) 521
663 N-[4-[[3-[[4-(phenylmethyl)-1 -piperaziny l]methyl]-5JH-pyrrolo[2,1 -c][1,4]benzodiazepin-10(11 jd)-yl] carbonyl]phenyl]-2-methylbenzamide, solid; mass spectrum (M+H) 610
664 N-[4-[[3-[(dimethylaminomethylJ-5jH-pyrrolo[2,1-c][1,4]benzodiazepin-10(11jj)-yl]carbonyl] phenyl]-2,4-dichlorobenzamide, solid; mass spectrum (M+H) 535
665 N-[4-[[3-(1 -pyrrolidiny lmethy l)-5jd-pyrrolo(2,1 -c][ 1,4]benzodiazepin-10(11 H)-yl]carbonyl]pheny I]2,4-dichlorobenzamide, solid; mass spectrum (M+H) 561
666 N-[4-[(3-(4-morpholinomethyl)-5jH-pyrrolo[2,1-c][1,4]benzodiazepin-l0(11H)-yl]carbonyl]phenyl]2,4-dichlorobenzamide, solid; mass spectrum (M+H) 576
667 N-[4-([3-[(diethylamino)methyl]-5jH-pyrrolo[2,1-cJ[1,4]benzodiazepin-10(11H)-yl]carbonyl]phenyl]2,4-dichlorobenzamide, solid; mass spectrum (M+H) 562
668 N-[4-[[3-[(dimethylamino)methyl]-5jj-pyrrolo[2,1-c][1,4]benzodiazepin-10(11ld)-yl]carbonyi]3-chlorophenyl]-5-fluoro-2-methylbenzamide, solid; mass spectrum (M+H) 531
669 N-[4-[[3-((dimethylamino)methyl]-5IH-pyrralo(2,l-c][l,4]benzodiazepin-lO(11jj)-ylJcarbonylJ3-chlorophenyl]-2-methylbenzamide, solid; mass spectrum (M+H) 513
Example 670
N-r4-f(3-Acetyl-5iļ-pvrrolof2,1-c1f1.4lbenzodiazepin-10(11hļ)-vlļcarbonvllphenvH-2,4-dichlorobenzamide
A stirred solution of 0.954 g of N-[4-(5jj-pyrroloļ2,1-c)[1,4]benzodiazepin-10(11jH)-ylcarbonyl)phenylj-2,4-dichlorobenzamide in 25 ml of methylene chloride and 5 ml of acetic anhydride is heated at reflux for 24 hours. The volatiles are evaporated in vacuo to a residue vvhich is purified by column chromatography on silica gel by eiution vvith ethyl acetate-hexane (7:3) to give 0.800 g of a vvhite solid; mass spectrum (M+H) 519.
115
Example671
1-l2-Nilro-5-(ethoxvcarbonvl)benzvll-pvrrole-2-carboxaldehyde
To a stirred slurry ol 2.2 g of sodium hydride (60% in oil, vvashed vvith hexane) in tefrahydrofuran is added at 0’C a solution of 4.5 g ot pyrrole-2-carboxaldehyde in 25 ml of tetrahydrofuran. After the addition is complete, a solution of 15 g of ethyl 4-nitro-3-bromomethyibenzoate in 30 ml of dry tetrahydrofuran is slowly added under nitrogen. The reaction mixture is stirred at 20’C for 8 hours and carefully quenched vvith vvater. The reaction mixture is extracted vvith chloroform vvhich is vvashed vvith vvater, dried vvith Na2SO4 and concentrated in vacuo to give 12 g of the desired product as a solid; mass spectrum (M+H)349.
Example 672
1-[2-Nilro-4-(ethoxvcarbonvl)benzyll-pyrrole-2-carboxaldehvde
The conditions of Example 671 are used vvith ethyl 3-nitro-4-bromomethylbenzoate to give 13.0 g of the desired product as a solid; mass spectrum (M+H)349.
Example 673
Ethvl 10,11-Dihydro-5lļ-Pvrrolo[2,1-Glf1,41benzodiazepine-7-carboxvlate
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 hours under 40 psi of hydrogen. The reaction mixture is filtered through a pad of diatomaceous earth and the filtrate concentrated in vacuo to a residue of 5.5 g of the desired product as a solid; mass spectrum (M+H)255.
Example 674
Ethvl 10,11 -Dihydro-5hl-pvrrolof2,1 -clf 1,4ļbenzodiazepine-8-carboxylate
The hydrogenation conditions of Example 673 are used vvith l-[2-nitro-4-(ethoxycarbonyl)benzyl]pyrrole-2-carboxaldehyde to give 5.0 g of the desired product as a solid; mass spectrum (M*H)255.
Example 675
Ethvl 10,11-Dihvdro-10-(4-l(2-methvlbenzovhaminolbenzovll-5iJ-Pvrrolo[2,1-i:ll1,4ļbenzodiazepine-7-carboxylate
A solution of 1.2 g of ethyl 10,11-dihydro5H-pyrrolo[2,1 -c][1,4)benzodiazepine-7-carboxylate in 100 ml of methylene chloride is cooled to 0’C and 10 ml of triethylamine added follovved by 1.5 g of 4-[(2-methylbenzoyl)amino)benzoyl chloride. The reaction mixture is stirred at room temperature for 13 hours and concentrated in vacuo to a residue vvhich is partitioned betvveen vvater and chloroform. The organic layer is dried over NajSC^ and concentrated jņ vacuo to a residue. The residue is purified by column chromatography on silica gel by elution vvith 40% ethyl acetate-hexane to give 1.0 g of the desired product as a solid; mass spectrum (M+H)494.
Example 676
Ethvl 10,11 -Dihydro-10-f4-f(2-methvlbenzoyl)aminolbenzoyll-5jj-pyrrolof2,1 -clf 1,41benzodiazepin-8carboxylate
The conditions of Example 675 are used vvith ethy110,11 -dihydro-5H-pyrrolo(2,1-c][1,4ļbenzodiazepine-8-carboxylate to give 1.2 g of the desired product as a solid; mass spectrum (M*H)494.
The subject compounds of the present invention are tested for biological activity as follovvs:
Example 677
10,11 -Dihvdro-10-(4-nitrobenzoyl)-5hl-imidazof2,1 -£lf 1,4ļbenzodiazepine
A 292 mg sample of sodium hydride in oil is vvashed, under argon, vvith pentane. The residue is diluted vvith 17 ml
116 ol dioxane and than 1.35 g of 10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine is added. The reaction mixture is vvarmed slighfly until the hydrogen evolution ceases. To !he cooled reaction mix!ure is added a solution of 1.36 g of pnitrobenzoyl chloride in 45 ml of dioxane and the mixture is stirred at room temperature for 16 hours. The solvent is evaporated in vacuo and the residue is heated vvith CHCI3, filtered hot and the filter cake vvashed vvith hot CHCI3. The combined CHCI3 layers are vvashed vvith vvater, saturated NaHCO3, treated vvith activated charcoal, filtered through a pad of MgSO4 and the filtrate evaporated jņ vacuo to give 1.92 g of brovvn solid residue. The residue is purified by flash chromatography by elution vvith CHCI3-MeOH to give 630 mg of the desired product as a solid. HR FABMS:(M+H) =335.3433.
Example 678
10,11 -Dihvdro-10-(4-aminobenzoyl)-5ij-imidazof2,1 -alf 1,4ļbenzodiazepine
A mixture of 0.550 g of 10,11-dihydro-10-(4-nitrobenzoyi)-5H-imidazo(2,1-c][1,4]benzodiazepine and 1.86 g of SnCI2.2H2O in 22 ml of ethyl aicohol is refluxed for 1 hour under argon. The mixture is diluted vvith vvater and then a solution of 10% NaHCO3 is added until the reaction mixture is basie. Additionai ethyl aicohol is added and reaction mixture evaporated in vacuo to give a residue vvhich is triturated vvith 1:1 CHCI3-CH3OH several times and filtered. The filtrates are combined, treated vvith activated carbon and filtered through diatomaceous earth. The filtrate is evaporated jn vacuo to give 680 mg of tan crystalline solid. The solid is stirred in ethanol, vvater and 10% NaHCC^ to pH=8, for 5 hours and extracted vvith CHCI3 three times. The combined extracts are treated vvith activated carbon, filtered through MgSO4 and evaporated in vacuo to give 370 mg of tan crystalline solid. CIMS (CH4): MH+=305.
Example 679
N-f4-(5fcl-lmidazo|2,1 -plf 1,4ļbenzodiazepin-10( 11 iJ)vlcarbonvl)phenvl1-2,4-dichlorobenzamide
Aslurry of 0.330 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine in 15 ml of dioxane is stirred and vvarmed slightly to obtain a nearly complete solution. The reaction mixture is cooled to room temperature and 43 mg of sodium hydride in oil added. The mixture is vvarmed slightly. Gas evolution stops in a fevv minūtes. The reaction mixture is cooled to room temperature and 153 μΙ ot 2,4-dichlorobenzoyl chloride in 2.5 ml of dioxane added. An additional 3.5 ml of dioxane is added and the reaction mixture stirred at room temperature for 2 days. The volatiles are evaporated jņ vacuo to a residue vvhich is partitioned betvveen vvater and chloroform. The organic layer is separated and the aqueous phase extracted vvith chloroform tvvo more times. The combined organic layers are trated vvith activated carbon and filtered through MgSO4. The filtrate is evaporated in vacuo to a tan foam vvhich is purified by flash chro- matography on silica gel by elution vvith CHCI3 and 3-7% CH3OH in chloroform to give 310 mg of tan foam.
Example 680
6.7- Dihydro-5-(2-chloro-4-nitrobenzoyl)-5hl-pvrrolofl,2-a1[1,5lbenzodiazepine
To a solution of 0.28 g of 6,7-dihydro-5JHpyrrolo[1,2-a][1,5ļbenzodiazepine in 6 ml of methylene chloride is added 0.30 g of triethylamine follovved by 0.50 g of 2-chloro-4-nitrobenzoyi chloride in 0.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 1 hour then quenched vvith 5 ml of saturated NaHCOj. The methylene chloride is evaporated in vacuo and the residue is diluted vvith 5 ml ot vvater and extracted vvith 20 ml of ethyl acetate. The organic layer is separated, vvashed vvith saturated NaHCO3 and brine, dried vvith Na2SO4 and evaporated in vacuo to give 0.59 g of a yellow foam vvhich is triturated vvith ether-hexanes to give 0.56 g of the desired product as off-white solid. MS(CI): 368 (M+H) (Cl35)
370(M+H) (Cl37)
Exarople 681
6.7- Dihydro-5-(4-amino-2-chlorobenzoyl)-5ht-pyrrolofl ,2-alf 1,5ļbenzodiazepine
To a solution of 0.50 g of 6,7-dihydro-5-(2-chloro-4-nitrobanzoyl)-5H-pyrrolo(1,2-a][1,5]benzodiazepine in 10 ml of ethyl aicohol and 2 ml of tetrahydrofuran is added 2.35 g of SnCI2.2H2O and the mixture slirred at 55’C for 30 minules. The solvents are evaporated in vacuo to a residue vvhich is stirred vvith 20 ml of 1 N NaOH and 40 ml of ethyl acetate for 15 minūtes and filtered through diatomaceous earth. The filter pad is vvashed vvith 2x10 ml of ethyl acetate and the combined extracts vvashed vvith brine, dried (Na2SO4) and evaporated in vacuo to give 0.47 g of solid residue vvhich
117 is triturated vvith ether-hexans to give 0.43 g of light yellow crystalline solid.
MS(CI): 338(M+H, Cl35)
340(M+H, Cl37) ® Example 682
N-f4-f(6,7-Dihydro-5fcl-Pvrrolof'l.2-alf1,5lbenzodiazepin-5-yl)carbonvll-3-chlorophenvH-3-fluoro-2-methvlbenzamida
To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo-[1,2-a][ 1,5]benzodiazepine and 0.06 g ol triethylamine in 6 ml of dichloromethane is added 0.08 g of 3-fluoro-2-methylbsnzoyl chloride in 0.5 ml ot dichloromethane. The mixture is stirred for 2 hours at room temperature and then 2 ml of 1 Ņ NaOH added. The volatiles are evaporated under vacuum and the residue dissolved in 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture is stirred lor 2 hours and evaporated and the residue diluted vvith 2 ml of 1 N NaOH and 5 ml of vvater. The mixture Is extracted vvith ethyl acetate (15 ml) and the extract vvashed vvith brine and dried (Na^O*). The solvent is removed is and the residue triturated vvith diethyl ether-hexane to give 0.15 g of vvhite solid; Mass Spectrum (CI)474(M+H, Cl35);
476(M+H, Cl37).
Example 683 20 N-f4-[f6,7-Dihvdro-5H-pvrrolof1.2aļf1,5lbenzodiazepin-5-vl1carbonvl1-3-chlorophenvll-2.4-dichlorobenzamide
To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine and 0.06 g of triethylamine in 6 ml of dichloromethane is added 0.10 g of 2,4-dichlorobenzoyl chloride in 0.5 ml ol dichloromethane. The mixture is stirred at room temperature for 2 hours and 2 ml of 1 N NaOH is added. The volatiles are removed under vacuum and to the residue is added 2 mi of tetrahydroluran and 1 ml of methanol. The mixture is stirred at room temperature for 2 hours and the volatiles removed. To the residue is added 2 ml ol 1 N NaOH and 5 ml of H2O. The mixture is extracled vvith ethyI acetate and the extract vvashed vvith brine and dried (Na2SO4). The solvent is removed and the solid triturated vvith dielhyl ether-hexane to give 0.15 g of vvhite solid, Mass Spectrum (Cl): 510(M+H, CI3S).
oo Example 684
N-|4-(5h(-Pvrrolol2,1 -cll 1.4ļbenzodiazepin-10(11 ļj)ylcarbonvl)phenyl1-2-i 1ļļ-| 1,2,4ļ-triazol-1 -vllacetamide
To a suspension of 0.20 g of 1,2,4-triazole sodium in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone is added 0.10 g of 2-chloro-N-[4-(5H-pyrrolo(2,1 <][1,4]benzodiazepin-10(11 H)-ylcarbonyl)phenyl]acetamide in 1 mi of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone follovved by stirring at room temperature for 3 hours. Tha reaction mixture is quenched vvith 15 ml ot vvater and the resulting solid is collected, vvashed vvith vvater and hexanes to give 70 mg of the desired product as a tan solid.
MS(CI): 413(M+H).
Ettample 685
N-f4-(5H-Pyrrolof2.1 -clfļ ,4]benzodlazepin-10(11ļj)vlcarbonvl)phenvll-2-(2-lormvl-1 -pvrroloļacetamide
To a suspension ol 72 mg of sodium hydride (60% in oil) in 5 ml of tetrahydrofuran is added 0.14 g ol pyrrole2-carboxaldehyde. The mixture is stirred for 1 hour at room temperature and 94 mg of 1,3-dimethyl-3,4,5,6-tetrahydro2(lH)-pyrimidinone and 0.19 g of 2-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin10(11H)-ylcarbonyl)phenyl] acetamide added. The mixture is stirred at room temperature, vvater added and the tetrahydrofuran evaporated jn vacuo. The resulting suspension is filtered and the precipitate vvashed vvith vvater and hexanes. The collected solid is so purified by column chromatography on silica gel by elution vvith 3:2 ethyl acetate-hexanes to give 50 mg of pink solid.
MS(CI): 439(M+H).
£xample 686
N-(4-(3-Chloro-4Jj-Pvrazoiof5,l£ll1.4lbenzodiazepin-5-f10kl)-vlcarbonvl)phenvll-2-methyl-5-fluorobenzamide
A mixture of 356 mg of N-[4H-pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)-3-chlorophenyl]5-fluoro2-methylbenzamide and 122 mg ol N-chlorosuccinimide in 5 ml ol methylene chloride is refluxed on a steam bath for
118 hours. The reaction mixtura is vvashed vvith saturated NaHCOa, H2O and brine, than driad ovar Na2SO4 and passed through a pad of hydrous magnesium silicate. Tha filtrate is evaporated in vacuo to giva 190 mg of tha dasirad product as a solid.
Tha follovving axamples are prepared using the conditions of Exampla 465.
Exampla No. Compound
687 Ņ-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-bromobanzamide, vvhite
solid
10 688 Ņ-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phanylļ-2-(acetoxy)benzamide, light yellow solid
689 Ņ-[4-(5H-pyrrolo[2,1-c][l ,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-hydroxybenzamide, light yellow solid
690 Ņ-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(l1H)-ylcarbonyl)phenyl]-1-naphthylcarboxamide,
15 vvhite solid
691 Ņ-[4-(5H-pyrrolo[2,1 -c][ 1,4jbenzodiazepin-10( 11 H)-ylcarbonyl)-3-methylphenylJ2-mathylbanzamide, amorphous solid
692 Ņ-[4-(5H-pyrrolo[2,1 -c][1,4]benzodiazepin-10(11 H)-ylcarbony l)phenyl]-2-chloro4-fluorobenzamide, vvhite foam
20 693 Ņ-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(l1H)-ylcarbonyl)phenyl]-2-(trifluoromethyl)4-fluorobenzamide, vvhite solid
694 Ņ-(4-(5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10(11 H)-ylcarbonyl)-3-methylphenyl]-5-fluoro2-methylbenzamide, m.p. 1S0-182“C
695 Ņ-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-l0(11H)-ylcarbonyl)-3-methoxyphenyi]-5-fluoro-
696 2-methylbenzamide, amorphous solid Ņ-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-l0(1lH)-ylcarbonyl)-3-chlorophanyl]-2-fluoro-4 (trifluoromethyl) benzamide, m.p. 140-154°C
697 Ņ-[4-(5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10( 11 H)-ylcarbonyl)-3-chlorophenylJ-
30 698 2-methylbenzeneacetamide, vvhite glass Ņ-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]-2-fluoro-6(trifluoromethyl) benzamide, vvhite solid, m.p. 150-230’C
699 Ņ-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]-2-fluoro-3(trifluoromethyl) benzamide, vvhite glass
35 700 Ņ-[4-(5H-pyrrolo[2,1 -c][ 1,4]benzodiazepin-10(11 H)-ylcarbonyl)-3-chlorophenyl]-2-chloro-5(methylthio) benzamide, vvhite crystals, m.p. 124-134°C
701 Ņ-(4-(5H-pyrrolo(2,1-c][1,4]benzodiazepin-lO(11H)-ylcarbonyl)-3-chlorophenyl]2,5-dimethylbenzamide, crystalline solid, m.p. 253-255°C
702 Ņ-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]-2-chloro-
40 703 3,4-dimethoxybenzamide, yellow foam Ņ-[4-(5H-pyrrolo[2,1-c]{1,4]benzodiazpin-10(11H)-ylcarbonyl)-6-chloro-3-mathoxyphenyl]2-methylbenzamide, crystals, m.p. 214-215°C
45 704 Ņ-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-math0xy phenyl]- 2,5-dimethyibenzamide, crystals, m.p. 174-175°C
705 Ņ-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-chloro3,4-dimethoxybenzamide, vvhite crystals, m.p. 242-244’C
706 Ņ-[4-(5H-pyrrolo(2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenylJ-2,5-dimathyibenzamida, crystais, m.p. 158-160’C
50 707 Ņ-[4-(5H-pyrrolo[2,1-cJ[l ,4]benzodiazepin-10(l1 H)-ylcarbonyl)-3-chlorophenylJ-2(trifluoromethyl)-4-fluorobenzamide, vvhite glass
Example 708 ss Methvl 4-f2-(2-chlorophenvl)-2-cvano-2-(4-morpholinyl)e!hylfbenzo3te
A 0.876 g sample of 60% sodium hydride in oil is vvashed vvith hexane follovved by tha addition of 60 ml of dry N, N-dimethylformamida. Tha reaction mixtura is stirred for 1 hour undar argon at room temperatūra after tha addition of
119
4.73 g of a-(2-chlorophenyl)-4-morpbolineacetonitrile. To the reaction mixture is added 4.5S g of methyl 4-(bromomethyl)benzoate and stirring continued for 3 hours. Several drops of acetic acid is added to ice vvater and the reaction quenched. The pH is 3-4 and saturated NaHCO3 added to adjust the pH to 6-7. Upon cooling a solid forms vvhich is filtered, vvashed vvith vvater and dried to give 5.92 g of yellow solid. Crystallization from methylene chloride-hexane s gives 2.10 g of the desired product as a crystaliine solid, m.p. 116-118°C.
Example 709
Methvl 4-f2-(2-chlorophenvl)-2-oxoethyl|benzoate īo
A mixture of 1.0 g of methyt [4-(2-chlorophenyl)-2-cyano-2-(4-morpholinyl)ethyl]benzoate and 14 ml of vvater is heated at reflux for 20 minūtes then poured over crushed ice. After stirring for 15 minūtes the resulting solid is collected, vvashed vvith vvater and air dried to give 0.63 g of tan solid, m.p. 40-42°C.
Example 710
4-(2-(2-Chlorophenyl)-2-oxoethyl1benzoic acid
A mixture of 18.78 g of methyl 4-[2-(2-chlorophenyl)-2-oxoethyl]benzoate in 288.8 ml of CH3OH, 72.2 ml of vvater 20 and 5.2 g of NaOH is refluxed for 3 hours then acidified vvith 2 N citric acid. The reaction mixture is evaporated jņ vacuo to remove the CH3OH. The aqueous phase is extracted vvith CH2CI2 and acidified vvith 1 N HCI. The resulting solid is collected and dried under vacuum to give 17.27 g of the desired product, m.p. 168-172°C.
Example 711 25
3-Methoxv-4-nitrobenzoyl chloride
A stirred suspension of 1.0 g of 3-methoxy-4-nitrobenzoic acid and 1.40 ml of thionyl chloride is heated fo reflux for 2 hours. The mixture is cooled to room temperature, 2 ml of iso-octana added and the mixture evaporated in vacuo to a solid residue. The residue is vvashed vvith iso-octane (2x2 ml), dried in vacuo to give 1.08 gof creamcolored solid.
Example 712
10,11 -Dihvdro-10-(4-nitro-3-methoxvbenzoyl)-5H-pvrrolofP 1 -cļf 1,4ļbenzodiazepine 35
To a solution of 0.55 g of 10,11 -dihydro-5hļ-py rrolo[2,1 -c][ 1,4]benzodiazepine in 8 ml of methylene chloride is added 0.55 g of triethylamine follovved by 0.97 g of 3-methoxy-4-nitrobenzoyl chloride. The reaction mixture is stirred at room temperature for 2 hours and then quenched vvith 10 ml ol 1 N NaOH. The methylene chloride layer is evaporated and the resulting suspension filtered. The precipitate is vvashed vvith 1 N NaOH (2x5 mt), vvater (3x5 ml) and hexane (2x5 ml). The collected solid is dried jņ vacuo to give 1.13 g o( off-white solid. MS(CI); 364(M+H).
Example 713
10,n-Dihvdro-10-(4-amino-3-methoxybenzovl)-5ļ|-pvrrolof2,1-c]f1,4lbenzodiazepine
Amixtureof0.91 gof 10,11-dihydro-10-(4-nitro-3-methoxybenzoyl)-5jj-pyrrolo[2,1-c][1,4]benzodiazepine, 4.51 g of SnCIj^HjO, 6 ml of ethyl alcohol, 6 ml of tetrahydrofuran and 16 ml of methylene chloride is stirred at 50°C for 2 hours. The solvents are evaporated in vacuo and the residue dissolved in 80 ml of ethyl acetate. The solution is treated vvith 50 ml of 1 N NaOH vvith stirring for 30 minūtes. The resulting suspension is filtered through diatomaceous earth. so The pad is vvashed vvith ethyl acetate (3x15 ml). The combined ethyI acetate Solutions are vvashed vvith brine, dried (Na2SO4), filtered through hydrous magnēsium silicate and evaporated jņ vacuo to 0.99 g of residue vvhich is stirred vvith ether-hexanes to give 0.90 g of cream colored solid. MS(CI): 334 (M+H).
Example 714 55
10,11 -Dihvdro-10-[4-f (3-methvlpropvloxvcarbonyl)aminolbenzoyll-5hļ-pvrrolof2,1 -ali 1,41benzodiazepine
Toa stirred solution of 0.15 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 2 ml
120 of methylene chloride is added 0.10 g of triethylamins follovved by 0.10 g of isobutylchloroformate. The reaction mixture is stirred for 3 hours and then quenched wiih 1 N NaOH. The organic layer is evaporated in vacuo to a residue vvhich is stirred in 5 ml of tetrahydrofuran for 1 hour, then evaporated jņ vacuo to a residue. The residue is extracted vvith ethyl acetate-methylene chloride, vvashed vvith brine, dried (Na2SO4), filtered through hydrous magnesium siiicate and evaporated in vacuo to give a residue vvhich is stirred vvith ethyl acetate-methylene chloride to give 0.22 g of cream colored solid. MS(CI): 404(M+H).
Example 715
10,11 -Dihvdro-10-f4-(pentanovl)aminobenzoyl)l-5hl-pvrrolof2,1 -slf 1,4ļbenzodiazepine
To a stirred solution of 0.15 g of 10,11 -dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1 -c][1,4]-benzodiazepine in 2 ml of methyfene chloride is added 0.10 g of triethylamine follovved by 0.09 g of valeryl chloride. The reaction mixture is stirred for 3 hours and then quenched vvith 4 ml of 1 N NaOH. The methylene chloride is evaporated in vacuo and the residue dissolved in 5 ml of tetrahydrofuran tor 1 hour and evaporated in vacuo to a residue. The residue is extracted vvith ethyl acetate-methylene chloride, vvashed vvith brine and the organic layer dried (Na2SO4), filtered through hydrous magnesium siiicate, and evaporated jņ vacuo to give 0.23 g of a residue vvhich is stirred vvith ether-hexanes to give 0.19 g of a vvhite solid.
MS(CI); 388 (M+H).
Example 716
10,11 -Dihvdro-10-f4-[(3-methvlbutanoyl)aminoļbenzoy l]-5hļ-pyrrolof2,1 -clf 1,4ļbenzodiazepine
To a stirred solution of 0.10 g of 10.11-dihydro-i0-(4-amino-3-methoxybenzoyl)-5H-pyrrolo(2,1-c] (1,4]benzodiazepine in 1 ml of methylene chloride is added 0.06 g of triethylamine followed by 0.05 g of iso-valeryl chloride. The reaction mixture is stirred for 3 hours and then quenched vvith 1 N NaOH. The organic layer is evaporated in vacuo to a residue vvhich is stirred in 5 ml of tetrahydrofuran for 1 hour, then evaporated in vacuo to a residue, The residue is exlracted vvith ethyl acetate-methylene chloride, vvashed vvith brine, dried (NajSO^, filtered through hydrous magnesium siiicate and evaporated in vacuo to give 0.15 g of residue vvhich is stirred vvith ether-hexane to give 0.13 g of light yellow solid. MS(CI): 418(M+H).
Example 717
10,11-Dihvdro-10-f3-methoxv-4-f(butvlsulfonyl)aminoļbenzoylļ-5H-pyrroio[2,1-c1f1,4ļbenzodiazepine
To a stirred solution of 0.10 g of 10,l1-dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo(2,1-c] [1,4]benzodiazepine in 2 ml of methylene chloride is added 60 mg of triethylamine follovved by a solution of 56 mg of n-butylsulfonyl chloride inO.5 ml of methylene chloride. After stirring at room temperature for 2 hours, the reaction mixture is evaporated in vacuo to a residue vvhich is dissolved in methyl alcohol, stirred for 1 hour and evaporated in vacuo to a residue vvhich is treated vvith 2 ml of NH4CI and extracted vvith 15 ml of ethyl acetate. The organic extract is vvashed vvith saturated NaHCOg, brine, dried (Na2SO4), filtered through hydrous magnesium siiicate and the filtrate evaporated toa residue. The residue is stirred vvith ether-hexanes to give 0.14 g of light yellovv solid. MS(CI): 454(M+H).
UTILITY TESTING
Binding Assav to Rāt Hepatic V, Receptors
Rat liver plasma membranes expressing the vasopressin V, receptor subtypes are isolated by sucrose density gradient according to the method described by Lesko et al., (1973). These membranes are quickly suspended in 50.0 mM Tris.HCi buffer, pH 7.4, containing 0.2% bovine serum albumin (BSA) and 0.1 mM phsnylmethylsulfonylfluoride (PMSF) and ķept frozen at -70°C until used in subsequent binding experiments. Fcr binding experiments, the follovving is added to the vvells of a ninety-six vvell format microtiter plate; 100μ1 oi 100.0 mM Tris.HCi buffer containing 10.0 mM MgCI2, 0.2% heat inactivated BSA and a mixture of protease inhibitors: leupeptin, 1.0 mg %; aprotinin, 1.0 mg %; 1,1 O-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mM PMSF, 20.0 μΙ of [phenylalanyl-3,4,5,-3H] vasopressin (S.A. 45.1 Ci/mmole) at 0.8 nM, and the reaction initiated by the addition of 80 μΙ of tissue membranes containing 20 gg ot tissue protein The plates are ķept undisturbed on the bench top at room temperature for 120 min. to reach equilibrium. Non-specific samples are assayed in the presence of 0.1 μΜ of Ihe unlabeled antagonist pheny121 lalanylvasopressin, added in 20.0 μΙ volume.
For tēst compounds, these are solubiiized in 50% dimethyisulfoxide (DMSO) and added in 20.0 μΐ volume to a finai incubation volume of 200 μΙ. Upon completion of binding, the content of each vvell is filtered off, using a Brandel® celi Harvester (Gaithersburg, MD). The radioactivity trapped on the filter disk by the ligand-receptor complex is ass sessed by liquid scintillation counting in a Packard LS Counter, with an efficiency of 65% for tritium. The data are analyzed for IC50 values by the LUNDON-2 program for competition (LUNDON SOFTVVARE, OH).
Binding Assav to Rat Kidnev Medullarv V? Receptors to Medullary tissues from rat kidneys are dissected out, cut into small piecas and soaked in a 0.154 mM sodium chloride solution containing 1.0 mM EDTA vvith many changes of the liquid phase, until the solution is clear of blood. The tissue is homogenized in a 0.25 M sucrose solution containing 1.0 mM EDTA and 0.1 mM PMSF using a PotterElvehjem homogenizēt with a teflon pestle. The homogenate is filtered through several layers (4 layers) of cheese cloth. The filtrate is rehomogenized using a dounce homogenizer, vvith a tight fitting pestle. The finai homogenate is is centrifuged at 1500 x g for 15 min. The nuclear peliet is discarded and the supernatant fluid recentrifuged at 40,000 x g for 30 min. The resulting peliet formed contains a dark inner part vvith the exterior, slightly pink. The pink outer part is suspended in a small amount of 50.0 mM Tris.HCl buffer, pH 7.4. The protein content is determined by the Lowry's method (Lowry et al., J. Biol. Chem., 1953). The membrane suspension is stored at -70°C, in 50.0 mM Tris.HCi, containing 0.2% inactivated BSA and 0.1 mM PMSF in aliquots of 1.0 ml containing 10.0 mg protein per ml of suspension until use in subsequent binding experiments
For binding experiments, the follovving is added in μΙ volume to vvells of a 96 vvell format of a microtiter plate: 100.0 μΙ of 100.0 mM Tris.HCi buffer containing 0,2% heat inactivated BSA, 10.0 mM MgCI2 and a mixture of protease inhibitors: leupeptin, 1.0 mg%; aprotinin, 1.0 mg %; 1,10-phenanthroline, 2.0 mg%; trypsin inhibitor, 10.0 mg%and 0.1 mM PMSF. 20.0 μ| of [aHļ Arginine8, vasopressin (S.A. 75.0 Ci/mmole) at 0.8 nM and the reaction initiated by the addition of SO.O μΙ of tissue membranes (200.0 μg tissue protein). The plates are left undisturbsd on the bench top for 120 min to reach equilibrium. Non-specific binding is assessed in the presence of 1.0 μΜ of unlabeled ligand, added in 20 μΙ volume. For lēst compounds, these are solubiiized in 50% dimethylsulfoxide (DMSO) and added in 20.0 μΙ volume to a finai incubation volume of 200 μ). Upon completion of binding, the content of each vvell is filtered off, using a BrandeK® celi Harvester (Gaithersburg, MD). The radioactivity trapped on the filter disk by the ligand-receptor complex is assessed by liquid scintillation counting in a Packard LS Counter, vvith an etficiency of 65% for tritium. The data are analyzed for ICso values by the LUNDON-2 program for competition (LUNDON SOFTVVARE, OH). The results of this tēst on representative compounds of this invention are shovvn in Table XIII.
Radioligand Binding Experiments vvith Human Platelet Membranes (al Platelet Membrane Preparation:
Frozen platelet rich plasma (PRP), (Platelet Source: Hudson Valley Blood Services, VVestchester Medical Center, Valhalia, NY) are thavved to room temperature. The tubes containing the PRP are centrifuged at 16,000 x g for 10 min.
at 4°C and the supernatant fluid discarded. The platelets resuspended in an equal volume of 50.0 mM Tris.HCi, pH 7.5 containing 120 mM NaCl and 20.0 mM EDTA. The suspension is recentrifuged at 16,000 x g for 10 min. This vvashing step is repeated one more time. The wash discarded and the lysed pellets homogenized in low ionic strength buffer of Tris.HCi, 5.0 mM, pH 7.5 containing 5 0 mM EDTA. The homogenate is centrifuged at 39,000 x g for 10 min. The resulting peliet is resuspended in Tris.HCi buffer, 70.0 mM, pH 7.5 and recentrifuged at 39,000 x g for 10 min. The finai peliet is resuspended in 50.0 mM Tris.HCi buffer pH 7.4 containing 120 mM NaCl and 5.0 mM KCI to give 1.0-2.0 mg protein per ml of suspension.
(b)Bindingto Vasopressin V, receptor sublype in Human Platelet Membranes:
|n vvells of a 96 vvell format microtiter plate, add 100 μΙ of 50.0 mM Tris.HCi buffer containing 0.2% BSA and a mixture of protease inhibitors (aprotinin, leupeptin etc ). Then add 20 μΙ of [3H]Ligand (Manning or Arg8Vasopressin), to give finai concentrations ranging Iram 0.01 to 10.0 nM. Initiate the binding by adding 80.0 μ| of platelet suspension (approx. 100 pg protein). Mix ali reaģents by pīpetting the mixture up and dovvn a fevv times. Non specific binding is measured in the presence of 1.0 μΜ of unlabeled ligand (Manning or Arg®Vasopressin). Let the mixture stand undis55 turbed at room temperature for ninety (90) min. Upon this time, rapidly filter off the incubate under vacuum suction over GF/B filters, using a Brandel Harvester. Determine the radioactivity caught on the filter disks by the addition of liguid scintillant and counting in a liguid scintillator.
122
Binding to Membrānās of Mousa Fibroblast Celi Line (LV-21 Transfected wi1h the cDNA Expressinq the Human Vo
Vasopressin Receptor (at Membrane Preparation
Flasks of 175 ml capacity, containing attached celis grovvn to confluence, are cleared of culture medium by aspiration. The flasks containing the attached celis are rinsed vvith 2x5 ml of phosphate buffered saline (PBS) and the liquid aspirated off each time. Finally, 5 ml of an enzyme free dissociation Hank’s based solution (Specialty Media, Inc., Latayette, NJ) is added and the flasks are leit undisturbed for 2 min. The content of ali flasks is poured into a centrifuge tube and the celis pelleted at 300 x g for 15 min. The Hank's based solution is aspirated off and the celis homogenized vvith a polytron at setting #6 for 10 sec in 10.0 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 ghost membranes. The supernatant fluid is centrifuged at 100,000 x g for 60 min to peliet the receptor protein. Upon completion, the peliet is resuspended in a small volume ot 50.0 mM Tris.HCi butter, pH 7.4. The protein content is determined by the Lowry method and the receptor membranes are suspended in 50.0 mM Tris.HCi buffer conlaining 0.1 mM phenylmethylsulfonylfluoride (PMSF) and 0.2% bovine serum albumin (BSA) to give 2.5 mg receptor protein per ml of suspension.
(b) Receptor Binding
For binding experiments, the follovving is added in pl volume to vvells of a 96 vvell format of a microtiter plate: 100.0 μΙ of 100.0 mM Tris.HCi buffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl2 and a mixture of protease inhibitors: leupeptin, 1.0mg%; aprotinin, 1.0 mg %; 1,10-phenanthroline, 2.0mg%; trypsin inhibitor, 10.0 mg%and0.1 mM PMSF., 20.0 μΙ of [3H] Arginine8, vasopressin (S.A. 75.0 Ci/mmole) at 0.Θ nM and the reaction initiated by the addition of 80.0 μΙ of tissue membranes (200.0 pg tissue protein). The plates are left undisturbed on the bench top for 120 min to reach equilibrium. Non specific binding is assessed in the presence of 1.0 μΜ of unlabeled ligand, added in 20 μΙ volume. For tēst compounds, these are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 μΙ volume to a final incubation volume of 200 μ). Upon completion ot binding, the content of each vvell is filtered off, using a Brandel® celi Harvester (Gailhersburg, MD). The radioactivity trapped on the filter disk by the ligand-receptor complex is assessed by liquid scintillation counting in a Packard LS Counter, vvith an efficiency of 65% for tritium. The data are analyzed for IC50 values by the LUNDON-2 program for competition (LUNDON SOFTVVARE, OH).
123
Tot> I » XIII
Binding λοηβγ tn Rnl Htpatle V, Rieipltri and Rot Kldnoy
Madullorp Vj Rnenplars or 'Binding tn V, Rncaptnr Sublļrpn ln Human
Flata I at and ♦♦Binding to Mnmbrnnii at Hounn flbroblast CnII lln«(tv-z) Transfected nlth tho cOHA Espraoalng tho Human Vt Rncnptor V ļ V j
Ex.No. Structure I C 5 Q [p U ) ICJ0(AU)
0.029
0.022
0.038
0.004
124
To b I · XIII (cont'd)
Binding Aiiay I· Bet Hipellc V, Rtaiptari and Rat Kldnap Madullarp V, Raaaptar· ar ·1IndIng ta V, Raaaptar Suktppa In Human Flatalat and » * I I n d I n g t» Mimbranii ot Mauga Flkrablagt
Call Llna(LV-2) Troni licIid «Ith tha eDMA Ekpraillng tha
Human V, Raeaptor v
- V, y2
Εχ.Ηο. Slrucfur· I C 5 0 (/Q M ) 1 c s o (// M )
125
Tobl* XIII (eent'd)
InHInf Aaauy I· lot Hipilli V, taauptara anU tai KlUntf
HaHullar; V, laiipiari ar MlaUlng ta V, taaaplar Suklfpa In Human Piala lai anU ••BlnUlnj It Uamkranaa ·( Hauaa Flkrekluat Call Llna(LV-i) Tranaftelad allh tha «DNA Eipraialnj tha
Human V, taaaplar „
-ί- V,
Ei.N·. Sl r u c tur» IC 1 Cse(//M)
0.01 0.005 θ'
NH-C-:
. ost
126
TQb l « XIII (cont'd}
Β I n d I n f A s · α y t · R α I Η · ρ α I I c V t R · e · ρ t · r i md Rat K t d η α χ Uadullarj V, ftao«pt»r« <r ««Bīndlnļ t· V, lieiptor 3ubfyp« In Human Platai «I and **11 nd I n; S Hambranap ifM^unFlbroblut
Call tlrtt(LV-2) Tramfactad tHh tha ePHA E>prmlny tha
Human Vs Raaaptar
- V, Vj
Εχ,Νο. Struefur· I C ao^H) IC80^ U)
127
Tob I α XIII (cont'd)
Itndlng *iu| (· Rat Hapatla V, Raeaptoro and Rat Ktdnap Madullarp V, Raaaptar· ar 'Binding ta V, Raaaptar Suktppa In Human
Blata Iot and ''Binding ta Mambranta »t Mauta Ftbrablait Calt Llna(LV-2) Tranafactad «Ith tha eBHA Eapraaalng tha
Human V, Raaaptar
Ex.No. Structura
128
Medullarf V, ianpliri ar 'llndlng la V, Implir Suklppt In Human cso(//“) cso(A“)
Table XIII ( c on I ' d) llndlng Aaaag I· lai Hapatla V, (mpliri and lai Kldntp
Plaltlal and · ·I I n d I n g la Mamkranaa af Mauta flkrahlatl Cal I Llna(LV-J) Tranataalad vilk Iha «OMA Capraaalng tha
H uman V, laasplar
Ex.No. Sfructuro
129
Τ β b I · XIII (cont'd)
Iln4lbf »<ι«Ι ta bet Hepatle V, leeeptara an4 bat KI4a«r H<4allarp Vj beeaplera er *lla4lap ta V, beeepter Subtppa la Human Matētai an4 *alln4lnp ta Hambranaa af Hauaa Flbrablaat
CaII Llna(LV-I) Fraaafaata4 alth the eUMA Capreeitnf the
Human V, Iteeepter Vj
Εκ.Μβ. Structure ^50(//^) 1
0.377
130
Tab I « XIII (cont'd)
Binding Aaaay te Rat Hapalla V, Racaptara and Rat Kldnay
Madullarp V, Racaptara ar ‘Binding ta V, Raeaptar Subt/pa ln Human
Ex.No. Slructuri
Flntalat and ‘‘Binding la Mambranaa af Mauta Flbrablnat
Call Llna(LV-R) Tranataalad «Ith
H uman Vf Beaaptar tha «DMA Eapraaalng tha ic50Ļ/m)
131
Tobli XIII ( c # n t * d) llndlng Aaaay ta (at Hapatla V, (aaaplara and (at (Idnap
Madullarr V, (aaaplara ar ‘llndlng ta V, (aaaptar Subtjpa In Human
Flatalat and ♦•llndlnj ta Mambranaa at Mauaa Flbrablaat Call Llna(LV-Z) Tranalaaltd altb tha aDNA Capratalitp tha
Human V, (aaaptar
Structure
357
0.019 0.017
358
384
II
NH-C-CH,
0.011 0.018
II
NH-C
0.188 0.059
132
Table XIII (cont'd)
Itndlng Aasay t» Rat Hapatle V, Raeaptart and Rat Kldnay
Madullarp Vj Ιιββρίβπ ar *8lndlng ta V, Raaaptar Subtypa In Human
Nil l I i ♦ flfld *Mlndtng ta Mamb ranai at Mo υ α α Γ ī b r > b I α ι I Call Llna(LV-2) Tramfaatad wlth tha «DMA Eipraaalng tha Huma n Vž *a « ap t a r V1 Vj
Εχ.Ηο. Struc * u r *_* so (//Κ) I 5o (/7K )
7
SO
0.031
0.014
0.004
0.11
133
Tob I « XIII ( can t ’ t>) llndlng Aiiap Ια Int Hipallc V, liiaplgrt and lai Κ I dn<y
Uadullarp V, lacaplart ar 'Binding la V, Ractplar Subljpa In Human
PIa t αIαI and ''Binding la M amb rnnai al Mauta Flbroblo»!
Cp I I llna(LV-ž) Trinificlid allh lh» cDHA fipri « I n g tha H urna η V, Raeip tar V ( Vj
Ex.No. S true tura I C s 0 (// U ) ICS o ) ,79
0.087
0.054
0.007·*
134
Τ α b I « XIII (conl'd)
Binding Aaiajr la tel Hapallc V, laatplara and lai X I d n a y
Madultarr V, Kacaplara ar «Binding la Vj liciplir Subtfpo la Kymen
Platalat and ««Binding la Hambranaa of Hauaa Flbreblaat
Call Llna(LV-ž) Tronalaclad allh tha e OH A Eipraialnj tha
H uma n V, 11 c a p t a r V ļ V j
E» .No_Struetun_ICS0Ģi/M) ICS0(/fM)
0.010
217
0.058 0 . 1 3 ‘
0.005
0.01”
NH-C135
Tobl ι XIII (toni ’d) llndlng Auay to Rat Hapotle V, licipltrt and Rat Kldnar
Medu111 ry Hicipltn ar *Blnd1ng 1 • V, Baeapter Sublj.pt
Rieta la 1 and ••llndlng t« Mimbran*» of U « u·« Flbrobleot
Call Llna(lV-ī) Trantftcftd «Ith th· e DM A Eiprm Inļ tha
Huma η V, lltciplir
Ea .No.
Structure
V, Vi * ^50 Ci/1*) 1 cso M)
287
271
274
297
298
136
Tab I» XIII (cont'd)
Binding Aaaap te Rāt Hepatic V, Reccptere and Rat Kldnep
Madullarp Vj Reeepter» er 'llndlng te V, Reeepter Subtppa In Human
Platelet and *»ilndlng te Membrgnee tl tdeuee Flbrebleet
Celi 11 e ( l V-2 ) Tronefeeted alth the cOHA E»pre l «Ing t ti e
H uman Vt Reeepter V, V j
Structure» c 3 o (/JM
465
466
. 020 ’ 0.0015”
0.026 0.004
467
0.031 0.005
CHj CHj
NH-C•č
137
T o b I · XIII (cont'd) llndtng Αα«αχ te Rat Hepatle V, Recapten ond Rat Ktdnep
Uadullarp Vj Raccplart ar ’BIndlng ta V, Racepter Subtppt I n Human
Rlatalat and *tllndlng ta Hambranaa af Hauaa Flbrablaat
Call Llnc(LV-l) Trenc facted » I 1 h the «OHA £χpr e«ι I n g the
Humoη V, Receptor V, Vj
Struetura_I C , „ W ) I C 5 „ (// M )
488
46»
0.027 0.029
0.094 0.01S
470
CH j .,:n
0.054 0.0045
138
Tab ) a X Η I (cont'd) llndlnp Αιιαχ ta Rat Hapetle Vj Raaaptar· and Rat Kldnap
MaduHarr V2 Raaaptara ar •llndlng ta V, Raaaptar Subtfpa In Human
Matataf and I ndIng ta Hambranat at Mauaa flbrablaat
Call Llnt(lV-Ž) Tranifactad «Ith tha cOHA Eipfi t1 I n g tha Human Vt Raaaptar V V 2
Ex.No. Structur· ,cso(X/M) 1 c 3 o (//U )
471
0.0033
472
.39 (10//M)22x
473
139
Τ α b I « XIII (cont'd) llndlng 4eeay te Rat Htpatle V, Racaplere and Rat Kldntp
Medullerp V, Recapter· er ‘Binding te V, Recapter Sublppe ln Human
Fletelet end ‘‘Binding te Membrane» at Meuee flbrebleet Celi Llne(LY-2) Tranelectcd nlth the cDNA E»pre·ιIn g Ihe Human V, Reaeplar V, Vj
Ex.No. Structure I C 5 0 U ) I C s 0 (4/ M )
474
476
0.087
0.084
477
0.003·
0.038
0.069
0.0032··
140
Τ α b I · XIII (cont'd) lindtng Anoy I· tel Hspafle Y, tesspfsri and tai Kfdnty
badu 1 1 a rj Vt latiplon ar ‘llndlnj te V, l.e.pt.r Subtfpe ln Human
F1.I.1. 1 and ·-8 1 n d ! n 1β Membrānās af Uauta Tlbrablaal
Celt L 1 na ( LV-2 ) Tnm'iclH » 1 t h 1 h « a ON k Cipraaalng tha
Human V, ( ai « ρ 1 e r V, *2
Ex.No. S t r υ ο I u r · ,CSoU/“) ICS0(//M)
480
0.54· 0 . 028· ·
HH-CMOj
141
Τ α b I α XIII (eont'd) llndlng A»«ey to Rat Hapatle V, Juipliri and Rat Kldnoy
Madullar/ V, litipltn or 'tlndlng Ια V, Raeaptar Suhlfpa In Human
Platalat and **llndlng la Vimbrpnii ot Uauoa Flbrablaat
Call Llna(LV-2) Tranafaetad vlth tha eOMA Eiproailng tha
Humgη V, Raeaptar V , V j £« -N»._S t rue tura_IC5O(4/M) < C s ο (/Ζ M )
482
484
0.4t
0.097 . 0023
0.025
142
Tabl* XIII (can I ' d )
Indlng Amj li lol Hepatic V, I e e · p I · r t and lil Kldney
Madullarp Vt Reeeptar» er ’llndlng 1» V, «ecepler Subtppe In Human
F1·t·1·t β rt 4 ··81n4 1 n9 f 0 Mimbren» » • l U « tf « « F 1 b r « b 1 « t
CpII Llne(LV-I) Transfected elth Ihe aDHA Eiprni 1 nj tha
Hum·η V, Kuiplef V,
Ex.No. Structure ' C50 (//M) ’ C5O Ģi/M )
485
0.24 0.013
48S
(10//M)39x ( 1 0//M ) 7 7 x
488
(10j/M)96x (10/»M)87x
143
Tab)· XIII (cont'd)
Rtndlng Aste; le Rot Hapattc V, Ritipliri and Rat Kldnap
H a d if 1 I α r γ V2 ar Mlnilng to V, Jtaaapter Subtfpa In Human
Matalat and **Sīnd1ng ta Mambranaa »1 Mauaa Flbrablaat
Call Llna(LY-2) Tranafaetad w)th tha «OMA C X pr a11 I n ļ tha Human Raceptar V V j
Ε x . No. 5 1 r u c tur· I Cso Ģ/X) icļa(^M)
48«
490
N-C
1 (CHj),*
( I 0//U)8 2«
144
Τ α bI· XIII ( c ο η t 'd )
Binding Au«y I· Mol Htpatle V, KicipUn and Hat Κ I d n · y
Modwllary Vj l»eipliri tr *8lndlng I· Vt Rīcipltr Subtppa In Human
Rlalalil and * * 8 I n d I n q la bambron·· of Mauig flbrabfaot
Call LIπι(IY2) T ron » I · c I «d » 1 t h lh· oONA E » p r · i «Ing Ih·
Human Vt Eaaoplor V j V j £x,Ho, Sfruetura _'Cso^n) icia(AM)
145
Τ q b I » X I I i ( c ο η l* d ) llndlng Attop te Iet Htpallc V, lacaplart and Int Kldntp
Uadullarp V, Itetpltrt tr 'Binding It V, Rtetpttr Sublppt In Human
P I α t e t e t end to Membraneι o Γ Μoue Ffbroblaet
Ctll Llnt(iv-I) Trantftcltd tllh lh. DMA Etprattlng the
H urna η V, 11 c t p I o r v, *2
Ex.No. Struelurt •CjoU/M) 1 <· jo (//H )
518
519
HH
CH
0.11 0.015
0.22· 0.0017··
0.12· 0.0032··
146
Tob i α X I l t (cont’d)
Binding Α α α α y t · Iet Hapatle Raeaplara and Rat Κ i d η a y
Madullarp Vt Racaptara ar «Binding la V, Raaaptar Subtfpa In Human
P I a t α 1 a t and ««Binding t b M amb rgnu af Mauaa F I briblu I Call Llna(LV-2) Tranifactad wlth tha αΡΗΑΕκρτααIn g tha H uma n Va Raeaptor V j Vj
Ex.No._Structur»_ICsg(pU) )C80(#M)
520
0.85· 0.0044·· '/ \y-c,
0,11· 0.0028··
0.17· 0,0012··
147
Table XIII (cont’d) llndlng A · · eļ I* Del Hepetle V, Receptera end Rel Κ I dηej
Medutlerf Vj Reeepler» ir ‘Binding te V, Recepter Subtppe ln Humen
Flelelel end ‘‘Binding te Membrane» il Meuee flbrebleet Celi llne(LV-Ž) T r α n » I » e t » <l wļ Ih Ih» cOHA Eepr» e a I n g Ihe Htimen V, Reeepler V ( V 2
Cx.No. Slruclure IC5oQ/M) 1 cJo(>ZM)
52S
0.43·
0.00042··
528
0.05·
0.0033··
527
0.00067··
148
Tab l a XI I I (cont’d) llftdlftf Aitey H Rat Hepatle ¥, lieipliri «nd lat JCIdntp
M·d U I Iaf y Vi R»c »p f · r i er ·8 I nd I ng I· V R«e«p I ir 3 u b t y p · In Human
Ρ 1 a t a I a I and **8 I nd 1 ng I o M<mb ranu of Motni Flbrablaat Call Lln«(LV*2) Tramfiotid wlth the cDHA Eiprt · · I n 9 the H urna w V 3 Rtcip I a r V ļ V 2
Ex.No. Struetura _' C50 (//**) * Cļļ(/fM )
149
Table XIII (cont'd) llndtng Aeeep te Rat Hepatic V, Receptere end Rat Ktdnep
Madutlarp Vj Receptere er 'Binding ta V, Reeepter Subtppe In Human
Platelet and ''Binding ta Membrenee «( tdauie flbreblaat
Call Ulne(LV-2) Traneteeted alth the eŪHA Cepret e I w g the H urna w Vļ Reeepter V, V j
Ex No _St ruelurt_lcļ0(//M) ICS0(//H)
547
52«
0.01«· 0.004··
0.99· 0.002··
530
0.003· 0.0037
CH j
150
Table XIII (conl'd) llndlng Aaa«y H Iet HipatH V, Μ · β«ρ1·ra and ftat Kldnif
M · d u I I o r y V2 β·e β ρ I · r o r «Binding to V, H t e a ρ I a r Subt y ρ a In Human
Pliidlol d w 4 * * Β I n d 1 n g to Hombranii of Mouio Γ I b r o b I a »♦
Coli lfno(LY-2) Tranafocttd ir H h tha «DMA £xpre a i t n g I h a Human V, Haaeptor V ļ V j
Ex.No, Slruclur· IC 5 0 ζΖ/ M ) 1
580
581
582
0.021
0.08
0.0053
0.13
0.014
151
Τ o b I . XIII (c ο n t ' d )
Bladtng Ααααγ 1« Rat H«patl< v, tuiptir» and Rat Ktdnay
Madutl«ry Vj tacoptari or · 9 I η «I I n g I· Υή R«««pt«r Swbtypa ln Human
Rlafilat and ••Binding I· bambrant· of Houaa Flbrablail
Call Ļlno(LV-2) Trana ftctad <I th th· cPHA Caproα » I n g Hu Human Vž Rtcept ar V j V j
Ex.No. Strveturi ICse(X/M) ICse^/N)
582
584
585
0.027
0.48
152
Table Xl I l (cont'd)
BJadlfif te Jtet Hepette V, Reeeptere «nrf Iet Kldftep
u«5«ll<ry V, loeopltr· or ‘llnilnļ Ιο V, Kootļtor 5ubtyp«
F 1 «1 ο 1 ο 1 on< · · 1 1 n41«g le Membrenee ef Uiuai Γ1brab1ai1
Celi LĪBe(LV-Ī) Treni f · « t · d «Ith the β OH A Cipreeelng the
Huw«η Vļ Imp I > r V j Vļ
Ex.No . S t r u « t u r t I C »(//“) * Cļfl (z/u)
585
587
5B8
0.022
153
To b I a XIII (cont'd) * IndIng A·««y I* Rat Hipallc V, Raaaptara and Rat Kldnaj
Medullurf V, Raaaptara ar ‘Binding ta V, Raaaptar Suklgpa In Human
Flutalat und ‘‘Binding ta Mambranai «I Mauaa Flbrablaal
Call Lfna(LV-2) Tranifactad «Ith l h a e 0 Η A Ε « p r aaa I n g tha Human V, Raaaptar V, V j
Eī.No. Structura ICSoĢ/M) 1
583
580
591
(10//M)45i (10//Μ)β4χ
Γ7
M 0 v_y
154
Τ o b I « X I I I ( c ο n t * d )
Indlnf Aaeay 1· Rat Hapatla λβ · pt · r · an4 Rat Kldner
Malu 1 1 ary *« Kiiap 1 ir ar * 1 f n d ( n g t « V, Kaaaptar Sukffpt ln H#nqn
Platai·! «nd • · 1t n d 1 n 9 ta Membrānai • f Uouii Γ ! b r b 1 a · t
Call Lina (LV-2) Iraiilntid «Ith the a OMA Cipraaalng t ha
Human V, Raatp t·r εχ .No.
lcsott/K) ΐε,,^Μ)
512
SIS
514
0.21
0.042 ( 1 Οχ/U ) 7 8 i ( 1 O irM ) 2 Ϊ «
155
Table XIII (« ο η I ' d ) llndlng A · · y It (at Η · p α I I < V, R · c · p I « r and Rat Kldnagt
Madullary Vj Raaaptare «r 'llndlng 1« V, lanaptar Suktjpa In Human flatalat and ''llndlng la Mtmbranei it Mauta flbreblaet
Call ļ.lna(LV-2) Trinifttiid »1 lh th» cOHA Ēipn α α I ng tha Humg η V, Raeaptar V, V j
Ex.No. Slrueturi ICSQ(^U)
.002*
0.007··
5J7
NH-C
(10/tM)100« (lQy0M)97x
156
T q b I α XIII (cont'd) llnilAf Aueajr f» lel X · ς « p t · r * and Rat KJdnujr
Midullar? Y| R««ept»r« tr ’llnding f· Y( Raaaptar Subtppe ln Human
Rlatalat and **Blndlng ta Himbran·· af Mauua Flbrablaat Call ί I i>a( LV-l ) TraniJ»cl>d >Hli th» «OHA C<p/a * «Ing I h ♦ H urna n Yž R u u « p t « r
Ex,N«. Strui(uri V. vi
ICS0(Z/M) ICJ0(2/H)
59S
599
0.04( 0.014
157
Tab I a Xlll (cont‘d) llndlng Aaaaļr »a <«· Hipilli V, lacaplara and lai Kldnap
Nadallarp Vj Im.ltri ar 'llndlng la V, laaaplar Sublfpa ln Hvman
Plalalat and a»llndlng la Mambranta a< Mauaa flbrablaat
Call llna(LV-ī) Tr anafae tad alth Iha e ΟΝA Eipraa a I η g Iha Human «aaaptar ¥ j V j
Ex.No. Strutlura IC50(//N) 1CJO(^N)
158
Τ οb I XIII (cont'd)
ΙΙ«4Ι·| 1« λ«Ι Η·ρ·Ι | « V, l«tipt«ra and Rat X14 Μ·f
V| t«««pteri «r *·ΐ«41η< ί· V, Sufctyp« f« Hvm«<t «nd ••lndlng t· Mtmbran·· ef Mouu Flfcrtbliit C·I I LIMt(LV-Ž ) TramHcUd wlth 1h< cOHA Expr«« » I n g t h »
Mum· «i Vļ V ļ Vj
Εχ.Μβ. Strvclur» ,cso(/ZM) *C50QyM)
159
Table XII) (cont'd) |l*dtft| Un/ I» l«t Hapatla V, Raaaptara and Rat Kldnaj
M«4attary Yj Raeaptara «r ettnd1n9 !a V, Raeaplar Sobffpt
Maltiet and llndlrt» ta Mambranaa ai Mauaa Flbrablaat
Ct11 LI*«(LV-Z) Irmlttltd »1th th« «DNA Ciprttllnf 1h<
Hmwi η V, Ihtiptir V j V j
Ex.No. Sfructur» ICJ0(//N) ICsa(//U)
IS
160
Table XIII (cont'd)
II*dIaf λ e·y le Xα ( Η · p e t I i V, Reeiņtera and Iet Κ1deγ
Medallerjr V, leeefter· ir ♦·! »4 I nj 1· V, taeefter Subfjpe I n Human
Platei·! end · · 1 1 n 4 I n f te Membrānai «I Meuae flbrebleet
Celi Llee(LV^2) Tronifected elth thi cOHA Eipraa ι I π ļ the Humee ¥j leeeyter V V j £«.!<«· _ S f r u e t urt__lcsoUyM) 1 Cļ a )
117
sea
0.029··
. 035··
161
Table XIII (cont'd) tIMliif Aiiif I· *«l Htpatle V, l»eipliri entf lat MlMnap
Unduller? Vj laaaptari er *llnMlng f< V, laaaptar Subtfpa ln Humen
Fl«tnI·I nnrf *eIIndFftf fa Uambranaa tf Mauta Flferablaal
Call Llna(iV-l) TranafaalaM «Ith tha tOMA Eipraaalnļ tha Human Vt Haa < p t a r V j Vj tx Ho ._Structure_ICsoLž/U) ICi0ĢyM)
162
T q b I « XIII ( c ο n t ‘ d )
81rt41 πQ Aiioy to Rot Hopotlc Vt Roeoptor· end Rot KIdnoy
Uo d υ ί 1 β ry V t Roeoptor· or «Binding to V, Roeoptor Sub f y po I n Humon
Flotolot ond **Blnd1nļ to Mombranoo ot bomi flbrobloot Coli L)no(LV-2) Tronotoctod * I t h t h o c 0 HA £ i p r ο ο ο 1 n g the Huffgn Vj R o c o pt »r V j 2
Em .Ho._Struelurt_I C a 0 (// M ) IC^^M)
685
612
0.061·
0.061··
1.7· 0.01··
163
Tabl* XIII (cont'd)
Binding Α i a jr lo Rat H > p g I I c V, Roc · p I β r · and Kal Kldntļt
Utdullorg V, Rgggplari ar 'Binding la V, Raeiplor Sublfpa In Human
Flalalat and ''Binding la Mambrgnii α ( Μ o u 11 F I b r a b I α ι I Call Llng(LV-l) īramlittid »lth lh» cDHA £ » p r α · «Ing tha Huma n Vt Βια α p tar V V j
Ex.No. Structurg I CJ0(//M) ICgat^U)
164
Tg b1a X I 1 I (cont'd) llntftittf A t a«γ It ft< t V, «n4 Rat Kldaa?
Mtdullarf V, liuptiri »r *|lndln| t· V, Imptir Svbtjpa In Human
Ρ I a f α I a t and · · I J n41n j I β U <mb rα η· ·t Mauta Flbrablaat
Call LInt(LV — 2} Tranctcelcd vltti lh· cDNA Capraialnp i h ·
Hurnan Vt Rtaaptar Y j V j
Ex.M«. Structure IC,IC,0QyM)
192
(93 (94
0.021·
0.12
0.005··
0.0017··
165
Table XIII (eanl'd)
Indi fig Αοοοχ to Rat Kopotie V, Roeoploro and Rol Κ I d n jr
Madullar; V, ΙκιρΙιπ or *llndlng to V, Rocoptor Subtjpa In Human
Ptfltilit and tlntltnj to Mombrant» ol Vauii flbroblaot
Coli Llno(LV-ž) Tronofottod » I t ti Iho cPHA Citpro 11 I n g t ll α Human V, Rooogtor Ϋ( V ,
C« -No ·_St rueluro_ICļ0Ģ/U) »CļaĢyM)
898
597
.0018··
166
Tgb Ια XI l I (cont’d) llodlo* A«aay ta «al Hapatla V, laasptari iiZ lot ΚI d··γ
Modallarp V, laaoplar· ar 'lladlag t· V, loaaptar Sabtpp· la Hmnii
Rlltolat «ad ··! I n d Ing la Mimbrim al Utu·· Flbrablott
Call llļio(UV-l) Tran»l««tad «llb tha cDHA tipra ·» I «ļ tha Hama R V, I a a a » 11 r Υ, V j
Ex.No. Structura ICSi (//Ν) I CS0QyM) (18
819
700
167
Tablo XIII (eent’d) llodlni Aooor I» lai H«»«tle V, ond lot Kldnop
Modullor/ V, litiplin »r ΜΙηΟΙη» t· V, Ι···οΙ·Γ Suktjp* ln Humon
Rlotolot ond ••llndlnj to Homkronti ot Movoo Flkrokloot
Coli llno(LV-Ž) Tron»l«ct«d allh tin cOHA toproοο I no t k o Humoο ν, lo oo p t o r V, Vj
Ex.No. Slructuro _icailU/H) iCaoU/M)
168 fatal» XIII (cont’d)
Binding Aa»ey 1« Rat Hipatlc V, Ueiptir» end Hat Kldna?
Madulfer? V2 Rioipfon ®r llndlng le V, RiespUr Subfype In Human
Ρ I o t ι I e t and * * Binding te Membrāna» a f M e u a a Flbrablaat Ct I I t lm( ty«_2) T rom f <e t id t Ith 11> e e DMA E«pn i « I n q the Human Vž Rae ·ρtor V j V j
Εχ.Μβ. Slruduri I C 5 „ (// U ) ICse(#M)
CF,
169 ī a b I ι XIII (eant'd) llndlng A«iey ta Rat ΗιριΙΙι V, liciļltri and Rat ΚI dnay
Uada 1 1 « r j Vj Raaaptara ar 'Binding ta V, Raaaptar Sublppa In Human
Flatalat and 9 1 nd 1 n } to dombronoi >1 Mauaa Flbrablaat
Call Lina (LV — 2) T r om ( < c t «4 «Ith tho cONA Eipraaatng tha
Human V, R a e a p t s r v, V2
Ex.No. S 1 ruc turt ICse(^M) ic S0 U/N )
0.023·
0.041··
II
NH-C-0
Vasopressin Vo Antagomsl Activitv in Conscious Hvdraled Rats
Conscious hydrated rats are treated with compounds under study from 0.1 to 100 mg/kg orally or vehicle. Two to
170 four rats are used for each compound One hour tater, arginine vasopressin (AVP, antidiuretic hormore, ADH) dissolved in peanutoil is administered at 0.4pg/kg inf taperitoneally. Two rats in each tēst vvould not receive arginine vasopressin but onty the vehicie (peanut oil) to serve as v/ater-loading controi Twenty minūtes Iater each rat is given 30 mUkg of deionized vvater orally by gavage and is placed individually in a metabolic cage equtpped vvith a funnel and a graduaīed glass cylinder to coJJect urine for four hours Urine volume is measured and osmolaJity analyzed by use of a Piske OneTen osmometer (Fiske Assoc,, Norvvood, MA. USA). Unnary sodium, potassium, and chloride are analyzed by use of ion-specific electrodes in a Beckman E3 (E!octrolyte 3) Analyzcr.
ln the follovving results, decreased urine volume and decreased osmolality relative to AVP-control indicates activity. The results of this tēst on representative compounds of this invention are shovvn in Table XIV.
Table X(V
Vasopressin V2 Antagonist Actīvity ln Conscious Hydrated Rats
Ex. No. Dose (mg/kg) N Urine Volume (ml/4 hrs) Osmolality (mOsm/kg)
* 78 13.3+0 3 22916
** S 12.111 497153
4 12.4+0.8 361130
«** 76 210 2 1226158
1 30 2 1.1 1504
215 30 2 0.7 1520
3 10 7 15.811 567133
3 3 9 610.9 584156
1 5 6.5+1 515179
4 10 2 16.9 571
3 4 9.511 2 6461115
1 2' 2 1129
5 30 2 7 7 955
10 2 8.5 1079
6 30 5 17.9+1 3 616187
10 9 20.4+1 1 346125
3 4 15±1.6 519130
1 2 6 970
7 30 2 12 4 815
10 2 9 780
S 30 2 9.1 1010
10 2 3 4 1211
14 10 2 5.2 836
3 ! 2 4.5 1000
82 30 2 1.7 1808
* Water-ioad control ·* Water-ioad
Control+DMSO(10%) (20%) “· AVP-control
171
Table XIV (continued)
Vasopressin V2 Antagonist Activity In Conscious Hydrated Rats
Ex. No. Dose (mg/kg) N Urine Volume (ml/4 hrs) Osmolality (mOsm/kg)
84 30 2 6.5 425
10 2 4.4 416
85 30 2 12.5 383
10 2 2 1123
87 20 2 4.3 1300
10 2 3 1488
89 30 2 3.3 1320
91 10 2 12.5 414
3 2 2.3 1267
93 30 2 5.1 594
98 10 4 10.3+1 3 647+63
3 2 4 4 716
116 30 2 8 1295
10 2 5.5 1242
354 10 2 8.8 1010
356 10 2' 5.8 1023
358 30 2 5.5 875
2 10 2 9.3 1015
9 10 2 5.3 702
99 30 2 15.2 334
467 10 2 18 365
466 10 2 14 1 522
17,160 30 2 4.1 1374
489 10 2 6.1 1194
490 io 4 71 5+1.5 487+38
590 10 2 3 1355
581 10 4 4+1 2 941+219
469 10 2 113 548
599 10 2 16 407
470 10 3 17 387
484 10 2 8 785
485 10 2 4 961
471 10 4 14 1 + 1 9 507+38
479 10 2 6 1042
482 10 4 22+0.9 372+17
54 io 2 5 1275
274 10 2 3 1177
465 10 2 21.8 361
172
Table XIV (continued)
Vasopressin V;, 'atagonist Aclivily in Conscious Hydrated Rats
Ex. No. Dose (mg/kg) l N Urine Volume (ml/4 hrs) Osmolality (mOsm/kg)
4Θ0 10 2 S.c 827
52S 10 2 11 3 647
529 10 2 10 5 569
520 10 2 1 & 5 394
519 10 2 1 9 9 399
523 10 2 5 1218
524 10 2 10 528
525 10 2 13 557
526 10 2 17 3 455
527 10 2 19 5 430
530 10 2 6 914
518 10 2 17 5 363
668 īo ') 20 7 378
609
611
472 10 2 4 3 1453
582 10 2 9 5 604
473 10 2 2 3 1493
474 10 2 1' 5 619
594 10 -t 4 91.1 2 1172±182
586 10 2 4.3 1196
584 10 2 2 5 1718
595 10 2 3 3 1474
588 īo 2 9 5 687
587 10 2 G 868
210,214 10 | 2 152 451
597 10 2 5.3 1250
517 10 2 14 7 411
217 10 2 14.3 466
585 10 2 3 3 1483
476 10 2 5 1233
593 10 2 11,5 577
596 10 2 2 5 1347
297(298) 1 0 Ί 796
477 10 2 5 3 701
478 10 ; ) 3 1399
481 257,271 592 10 2 17 2 473
Vasopressin V, Antagonist Activitv in Cont ous Rats
Conscious rats are restrained m a su “ic position vvith elastic tape. The area at the base of the tail is locally anesthetized by subcutaneous infiliraticn . in ;% procaine <0 2 ml). Using aseptic technique the ventral caudal tail artery is isolated and a cannula made ol P I C and 20 (henl-ftised) tubing is passed into the lovver abdominal aorta. The cannula is secured, heparinized (1001 ; u cc). sealed and tlie wound closed vvith one or tvvo stitches of Dexon 4-0. The caudal vein is also cannuiated m “ e ame manner (m intravenous drug administration. The duration of the surgery is approximately 5 minūtes Addifi· aai ecal anesthesia :?% procaine or lidocaine) is provided as needed.
Tha animais are placed tn plastic rest nniug cages in an upnght position. The cannula is attached to a Statham
173
P23Db pressure transducer and pulsatile blood pressure is recorded. Increase of systolic blood pressure responses to arginine vasopressin 0.01 and 0.2 interimtional unit (l.U )(350 I U.=1 mg) injections are recorded prior to any drug (compound) administration. after vvhich each rat is dosed orally vvith compounds under study 0.1-100 mg/kg (10 cc/ kg) or inlravenously 0.1-30 mg/kg (1 cc/kg). The vasopressin injections are repeated 30,60,90,120,160,240 and 300 min. later. Percentage of antagonism by llic compound is calculated using tha pre-drug vasopressin vasopressor response as 100%.
The results of this tēst on representative compounds ol this invention are shovvn in Table XV.
The results of this tēst on representative compounds of this invention in vvhich the dose, the maximum % inhibition and the time in minūtes, are shovvn in Table xvi.
174
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<η Ό η ιη »-< σ σν Γ* Τ Γ © Μ cn •’T m o f*· o CM 00 in rM ΙΠ Ό rH t4 CM <0 rM CM 4i 43
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CM β
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rM CM CM r-, CM r-i CM f-4 CM r-4 CM H CM tM CM >
o o o o a o o o o O o o o O o o H
cn
o o o o o o o o O o o o o o o o z
ω e«
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β.
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175
Table XV fegnVdi
VASOPRESSIN fVAS)VASOPRESSOR RESPONSE
4J •rt
JQ
Φ Φ θ' θ' Φ C u <β ® χ; > ο φ
θ'
C (0
Δ ϋ
<ο φ< α > c
Ο U α« Ο 44 Φ <Μ Λ <
rt
Ο
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>
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Μ
Ο <U
Φ ca
4->
β β ο α
Β
Η
X
Ο θ'
Φ θ' α ϋ ο\ a φ β
Ol ’T > ®
Γ P* |0 o r* cn o <o r>
in m in r* o * in » rt
Irt irt «rt irt in irt
rt o ® ® rt O irt • Irt <M |0 Irt p* rt
rt Irt MO rt rt rt σι rt rt CM rt Cl rt n
p*(noirt®incnr'>oioi0^rr*inin®rti0^eOrtrtOi*ininert'0rt Π (Μ ΐη « Η Η Η <-1 r-1 HrlHdrlNNHdriOJHrlnCi
Φ β
ιΰ
Μ σ» ο
® rtJ O irt O d· Irt M· rt Irt <N OT o c* ® rt OT O oi If) o tn tt tt CM tn M> O O 9
10 θ' σι rt rt ® d* ® -T CO Ί* σι rt OT ® d· P* tn CO -<r r- tn ® «r P* tn σι m· r* σι *
rt rt rt CM rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt *
ο r^Kmr’mtncop'rjirtOTrfnfNrnirtr*
M3np*cjr*nrs>rnr*rnr*np*nr-fn'O
Ο ιη σι (Μ ιη Γ* <Ν 10 ΓΜ 10 CM rt rt rt rt rt rt rf η ρ» rt to ρ* «Μ σι ιη
4J <-> ζ
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>
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rt 10 σι Cl tt 4» O
rt rt <N rt
rt (M rt CM rt CM rt (M rt CM rt CM rt <M rt CM
O O o O O o o o O O O O O O O O
o o o O α o o o o O o o o ό o o
(Ν ζ
χ
U (S
II
Β co s
£ u
ο.
>
X >
u w
o o
M
P· z
co
176
JO
W
Ul —I w «
4J C 0 o — w ce
Ul < >
Λ 0 Ul E-i <
>
Z
M ω
<n ω
os α
o w
«c >
c o
-H
4-1
-rl
Λ
-r|
Λ
C
M fl) fl) tP tp <0 c k <0 fl) Λ
5°
Φ tP
G
Λ
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Φ <
s>
Ο M Q> fl) 10 4-1 0) IH ot <
w >
IV □
Ή
0) m
4) (0 fl)
0 io
0. 0
c —1 X α
o Γ- Γ-' in m r* CO Ό If) © n r- © \O r4 Ν’ o o © fN tn
IT) tn m 1Λ tn in
• • • lf) • O
© tn in n CN r*> Γ* t-4 © CN © tn N» cn
tn tn rH CN r-4 r-4 i—4 <N m <n tn m
ο ο ιη ιη ο o t if) If) Η (Ί
CN © © r\ If) M H in
CN
O if) O O if) H CN Η (Ν H ininoooinifloo
NN<rrwiniflcīiri in o
\0
tn in O tn o in tn r-' o O in o tn o in in in o o tn tn in tn O tn o in tn
i—4 r*3 tn Ch σ\ o o cn O ch rH co o Ch o co o o fN ch o <*> σ> r-4 CN
CN CN CN CN r-4 CM CN r4 CN »-4 CN «—4 <N CN fN CN fN r-4 CN fN fN p-4 fN CN CN
tn tn tn ooinoiflinoiiiinintnintiioīnminininom m ο o tn
r* r- CO o co CO CO CO CO CO CO > > CO CO > r- > CO r· KO CO CO © CO co
r-4 rH rH CN r-4 r-4 r-t c4 H r-4 i-4 rd r-4 r-4 i-4 rH H r*4 r*4 H cM H «-< H r-4 H H r4
o o o r» ό σι o o o (N oo -r r-l r-l N <D tP 10 X
Q \ · r-4 ΓΝ i—4 CN r-4 CN r-4 CN r-4 CN r-4 CN r-( CN
Q · > O O o o O O o © o O o O © O
3 « •
W « w ί<ζ Ή > o O o o o o o o o o o O O o
0) o
tP ae
X σ>
β
J
Ο at
6z n
z
X w
SPONTAHEOUSLĪ HīPERTEMSIVE RATS n-2 Body weight(s):340,330 grams
177
Table XV fCONTi
VASOPRESSIN (VAS)VASOPRESSOR RESPONSE
V « o> o» ta c u n ai B °
«I o» c
<0
Λ υ
(0 β < α > S
Ο Μ α » α ν Ο <Μ « <
OT <
>
φ ο
Μ
V α
rt» rt» rt» vo rt* r» m irt rt» rt
Ό 00 tO rt r» co r* to
Irt tn tn tn o tn tn •
n <N tn o rt» rt» o rt» o rt» o rt* in
tn tn rt ni rt» rti rt rt rt rt rt
o rt ΐΛΝΟίηοοιηιηιΛΟοιηοοαοιη ο ιη ιη ο ιη ^O-f«5Hn-<N(NPI(M(NHH('J(NrtinV)(Nl<lrlrlMinininrt
tn If) tn tn o tn O in O O O tn in o in O tn o o tn O tn tn m tn m O tn
rt rt» rt» tn G0 r* θ' co σ» σ» Φ r* Γ* CO co rt* r* r* to CO co <o co rt» >0 rt* r*
rt» rt» rt» rt» rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt
O <*> tn © o Irt irt O Irt O o O Irt O Irt © © tn tn tn m © © «n © © tn O
rt» tO co σ» rt* tn rt^ t£> t0 tn rt* tO tO to to to to to to r* rt» rt» Ό rt» to Ό to
rt ι~4 rt rt rt c-1 cH r-H rt rt rt rt r-1 rt rH r-1 rt rt rt rt rt rt rt rt rt rt rt rt
•Ρ α » ο m ο ο
0< Ο η α
C
--4 £
ο ο ο νο σ\ <ν ο
ο «τ rt»
Φ θ' Q X ο\ α · 3
<3
rt rt» rt rt» rt rt» rt Γ» rt rt» rt rt» rt rt»
> o o o o o o o o o o o o α o
rt o o o o o o o o o o o o o o
ο»
X σ» β
ο ά
ο η
J
Ο «
η ο
ζ
X
Μ
SPONTANEOUSLV HīPERTENSIVE RATS η-2 Body ueight(s):340,340 grans
178
Table XV CCONTI w
CO
SS
OT
K a
os o
w m
w os o, o
OT >
co <
>
co w
«
o.
o co <
>
SO
SS
0) σ» o* (β c k <9 Φ X3 > u
Φ
Cn c
<9
J3 υ
co Φ < Λ > c
Ο k Οχ Φ « 4J Φ M4 OS <
k ω
o« c
•H
X co tn
P* tO ο ιη h tn ® ο -σ
CM p* o tn «h o H r> to in tn r- o tn tn u~>
<N tO r*' tn cn tn cn \o in •
n o m cm cn n in r* otnoomoom totn^rtOf-*^nj*k o tn ιη ο ο ιη o »-( <N 04 CM CN fk -Π ιη ιη ιη ιη Ο O «k <k tn n <v cn ο © © tn m o r» cn oj <r tn
in o o m m in tn © © © © © © n tn tn in tn © *n tn tn © tn tn tn ©
fk fN m n tO co > CA to © co co P-* P- o CD Ό ik <P Ό P' Ct tO © o fk
CN CN CN CN rH rM r—f »k ik »k »k k k k CN k k <k CN ik »k k H k k k CN CN
CO <
>
<u k
«u
Φ
CQ
Φ a
o a
in tn O cn O in tn tn O tn tn O tn o tn tn O σ tn O tn tn O tn tn © tn tn
tn to Ot r* ΙΩ r* Ifl r- tn tn tn to Ό tn tn tn to tn Ό Ν' tn tn to k· Ό tn to
fk »k fk ik <k <k k fk <k <k <k k fk fk fk k rk fk <k »k «k fk «k ik rt «k <k <k
Φ CP W \
© · >
CO ·
-k >
Φ cn o
α θ' a
© © © n \o σ» ©
CN o o k>
ik CN
CN *k CN rk CN k CN fk CN ik CN »k
© © © α © © o © O © © © ©
O © © o © O o o O o © O O
n
X w
<N o
©
SPONTAHEOUSLī HĪPERTENSIVE RATS n=2 Body vrelght(s):340,360 grams
179
Table XV tCONTl
VASOPRESSIH (VĀS1VASOPRESSOR RESPONSE
-P •H
J3 tt tt Oi 0» Λ C ρ α O J3 ί u tt θ’ c
<0
J3 υ
« < tt > C b Oi « n -p
V <W K <
w <
rt 0 >
b tt
P b
e O
0 <u
u V α
p ta o
cu c
-rt s
tt ia
Q ι-J 10 r- ve o 10 r» īo <-< 10 co tn
Ol rn tn eo o- tn t- r« Ol r~ tn
in tn m tn tn ·* in w in « m * in
in ** o CD o o » Ci o rt 9 •
rt tn rt rt rt rt tc rt rt oo rt d
d
M co cn o- oj tn nr OJ 10 nf C0 r-l rK oj
OJ p· r- o l-t ot to ιη m o oi o n OJ rt rt rt to ® rt O rt α Ot rrt o m irt Ol
Ot 00 d «T CO o Cl r> CO Cl ι—1 tn O d oo d o IA rt 9 rt O O
o Ot rt d Cl co Cl Ot Cl 00 rt CO d •*r co Ot d oo to C· to 9 tO 9 9 9 d rt
d rt d Cl rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt d
P* o o d tO Cl rt co tn o to CO Ό o d d tn o rt d to rt d o o in
to d d d rt d rt to rt d rt to rt rt to to Ό to to to to to in to to d to d
rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt
o o O o o o O
rt to σι d 9 V
rt rt d
o> on «i x
0 X · rt d rt Cļ rt d rt d rt d rt d rt d
α • > O o o o o o o o o o o o O o
3 ·
03 • rt o o o o o o o o o o o o o o
<-rt >
« <a o
α tp ot
O
X ω
SPONTANEOUSLY HYPERTENSIVE RATS n=2 Body velght(a):380,360 grams
180
Table XV (CONT1
VASOPKi-JSIN (VAS)VASOPRESSOR RESPONSE
-d
-Q
Φ Φ Cn <y» m c u «3 Φ χ:
°
Φ cn
G id
Λ
U
W Φ <
S>
O td α φ m x> Φ Md PS <
ω >
φ u
o
Md
Φ
X»
w <a
0 «
& o Q
c rd CO r* in
O co c* so cn oo vo in d f* d· in m r» o\ vo in m
m m m in σν in in
in r* in m
o d* rd VO rd Cl CM rd Cļ Cļ m in • «
d in rd rd rd Cļ rd rd ci «d Cļ in V0
η η in in r» ιη m d vo d·
VO CN O σ> m r-4 »—t □ co r> π co H rj Η Η d d VO 00 rd fN N d N *
ci r* ο n r* d (M(N d IN (N
Cļ rd n rd > d· Ci Cl in O O d· in Cl CO d n d· d O CO CO CO n Cl C0 n
co 00 rd 01 in d SO in in i? VO Γ* m n· VO d· in d· so d· SO ΓΪ SO d1 so d co m
rd rd Cļ rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd
r* vo o vo r* <n co d m in d d* n d· sO rd d· <N m m O m n m rd tf m
Ui d vo r· fx O η η η Ν (N rd rd rd rl td rd <N
Cļ
VO <M φ σ* m x
O \ · rd · > O · · W · Μ O >
Φ
V) o
Q
CP
X o o o n vo σι
O O O c» a> d <d rd CM
Cl rd
O O o o
X ω
CM
O rd Cl o o rs
O *d C| o o rd Cļ rd o o o ca o
o
0.01 300 146 166
124 137
0.02 153 100
134 155
SPONTANEOUSLĪ HĪPERTENSIVE RATS n=2 Body velght(s):500,390 grams
181
Table XV fCONT) vasopressin (vāsivasopressor response
Dose VAS Dose Min Post Control Response Average ī (mg/kg) l.u./kg Dose Before VAS After VAS Change Change Inhibition σι r* rso un © r* īo © © d r* d d * © *
© • © © © © ©
Φ d © CM d Ch CM CO o © d © «M • •
M· © d CM <N CM d CM CM d CM CM d Ρ» σ> ©
CM d Π
«Hf^r-somin^mco^eooo ^(M®dd^©©d©^o©©dp*d© invU)OlHrt(\(NH(NnMfN^ncNH(Sr<Hr((NnN{NO'Hr)(Ņ^nN (0 β
(0 k
Ο η © CM S © © n d © © CO © CM © © © d d CM CM © σ> CM © CM © © CM d σ» d
© © © © LO n © © sO © © © M* © © © © p» © © © © r* P* © f* f* © © p* P*
(Μ d CM d d d d d d d d d d d d d d d d d d d d d d d d d d d d d
tt
© <h © © d © O d d r· © © © <P d P» © © © © © © © CM CM © © d © © © £
M1 d CM *P © m· d «p d CM ir © d d d d * d rsi d rf σ»
d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d —<
tt o
σ>
o
CM o o
M· © cm d
d CM d CM d CM d CM d CM d CM d CM d CM
O O O O o O o © O o O © O O © o
O O O o o o o o o o o O o o o o
n d
z
X ω
>1
Ό β
CM
H
C
CO o§ w
co §
s u
o.
>
E cn
O ω
Z co
182
w tn z s tn w K
z K
o o
u tn
«M tn r»i
Ž « cu
V so
r-l <
43 >
ia
H
c ο
•Η
4J
J3 PP ·*«
H
0) 0)
σ< o<
w c
u to
0) JS
> u
·<
V σ' c
«j ω φ < cn > c o u
CU Φ W 4-> φ «H K <
o u
4J c
o u
ω <
>
0) μ
ο <u tu
CŪ
4J
0) O 0) CU o o c —( s tu to o
Q tn <
>
iO p» d n o rd σ» rH
IC lC lC IC lC lC
> « • • •
r· σι T Ό o tr co
tT tr tr m n tr r»
ιη ο σι ο ο η π 'ΰ
Ol tr co rM Ο Ό tr γμ tr d tr pm
IC d d lC rM r*
1 n 1 d H n tr
d iC d IC o IC in -< ot Φ
lC cn IC <n d d
r> ρ* ο o co Φ pm tn m īo κ tn η n lOOfOcniOdfHd
IC d tr tr n co CO <-h p* d d CO o rH σι o 00 P- ** n 00 IC d
f*· o σι r-d P- co o r· co O co Cl σι d σι P* σι fH co ps CD σι
r-4 d r-4 d r-1 rd r*l d r-i «M cH d iH τ-4 d rM iH rH d .H iH cH r*4
O d LC tr m σι tr V0 d VO IC cn r4 n d Ό fM Ό σι •M CO fH
tr tr LC IC m <n IC IC IC tr IC tr lC tr IO IC LO tr L0 tr tr tr
rH rH «H c-4 rH «H rK rH rd r-4 rH r-J «M rH «H f4 fH i-4 fH
tu σ' to x o \ Q σ<
ooo Ό σι IN o
ts
r-1 d d rH d rH d r4 d rH d
o o O o O o O o σ o o o
o o o o o o o o o o o o
o (X o
□
A
X u
0.01 240 148 169
133 170
0.02 158 184
SPONTANEOUSLī HīPERTENSIVE RATS n=2 Body weight(s):46O,510 grams
183
Table XV (CONTl
VA50PRESSIN fVAS)VASOPRESSOR RESPONSE ,5
9 O> θ’ (β C Μ ια 9 XJ > U 4 θ’
C «
u m
4
S>
§.« u «u
Φ <M ιη ιη m
Π
Γ*·
Π Ο Ν ««· ο ο ιη ιη φ
Φ
Γ*>
ιη co r»
Η 03 Ρ Η
Ο rd Γ* η
co σι ιη σι φ
d σι Ρ Η Η
ΟΙ
ΙΟ r*.
rd ιη η
οι ιη
Ν’ΰ’τηΗσισιβ'ΟιηπΗσκΝΡ α
β «
u σ»
Ο σι Ο Ό Ό Φ m 01 η Ο ιη ιη ΟΙ ιη ΟΙ Φ ιη Ο Φ ιη < οι ιη Ο Ο Ο rd rd rd Φ rd
Γ* Φ σι ΙΟ d· ΟΙ ιη ιη ιη ο m Ο ιη m ιη ιη m ο Φ τ ιη ο Φ * ιη Ο Φ Φ d* CD in 5t
ο rd ο rd ^4 rd rd rd rd rd rd rd rd rd ο rd rd Μ rd rd rd rd rd rd rd rd rd rd rd rd te
Γ*σΐ^ηΗΟΟΓ*^0^^00·Ηφΐη^ΟβΟΦΟ<ΐηθΟ»Ι
00^01^01^0^01^01^^^^^01^01^01^010 ιη » ο I Ο Η Ο
O o o o o o O o
o Φ σι Ol to ·* o
rd rd O| n
ο σ> a Jd ο \ a . >
gul ω
ca J4 o q σ> β η σι σι Δ Η Π Η tP
rd Ol rd n rd 01 rd n rd 01 rd Ol rd oi rd 01
O o o o o O O O O o o o O o o o
o O o o o o o o O o o o o o o o
>
•+4 ο
α >
τ» η
Η
C
Β s
Μ <η «
Μ
Οι ><
X >
J w
Ο
U
184
Table XV fCONT)
VASOPRESSIN iVAS)VASOPRESSOR RESPONSE
Λ C l-t co
01 Φ σ> o» 10 C tn tn
Μ (β co CM •
0) £ r cn cr tn
« σ>
c (0
Λ
CJ «
<U
2* 0 M O. 4) m 4J 4» <H 06 <<
O U-i U «1 (S
V θ' m w
<U cr Ul ο ·χ Q CP
B <M tO n
CM n
tO sO
ΓΊ cn tn o
rt cn
CM
O
CM tn w m cm tn «n o
rt tn
CM to r*
CM
Ο rt
M· to tn CM 'ūO^,nnHr*nr>sor»^H<ncixo®n(Mott-iH
CMiMCMrtrtiMfnrtrtrtfMCMrt^CMrtrt^CMrtrt^rt
© Ot tn CM co CM tn CO n © © CM cn CO co tn O Γ tO Γ- tn to © tO tn σ\
co co © O tn Ό to m Ό γ*· r» co tn Ό to €0 to © Γ- r* to to co CO r·
«—t rt rt CM c-4 rt rt rt rt rt rt rt rt c-4 rt c-4 rt c-4 rt rt rt r-4 rt i-4 rt rt
. co r* co I rt rt rt
cn CM rt CM CM r» r- © CM © tn tn T rt M* m rt CO CM co r* cn rt rt
M» Ό tn Ό tn tn tn r· M» to cn in tn tn *r tn rt tn tn * to tn
rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt r—4 rt rt rt rt rt rt rt rt rt rt
Xf © o
co a
σ\ o
CM o
co
CM
rt CM rt (M rt CM rt ΓΜ rt CM rt CM rt CM rt
© o © © O O o o o O O © O o ©
© © o © © © © © © o © O o © O
>
-rt ©
\o
X u
0.02 152 193
173 204
SPONTANEOUSLĪ HĪPERTENSIVE RATS n=2 Body weight (a) : 480,520 grams
185 μ
•d
Λ
Table XV (COHT1 yftSQ£BESSINiVĀS)VASOPRESSOR RESPONSE «i a e» e» <a c μ α o 4= «
2* tt
Λ u
tt >
B
M 0· tt tt V tt <W 06 <
<
0> μ «
C 0 0 <H U 41 a
-M α ® o a eu o o e
« cn a x « θ' η x ι2 ti β
CO P* CO r* co © co CM CO 00 P* O CO p* p» d © Φ IA 10 m © P- ia cn «A
ιΛ tn in
in in « lA « • in
P* © • • CM • d P*· n o •
IA © r- © CD © d σ\ d d CN CN o o d
d CN CN
r*· r- o cn σ π in m (n in d ο ιη ρ* σι r· cm d o ©oiAOfN^r*N»©iA®cNp*os HrlH(7\HrlHriN(NrtfNfMfnHCļH(N tt a
u
EP d Η □ N H co σ» h m
Κ Η H fN H
ΓΜ ©
os
LA snsnsnr*©osfM«NinoFMd®®®©©r*»®©®d^d ια-^ια^τ’ρια’Τ’τιαιαιαιαιαια^ιαιαρ^^’ιαιαρ-ια ©
in
1A a
.u
N* o o d CM P*· 0s © © © © <ρ fN P· cn Pl © Ν’ d © « © * os CN d d » © IA je
Ν’ d lA V IA •e LA d T d 5P d xp d d d d d N» d d d d CN d d CN d d B>
d d d c-l d d d d d d d d d d d d d d d d d d d d d d d d d d d d d
« »
►.
s
B
o o o o o o O © ΓΜ
d © σι CN © o 1
d d CN d c
d CN d CN d CN d CN d CN d <N d CN d CN >
o o o O O o o O O o o o o © O © d
• M
© o o © o o o © o © © o o o o © 2
>
-H o
«
Et
K
W
0« >
s n
u l
l m
186
Table XV (COHT)
VASOPRESSIN (VAS)VASOPRESSOR RESPONSE φ Φ θ' σ> 10 c u <0 Φ Λ > U
Φ cp c
m α
«
V
ω >
C
ο Μ
α Φ
(Α 4J
0) <Η
α <
W
*rt >
0
Iri Φ
4J Ρ
C 0
0 <W
υ Φ
03
-Ρ
ω Φ
0 «
α< 0
α
C
•Η
X
V CP
Μ χ
Ο \
α
3
01 •
< •rt
>
Φ cp η x o \ Q CP
S
M· m
co tfl
KO
KO σ»
KO o
P*· κθ
Ot tn
ΙΛ tn rt m
P* in in
CO fN σκ fN eo rt
CO
CN
O) in η γμ (N ko rt ο > ό fNa5p*rtOtnKOp*rtcN^rtp*inrtcoeooO ^(Ν^^1ΝΓ'(Ν!ΝΟ(ΝΗ(ΝφΗΗΗΗΗΗΗΗΗΓ)(Κ|ΗΗΠ(ΝΗΗΠΝ ffl a
M
CP
rt ο η σ\ 00 04 Ό Ο Τ Ο OJ •α· ’Τ 04 Ο CO -f κθ 00 KO CO 04 CN rt tn CO in rt tn rt rt tn
σι Ρ* rt 00 Γ* tn P* ΚΟ ιη Γ* κβ C0 tn Ρ* κθ Γ*» tn Ό tn n» tn (0 P* a> tn Ό P» p- *O KO 00 co
rt rt ΓΊ Μ rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt H rt rt rt rt *
tn co tn
P
Μΐη<ΝΓ*ΌΐηοσκιηοιηωκοθΓ4<-ΝΜ\οοοισνρ*οοοβοβΓ>σιηη»ηί»*Λ ^^•tn^m^inc»^m^tn’«rK0’TKO^,inrtK©rttnN»inrtN‘Otn,*^,tntnO*
ΗΗΗΗΗΗΗΗΗΗΗηΗΗΗΗΗΚΗΗΗΗΗΗΗΗΗΗΗΗΗΗΉ ο
κθ ο
<Ρ ο
<Ν ο
rt 04 rt 04 r-1 04 rt 04 rt fN rt fN rt <N rt CN
O © O O o o O O o © O © O O o o
o o o o o o O o o o o o o o o o
>
•rt ο
rt ω
Ο
CN
II
C (Α
Ε* έ
«
Η
Ρι
Η
X
X
X
J w
Ο
Η !
!
187
Table XV fCONTI
VAS0PRESS1H fVAS1VASOPRESSOR RESPONSE e
o •rt •P rt
Λ
0) σ» σ» « c k 0 0 j3 > υ <
C*
C jC u
« 2 g> Ο P 0.0 ω 4J 0 <M K <
w rt > o
Md υ 0 ffl
0 0
O 0
& 0
c •rt X Q
φ cn
ΙΛ d m in σ\ m d* φ LO n in in L0 rt Γ- ΙΟ σι rt CO tn rt rt in d rt r- *
ΙΛ m ic tn Ifi in
• • • • • • •
Cl O CJ n 9> CO T Cl 10 rt rt d rt m r·
Cl m rd Cl rt rd Cl rd rt rd d rd d rt d
IO CO O rt Η Η Π Γ» n m ’t rt O rt
Ο (Ο Ό © ΙΠ rt r( (Ν H cn CD c» rt CM rt
D «0 Η d (M rtrtrtdrtrtrtrt > ν η σ\ σι σ» o > «5 > > > d d d d Η Η H ο σ\ Ό Ό <nnr*o>dcndtf»<nd
ΙΟ«\Ο\ΟΓ-ί*·ΙΟ1Ο(**«0
CNn^nnHiDdOi^n^'OdrtOdoie'rt'fle'i^ddoe ',βνΟΦΏΐΑνΟΌΐηΌΐΩΙΩΐηνί'ύΙΧΙΐ^ΐΛίΑ^ΓΚΟΐίΙΐηΐηίΑΏΏΏΙΑ ddddddddddddHHHHrtHdddddddddd o
ci o o co d· rd Cl
cn nx ' \ σ> a
rt d rd CJ rd Cl rt CJ rt d rt d rt Cl
o o o o O o o o O O O © O o
o o o o © o σ o O © O o o o
0.01 300 145 160
150 165
0.02 150 180
155 179
SPONTANEOUSLī HĪPERTENSIVE RATS n=2 Body ueight(s):400,400 graus
188 »
cn ω
u %
o co co ω κ o, o co
Table XV (CON1 co co ta ta
o.
o cn *c >
c o —4 •P •rt Λ ’ Ή
X3 c
Η
Φ Φ tr tr ια c ρ ια φ Λ φ
θ' q
ια χ;
α cn φ 4 α > c ο Ρ CU Φ Φ -Ρ φ 4-4 Λ <
cn rt > ο
Ρ Φ Ρ Ρ C ο Ο Ρ □ φ
C0 «Ρ ω φ Ο Φ CU Ο
Q
C
rr (Ν ιη rt 10 ® (Ν r-4 ιη ΓΊ ιη ιη Ό ιη ΓΝ rt 0 0 rt θ' η ® rt Π η ΓΊ I
ιη ιη ιη ιη m ιη ιη ιη
• • • « • • • •
rt rt 0 ιη rt η rf 10 00 οο η σι (Ν fN η
V m η m Η Ο ΓΝ <Ν rt η rt V π * η ΙΛ
inortOairtrtin®rt®0rtrt,r4r*0>ai®iNnr*-Ortrt®0rtrtO®
Ί,ΐη’?\θΜΠΙΓΐΠΗΗπηΝ(ΝηΗΗΗΓηΠ(\Η««(ηΝα'η(*ΐΓΊΐηΐΛ ο
ια
Ρ tr
σι Ο σι 10 η ιη ® Ο Ο σ> rt rt ® ιη Ο η Ο Ο Ο rt Γ* Ο η Ο ® <Ν ιη rt 0 η rt
ο rt ΓΝ rt σι C0 rt t—4 co 0 σι ® ® 0 rt 0 rt 0 Ο σ' r* ιη σι rt rt· rt σι 00 00 0 Ο ο ό·
CN CN fN (Ν rt rt CN CN r4 rt <—I rt rt rt rt r-l rt γ-4 ΓΝ rt rt rt rt rt rt rt rt rt rt rt ΓΝ CN
ο
Γ*» φ cr ω >ί ·
Q · > 3 · cn · η < -rt >
rf Ο 0 0 0 ΓΝ ιη φ CN rt rt rt ω τ •f ΓΊ rt η rt fN σι σ\ Ο Ο rf η Ο 0 fN 0 0 rt P Λ
0 0 ® η η η 0 ιη 0 rf 0 η η rf rf rf η rf 0 ιη rf η η η rf rf η rf η η n rf &
«—4 rt rt Η ρ-4 rt rt r-l r-4 rt rt rt rt rt ι-4 ι-4 γ-4 rt rt rt rt Η Η rt rt rt rt rt rt rt rt rt •H
Ο σ\
Ο
Ο
ΠΊ φ
>
>
Ό
CD ίΜ
C w
(Ν
Ο
CN
Ο (Ν
Ο (Ν
Ο <Ν
Ο fN
Ο cn §
£ ω
β.
>
V cr s
W -X -rt •rt
0 X >
Q cr O O u
s rt fN co
-sr· s
o
CN CN ω
J ® ® z
o • 3
α 0 6
E-t 4m 2
2 • • o
O X X £
U ω ω to
189 rafelg.KV iC9HT)
VASOPRESSIN (VASIVASOPRESSOR RESPONSE c
o •H X» Ή Λ I «i ē
H « ® cn tn « c (4 « 0 Λ
Ž υ o» c
Λ υ
.2
Μ > C
Ο Μ Ο. β) (0 X) Φ <Μ Λ <
w >
φ μ
ο <Μ
Φ β
o* 0 o» 0 0 t/· π o» r* 0 CO 0 r* o* co n oi n ri (O o n
0 in ir» 10 0 to to to to
« • • • • •
«0 ri o i» 0 Π m 0 σι Ol * ri 0 o* C4 r>
«r 0 r-4 ri i—4 n Ol ri m Ol Ol o Ol
co ® σ\ 04 0 5J· ιη 0 ri γ-μ «τ
ΟΙ
ΟΙ ri ri c-4 04 Ο <ο ο ιη ο Γ* οι οι r-< Ν (Ν * Ν Ν Ν η σι η* ο* * ΟΙ Ο| η Ο 04
ri ri 04 to ’T CO 04 p- 04 r-4 0 co 0 n 0- 0 0 IO 0* CO o 01 Ol 0 to
01 ri ri 04 0 θ' 0 0* 0 0* o CD 0 0 O- « 0 0 P* CD 0 Γ* 0* CO to f*· 0 o
ri Ol Ol 04 ri ri r-4 ri ri ri Ol ri ri ri ri r-4 ri ri ri ci ri ri ri ri ri ri ri ri
r» O 0 Ol 04 σ 04 CO ri ·* n Ol 0 o n o O- ri 01 0 0 ri r» 01 0
0 0 0 Γ* 0 0 0 0 0 0 0 0 0 0 0 *· ’C ΤΓ Tf m *
ri ri ri r-4 r-4 ri r4 r-4 ci ri ri ri ri ri ri r-4 •-4 ri ri ri ri ri ri ri rī H
χ» α φ ο α
Οι ο ο ο ο α η ό
C ο σ σ' <ν ο ο β * •Μ Μ ri 0 ri οι *
Φ θ' ιο α ο \ α >
Φ θ' α χ
S □» β
ri 04 ri 01 ri Ol ri 04 ri O| ri 01 ri Ol
O O o o o o o O O o o o O o
O O © © o © o O © © o o o o
0.01 300 137 161
151 172
0.02 148 193
150 191
SPONTAJNEOUSLī HĪPERTENSIVE RATS η=2 Body veight(s) :600,490 graus
190
C
-H μ
—4 a
Table XV (CONTi
VASOPRESSIN fVAS)VASOPRESSOR RESPONSE ffl ffl θ' θ' ta c H «3 V Λ > o <
(U θ' c
ta
Λ
CJ w
0) < to > c o μ □i ffl m d v <u u <
o μ
c o
u w
$
V μ
o *μ
0) co ffl
O
CO c
-μ
X ffl ffl
Q w
ffl to □
tu n
o
Q o<
X \
ot
X tr β
r*i CO tn Γ-» r- <-> 0* °*r Ό φ o* tn Ol co Od °<r m tn tn ch «r tn tn ch
m tn if) LO tn tn tn tn tn
« • • • « • • • •
Ό m •’f ch <h <h r* Ch tn tn 9t CM oo Ol ¢0
OJ n rH rd cH cH cH
οοοεο'ώβΓΜΓ-σνΟΓ'αϊΓ' oo tn ve in oo r-tinotr-otinott^ot
OJ rt rt rt d rrt <4 tn(īiOtnmr'Oco(Noico'i>oinci(NO)'rc~<Nrtimr>r»rTtocjr^
OinotUJ'ūcjO(-ivotnOrtiiominmtnm«rm^'d-»cj'»<rttncj
-<r t O» 0* Ol 9\ Ό © tn tn <h i-4 m ΓΊ xf tn n σχ 0* tn CO ch tn © r» tn co
Ot m tn tn n tn Ol <n ot «n O| Ol r m n Ol Ol H O» © OJ o <n ©
r-t r-4 rH rH rM ^4 r“1 »-4 c-1 rH f-4 cH c4 c4 c-4 cH K rH ci H H rl rl i-4 r-4 r-4
O O o O © © O
n Ό Ch OJ C0 TT
<-4 c-4 Ol
c4 Ol r-4 OJ i—4 OI «—4 01 r-4 Ol r-4 OJ r-4 OJ
© © © o © o o © o © © o © o
o o o o o o o o o o o o O Q
J o
a
Z m
ts
O z
X w
0.01 300 129 144
107 116
0.02 135 152
108 127
SPONTANEOUSLY HĪPERTENSIVE RATS n=2 Body Veight(s):540,530 graus
191
Table XV fCONTl
VASOPRESSIN tVASlVASOPRESSOR RESPONSE so ss c
o xi
o <N
φ φ θ' σ< ιη ιη
<0 Β •
u « CN φ ο
Φ Β 5° 10 ιο ιη
Φ θ' c
B u
V)
V < α > C
O h O, « to Ρ
Φ <XI
X <
ui <
>
« h
<XI
Φ ca ®
tn o
Q θ’
ΑΧ \
θ'
ΑΧ θ'
Β tn r-t o
Ό in tn r~ co * tn * eo <n r·.
tn n tn o rtn in
-τ
ιη ιη ιη
CN ** m
η CN <η
ιη ιη ιη ιη • ιη
\ο »η \ο Γ* eo ο
<Ν η CN Λ CN r ΓΊ e
'»ΗθΊ'Γν'ίο + Γ'(ΝΗ',ηιοσιοΌΌ + Γ·ηο + Η>οιηΓ·Γ'ηη^ 'i'icO'rp-D^+rtd'iOinpivr-iiNiNvoīnrivnnnionncion tn a
«
Xt σ' o
ιη σι Γ* Γ* Ο rM h· CO o tn cM h» cn r·* r* O CN CN & r* r> Ol CN cn CN CN i-n © r* eM rM CD in
ο σι CN Ο FM π· CN co in in σι u> Ό oi 0 Γ* Oi r* i0 in Ol r* r» tn Oi 10 r* m o 10 tn
CN eM CN rM CN rM CN rM rM rM rM »M rM rM rM rM rH rM FM eM rM rM »M rM eM en eM eM eM <N rM *
o α
* (0 χΐ
•M co CO cn \0 in γ- m cn O m © rM 00 n L0 \0 CN © O Oi C0 CN m CN <0 cn O CO co B
cn rn N* cn M· in n· cn ’f tn n· Ν’ Ν' -<r T rn <r in tn cn cn T Ν’ cn cn cn cn CN cn <n σ>
rM rM tM rM rM rM rM rM rM rM rM rM rM rM rM eM eM eM rM rM rM rM rM rM rM rM fM eM rM eM eM rM •H
•α ο
α (Ν
o o o © © O O O II
cn īo σ\ CN co Ν’ o E
rM eM CN n
Ε+
X
rM CN rM CN rM CN rM ΓΝ rM CN rM CN rM CN eM CN £
© o O O © O © o © O O O o o o O w
cn
o o o O O © o o o o o o o o o o z
Μ
U
CU >
X
o rM o CN
Γ* >
J CO CO
o •
X O 0
t+ z z
55 • •
O X X
υ w ω
Ρ·
Ζ
192
Table XV (CONTt
VASOPRESSIN (VAStVASOPRESSOR RESPONSE c
Ή
4J •O <#> -rt £
<D φ tP (P «J C ij rd 01 Π > U ai ip c
Λ
U
OT < n > c
Ο H ο. οι η -μ 0) <w co <
ω
r4 >
0
u ν
P u
c 0
o <u
υ <U
CD
-u
Ul Φ
o ω
cu 0
O
c
-rt
X
o tr
m Αί
o
Q
©
OT •
< •H
>
ai
w >:
0
ώ cr
β
CO co (N © r-4 CO Tf co r-| CO o CD n KO Ό tn es n 00 Tf α n T r4 ci
tn tn tn tn to
• • • • • «
© CN tn in r- © Γ- CN ιΛ n- IO CN IA IA f*·
Tf KO r-4 r-4 rd CN CN n CN Cl CN
σιι-irir-iininoooifiininuio (N OT OT rt rt rt —( co in ifOininoininuioinviLTooino
Cl m CN © ιΛ O o O tn o o tn o tn o tn o o o © O © © © © © © tn ©
o r-4 CN Ό KO KO Γ KO r- co tn Γ- KO tn Γ- co KO 00 r- © KO CO F- © to CO
r4 CN CN CN r4 r4 r-4 r-4 «-4 r-4 u •-4 r4 r-4 r4 r-4 T-A r4 r4 r-4 c4 r4 r-4 r4 r-4 r-4 r4 r4 r-4
© co O r-4 in O © © O © tn tn o © o © O tn o tn tA tn o tn lA tn © © o O
Tf in tn KO tn KO O KO Ό KO m Γ' tn kO in KO Tf tn T tn n tn Ν’ tn ci tn Tf tn n tn
r-4 c4 r4 r4 r-4 t—1 r-t «u c4 r4 r4 r4 r4 r4 «-4 r4 r-4 r-4 «-4 r4 r4 r-4 r-4 r-4 r>4 r-4 r-4 i-4 r4 r4
O O o o o o o O
n ko o CN co Tf O
r-4 r-4 <N Cl
r4 CN r-4 CN «u CN r-4 CN r-4 CN r4 CN r4 CN H
O o © α o O O o O O O o O O O
o o α o o O o o O O O o O o o
o «
Z o
o tp co
Z
X w
O.O2 135 170 35 32.
160 190 30
SPONTANEOUSLĪ HliPERTENSIVE RATS n=2 Body «eight (s) : 610,600 grams
193
P
P «I «1 ο» &| ra c p ra i5
Ο σ\ co D r> © θ' 00 rt C0 o ®
tn ιη in in in
* » • »
eo ej tn r* © r» ej
rt· tD rt
rt <N tn cn ei Ό ©
r· P* m tn tn tn to
in tn tn tn
rt r* CN σ\ o σ' to CN
rt irt CN CN PN PN *rt n
Table XV fCONT)
VASOPRESSIN fVAS)VASOPRESSOR RESPONSE
Φ
CP c
Λ
Λ υ
ca φ < α > c ο u α φ w 4J φ «W £ <
ta <
rrt O
u φ
4J M
C O
0 u-l
u 4) ca
4J οι Φ 0 tfl 0« o o c
•rt £
Φ tp m x o
Q . > □ ca ·
C >
4) cn o
o σ» x
σ' β
tOrtOuitrt(noinmocovooaomoot4>r*.coo)(MQDOo9rt(Mr*aouiri(M Ν’ ιη Γ* <η Η rt rt rt rt ΓΜ rtrtOtPNrtrt’rtFHrt’H'rtrtCNrt* β
Μ σ» ο
oinoinainomoin®rtLnoinooOtnO'*inr'intnocpfN^rtp*otrt C'OCNrtintn®inO©intO'0OO\or'M'totOO'Oto©tOin«ointOtoto«0© rtPMPNPNrtrtrtrt·—IHHHHHHHr-(ΗΗΠΗΗΗΗΗΗγΙγΙΗΗΗΗ ' λ ^ooinoo©r-tnoinirti\ioooo®iN<Nnettntomr*intOO*r* ifiin'ū’i'tfiiCtninirinininininAin*n,n'’tr*^*TNTnu'^r9p
CN
O © α © n \o ot o o tN 00 o o
N· o cn n
4J
Λ θ' •rt
Φ >
>4
-σ ο
η <Ν η
c ω
ej
O ej o
CN ©
(N ©
PM ©
CN
O irt
O
CN
O cn ο
ζ
X
Μ
S2
Μ (Λ
Ζ ω
S
U
CU £
η ο
ο
U
194
Table XV (C0NT1
VASOPRESSIN (VAS1 VASOPRESSOR RESPONSE
SS
4i •rd
Φ Φ Oi θ' (0 C U fl Φ 42 > U <
Φ ζΡ q
φ
U w Φ < w > c
Ο M O< Φ 03 44 o <w « <
w <
o >
k Φ
•U u
d 0
0 Md
CJ Φ 03
•u
ω Φ
0 (fl
Or o Q
c «
n o
o w
β) σ> ta J4 o \ O cr> s
CN rΦ d d· οι οι oi in v
CN o O
Οι οι oi co co in n
eo d r* r*
Φ Φ d p* p» r* in^roimcNfNtn^rOkoinvoīnmcoOīnr-moior’-neoneOcN d* ΙΛ Φ P· rdrdrdrdrdrdrdrdrd
n CO CO in CN rd <N P- d· Ol O tn CO CN P* U? Ifi © 01 rd co d n CO <P Φ 00
o o ΓΝ ΓΊ Φ d· Φ tn Φ Φ P* in Φ Φ Φ Φ Φ Φ Φ φ Φ P* in Φ Φ m
CN CN <N CN rd rd rd rd rd rd rd rd rd rd rd rd rH rd rd rd rd rd rd rd rd rd rd rd rd
co d Ol o O 01 P- n d n rd d O n T rd rd co in © rd rd rd Ift in Φ CO 00 Φ
m in tn Φ Φ n in Φ ID Φ Φ Φ Φ Φ m Φ Φ u*> Φ m IC tt tn d in d» ΙΛ d·
rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd
© © o
Ο Φ Oi o o o cn eo 5t
H rd CN
o
Λ £*
Z o
u π
σ
Ο
Ζ
X ω
156 166 12
0.02 144 162 18 18.
154 171 19
SPONTANEOUSLī HYPERTENS1VE RATS n=2 Body «eight(e):500,460 grams
195 lablS XV ίΟΟΗΤΙ
VASOPRESSIN (VASiVASOPRESSOR RESPONSE
Dose VAS Dose Min Post Control Response Average % (mg/kg) i.u./kg Dose Before VAS After VAS Change Change Inhibition
ΙΑ d © Γ* © αθ © Ο Γ* d © Ρ· Ν’ d ΙΑ © V Ν’ V d ΙΑ V © Ν © η
ΙΑ ΙΑ ΙΑ ιη ΙΑ ΙΑ ΙΑ ΙΑ ΙΛ
I • • • • • • •
ΙΑ d σ» © ιΑ © d Ν © d Ν d Ν Ρ*
Ν» © ΓΜ LA d d d ΓΜ ΓΜ ΓΜ ΓΜ d ΓΜ d ΓΜ d
Γ''ΤΐηΓ-·οσιιηη'Γ'ηΓ'θτησισιθ«ο>-ΐΌ<ΊΐηΛΓηη''β'θ<ΝΡΐΌΐηο + + ΌΙί1ΠΙΝΐηΐηΗΗΗθΓ-(ΚΗ(ΝΐΝ(ΝΜΠΡΙΜΠΓ,ΗΠΐηηΝΝνΐη α
β α
μ σ» ο
ΓΜ σι ΙΑ σι d Ρ* ΙΑ Ρ' d ο Ρ* •Ν CO Ο Ρ· d Ρ* © Τ P* © d © d· © O © P* IA d d r-
Ο ο ΓΜ ΓΜ © σι ΓΜ ΓΜ Ρ* © Ρ» © © © Ρ* © © © P- © © © © © © © © © © r* © © N
ΓΜ ΓΜ ΓΜ ΓΜ d d ΓΜ ΓΜ d d d d d d d d d d d d d d d d d d d d d d d d ·»
ο rμ
lA lA O ΓΜ d © O O N © © ΓΜ P* © P* d d d © © N d d N» d IA CM d © Π £
tn © © P* © © P» P- A lA © © in © lA © N © IA © Ν’ in IA © IA IA cn © N IA N © tn
d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d •d
ΓΜ
II
C w
Η
Ο Ο r-Ι ΓΜ
If) A
J © ©
O •
Λ 0 0
z Z
2 «
o X X
u u ω
S
Ό
Ο
Μ η
ζ «
S
Μ
0« ζ
>
»3 ω
ο ο
U
Ε<
Ζ <0
196 is wi cn
O
Od cn ω
c o o cn cn w α α
VASOPRESSIH (VASIVASi c
o
Ή +J
Λ
JS c
« 0) tp θ' ιβ C U Φ ο ύ
Šu φ
σχ c
to
X u
Φ w
c o
α ω
φ
Λ cn <
>
Μ
Φ
4J «W <
ο u
-U
C ο
υ
4J (0 ο
Od
C
-Η
X φ
m ο
Ω cn <
>
φ ω
ο α
ω <
>
φ u
ο φ
X φ
φ ο
Ω σ>
X 'χ □
σχ χ
Εη
ιη Ό Ό νθ ω Γ* © > © ιη ΓΜ Γ*· Φ η Ο Γ* ΓΜ ιη ΓΜ Ρ· ΓΧ <Η ΓΧ - ΓΜ © Γ* ΓΜ
ιη
m ιη ιη ιη ιη m m ιη ιη • ιη ©
< * • • • © • • ω • «
ΓΜ Γ r4 σχ ΓΜ η γ4 γχ Γ* ιη © Η σχ © ΓΜ
η m γ4 ι-4 Γ* γ4 γ4 «-4 γ4 rM Η η γ4 ’T
σχ © © σχ σχ ν η ιη ιη η ©
ΓΜ ©ο©γμ©>*γγχ’’Τ
CDlOHHHHHHHrtH
Ή > ΓΜ γ4 ·*τ«οχ®γ*γμ©©
ΗΗΗΗΠίΤΗΗ
Ο β
φ
U θ' ο
ΓΧ Ο ΓΧ ΓΜ ΓΧ ο © σχ © © © © ο ΓΧ © σι r4 σχ ΓΧ η ΓΜ © ΓΧ Γ* *Γ ΓΜ © «Γ
© © σχ c4 m © ιη Γ © © © τγ © © © τΤ © © © © © © © © © Γ* Ο © © 00 C0
»Η γ4 ι—1 ΓΜ r4 γ4 γ4 »4 <4 c4 γ4 r4 Γ—1 ι—4 «—1 r4 ι—♦ γ4 r4 r4 γ4 γ4 γ4 Η Η r4 r4 Η Η γ4 γ4 r4 Η
ο ο
m
*τ *Τ Γ* σχ ’T σχ ΟΧ φ σχ O 00 ΓΧ Φ © © ’T © > 00 © O 0X © ΓΧ 00 © © CO r* r* 00 Λ
η ’T ΓΧ © ’T ΓΧ ’T χτ ’T ΓΧ ’T n ’T ΓΧ ’T ΓΧ ’T ΓΧ ’T σχ rx rx σχ σχ ΓΧ σχ ’T σχ CP
ί“4 r—4 c4 »—4 r—< «-4 r4 r-M t—t r-M «-4 r—1 »—4 c4 r—4 r4 c4 r-4 «“4 r4 H i-4 r4 H rM r4 r4 r4 r4 r4 *4
Ο
ΓΧ ο σ ο νο σι ΓΜ ο ο ο co ττ α «η cm σχ
r4 CM r4 CM r4 ΓΜ r4 CM c4 ΓΜ r4 CM rM CM r4
o o o o O O α O o o O O o o o
o o o o O o o o o o O o o o o
J
Ο
3S
Ε-ι ζ
ο ο
Ό
Ο\ ο
ζ
X ω
>9
Ό
ΓΜ
II
C
C0 ε-«
S £
ω
ο.
>
χ >
ι-Ι w
ο
Η ζ
«
197
Tāfrlfi XV_igpŅT)
VASOPRESSIN <VAS)VASOPRESSOR RESPONSE
-rt
X5 φ Φ tp tn Φ g b Φ φ χ; ► u <
φ cn c
«X
42 U tn
Φ <
in c >
0
0. Φ
u 4J
Φ
K
-U O >
u φ
U b
C 0
o rt
o 4J Φ m
α φ
0 (0
0. c X o Q
Φ cn
tn X
□ \
a 3
ta •
< *rt >
PS rs ep rs ® rt o rt rt rt rt rt rt p· rt co rt rt 0 O rs rs rt
0 0 in 0
« • • • 0 0
σι 00 PS 0 a> rt σι rs σι O co O 0 • •
<M N· PS rt rt rt rt rt rt er rt rt o rs rt
rt rs ef
rt 0 ρ· σι rt rs <*» rt 0 rs rs rs er CN γ* ο n 0 ® 0 ot rt rt rs rt rn rs rt σι rt ρ* σι to rt rt rt d» er ic u> i0 rt rt rt rt rt rt rt rs rs in
rt rt CO O rt <0 rt CO o o P* © rs rs rt co 0 σι rt co o 10 rt © σι rs CO P* 0 CO tn
<0 co σι rt co co σι σι ® P· σι σι co P* © co P» ρ- O σι r* P- o rt 0 p* CO σι P* ©
rt rt rt rs rt rt td rt rt rt rt rt rt rt rs rt rt rt rs rt rt rt rs rs rt rt rt rt rt rt rs
σι
co co rt rt O rs O 0 CO 0 O © cn P* rt rs P- OT P» rt P* 0 0 rt 0 rs 0 rt r* er
0 er 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 P* 0 0 0 0 0 rs 0
rt rt rt rt rt td rt rt rt rt rt rt īd rt td rt td rt rt rt rt rt rt rt rt rt rt rt rt rt rt
η
o o © O o o O o
rt 0 σι rs co er o
rt rt rs rt
* rt rs rt 04 rt rs rt rs rt rs rt rs rt rs rt rs
> O o o © o O O © o © O o © o o ©
w o o o © o © o o o o o o O o o o
ν σ> w
O -s. Q tn >
-H
O <0 o
z
X «
SPONTANEOUSLĪ HīPERTENSIVE RATS n=2 Body veight(s):4 60,570 grams
190
Table XV icont’d)
VASOPRESSIN (VAS)VASOPRESSOR RESPONSE
CM rt
I
a Φ θ’ θ' ιη tn
Ιβ C »
M ra © to © rt to
Φ Λ > <-> cn tn rt to cn
Φ θ' c
d £
u
Φ tn c
o α
(Λ φ
οί
Ο
Μ «Ρ
C ο
υ co tn © rt rt © ττ rt © O CD rt © © CM ©
CM
CO © Γ cn rt m tn • to © CM rt
N* CM CM
O O to © co ν· o pj «r «r r\ ©
CM rt rt
CO rt f*.
CN © CM CO rt rt CM tn • tn to to <M
CM * rt > © cm O CM CM tn ©
CM tn
CM tn tn
O © CN
N CN N © rt CN © p» tn © CM CM rt ’T Cl CM rt <
>
Μ
Φ
4-1
4-i <
w >
φ
Μ
Ο
Μ-4
Φ
-P
tfl Φ
0 to
0. 0
c -H z Ω
φ ω
Ω cn >
Φ ω
ο
Ω
Ν’ rt O © tn rt O (M CN 00 rt rt Ν’ rt 00 © rt © rt rt CD © tn rt C0 rt tn tn
© © rt O © © CN CM co o © rt rt © © © rt co C0 © to rt CD o tO © rt ©
rt rt CM CM rt rt CM CN rt CM rt CM rt rt CN CM rt rt rt CM rt rt rt CM rt rt rt rt
© © © O Ν’ CM Ν’ CM N· N* rt cn © CM o tn rt It © rt © cn rt © © rt ©
rf in xr © tn © tn © in © m rt tn © © © tn LO tn tn N* tn Ν’ tn rt N» N
rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt
ο ο ο η to © ο
<Μ
Ο Ο co ν· r-4 CM tr
2)4 tr χ
'χ σ>
rt CM rt CM rt CN rt CM CM rt CM rt Cl
o O O O o O o O o O O O O ©
© © o O o © o © o o © o © o
ο
CM
Ρ>
J
Ο ού
6η
Ο
U ο
X w
0.01 300 137 164
149 174
144 103
149 195
SPONTANEOUSLĪ HVPERTENSIVE RATS n=2 Body veight(s):570,460 grams
199
Table XV (C0NT1
VASOPRESSIN (VAS>VASOPRESSOR RESPONSE φ φ Ο» θ' «J c h <0 V X
Ž °
0)
Cn
C «
X
O » < tfl > s o o, □ w 4-> ai ή 2 <
o h
U c
u
Ui <
>
Φ
M
O <w ω
ffl ai ο η ' o Q « θ' m x □ oi · «C —i >
u o
Q tr
X \
o<
a
ιη 04 Ο 04 η 04 «ί* η σι ΓΊ Κβ rt η 04 0* rt κο σι ο» rt ιη 04 κθ 04
ΙΛ ιη ιη ιη ιη η ιη m
• • « • • » • • ιη ιη
Ο* ο Ο \β Η rt Ο κθ σκ 04 04 CD « I
rt 04 η OJ Π ΟΙ 04 η C*» ιη 04 ιη ιη
η 04
η η « ·ν η h ir, NnNnn(SN7i^NN«nnn«ifi(MnN.(NNrtifi α
a (0 h
θ' o
rt Ν’ *r ιη ιη ιη σ» C0 σ\ Φ rt η Ο- rt η n rt Κβ n Ό Ν’ tn κθ Ο- m Ο- in 04 co O o 0-
0* ιη 00 ο 0* Κβ σ> ο* θ' ιη σι 03 Κ0 03 co cn KO M3 co CO KO Ό co O> Ο <n Ο CD O o O· o
rt rt rt οι rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt 04 *
te
in rt CO O O OJ CO rt o tn O rt in rt CO 04 O CO o © rt 04 ο- o © m CD rt ffl rt O KO X Λ
rt 04 n tn rt in N· in in rt o tn O XP n rt rt V m rt rt η N* m rt N» rt m 0»
rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt -H
ο ο ο η Ό σι ο
Π|
Ο ο ο
-r Ο γί η
rt 04 rt 04 rt 04 rt 04 rt 04 rt Ol rt 04 rt 04
© O O © © O © © o O © o o o o o
O o O o O o © o o o O © o © o o
>
•Η
Ο
J o· in rt
o •
2 0
z
Z •
o X
u w
η
II
C m
Ρ<
ω >
Η ζ
Μ
Η ω
X
X
X
J η
□
S ρ>
X οι
200
Table XV (C0NT1
VASOPRESSIN (VASiVASOPRESSOR RESPONSE jG
G
Hd <u φ cp tn
Φ σ'
G «3
J=
U tfl Φ < w > G
O Jd α φ Vl x) <u α <
x>
W 0) <υ σ» Vl X o \ o *:
W ► rtC ’Fd >
<U CP Vl X 0 \ Ω θ'
Ē
o vo 03 vO θ' CO σν r* o 03 01 [— O CO co r- r» D r* VO VO rd C- rd Φ co Ό
m m m in in in
• • •
rd © VO VO d o CO o vo σι rd d d VO V0
d in rd rd rd rd rd rd rd rd rd
d Cl tfl W rd rd CJ rd rd rd rd rd rdrdrdrdrdrdrdrdrdfM rdCOr^fnO'lOOifNOa'C'rdnCMdCOrd oioiOt-iincoOr'VOsoīnr'inf^īnr^in rdHfMCdrdrdrdrdrdrdrdrdcdrdrdrdrd
OO'ddddfMOvndfMdP* r*<npxinr»inr*inr*c*p*vovo
VO rd > n d r» m d Ό d m d <N r* n CO o in Ό tn Ci ca ca m σν r* O
d V0 in VO d vo d vO m V0 d vo d v0 d V0 d VO r> Ό d VO d VO d in m vo
rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd rd
o vO o
σν o
co o
o r>
tin <->
0.02 148 169
158 169
SPONTANEOUSLī HĪPERTENSIVE RATS n=2 Body velght(s):500,460 grams
201
Table XV fCONTI
VASOEBESSIH MS)VASOPRESSOR RESPONSE
P •rt
0 ζΡ CP to c k /0
CP £
χ:
o
0 co <
0 >
C o k
α 0
0 P
0 <4d
£ <
rd co >
0 k 0
P k
C 0
0 M
o 0
ffl
P
0 0
0 0
cu 0
c •H X Q
0)
O
O co <
>
c· LO <P rt d· LO Irt Γ* CM Irt CM C» CO Γ* Irt LO C| (rt ΓΊ LO r*· LO rt LO CD d· OL Irt
crt m Irt in Irt in
« ♦ • • •
σι CM *y rt o r> rt CO r- Tf d m σι IO
rt en rt CM rt rt rt rt rt rt rd rd rt rd rt
O CO CO (Μ tM ιη o CM rt ol ol c»
Cl ·* rt CM ο ο η Ό d « -* rt rt rt Cl rt rt rt
© rd CM CO rt Ol Ol O rt rt Irt r* r* LO rt O rt LO irt r- CO «0 d Γ* rt rt d CO
σι CO rt co LO IO LO σι irt C· irt LO Irt LO LO P- (rt LO (rt LO (rt (rt IO LO (rt Irt LO (rt
rd rd CM rt rt rd rt rt rt rt rd rd rt rt rt rt rt rd rt rt rd rd rt rt rt rd rt rt
(Λ C If) «3 C H «n tn m lo τ ό
CM ό
n ci lD o
LO (M d·
LO CO rt V Ol Ol irt tn *r lo μ· ιλ rt irt c īo d σι d· in rt o o o η \o σι o
d·
CM
CP σ>
rd CM rd CM rt CM rt CM rd CM rd CM rt d
© © © o © O o o o o © o © ©
© © o o O O o σ o o © o o O
i4
O
Λ
Z
CO
Irt rt
X
X «
0.01 300 137 163
137 149
0.02 140 158
141 155
SPONTANEOUSLī HĪPERTENSIVE RATS n=2 Body ueight(a):520,515 graus
202
Table XV (C0NT1 cn z
o α
cn ω
α α
ο cn cn u
α o
cn cn ω
cu α
&
o cn <
>
c d
4J
Φ Φ CP CP tt C k (0 Φ aC > U <
0)
CP c
tt
JZ o
0) < w > c
O k OU Φ <n 4->
φ 4-1 (X <
•P m
o (X c
•d
X
Φ
0) o
Q cn >
φ ω
o
Ω >
Φ k
Φ co φ
ω o
Q
CP
X □
CP .X
CP a
CM © d © CM © CM r* CP M* © © © © CP © d © *T © d © CP © <P <· ©
© © © © © © ©
• a a e •
d Γ*» CP CP o CM © © d d d d © CM r*
fM d d d d d d d d d d d d d
’M'Or'r*iM©©dCP<POd©©Od©dCMdČMad©dd©^^Or»r'“
C\ (Ν Η η H d d ddd fMdr-tddddddddddddddd
Q β
tt k
CP o
© © CM o P* CM © CP o r- CM d O © Γ m CP fM fM © CM © r» © © © d CM CM © © o
© © © CP © © © © © © © Γ* r- © r· f*. © «f © © © © P* © © © P* © © © P*» ©
d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d *
© ©
P
d © © cn © © © © d © CM © © > CM © d O «e © © © O © © © O © «M d © Λ
•μ· M* ir © Ό· © © © © © © © © © © © •’T n © © © © © © © ir © iT © © © CP
d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d •d
ο ο o © © cm o o o
CO Μ» O d CM d
d CM d CM d CM d CM d CM d CM d CM d CM
o O o o O © O O O © © O o O O ©
© o o o © O O © © © o o o O O o
d· ©
d z
X u
s ffl cn e<
w cn z
ω e« «
w a, >
s >
j cn o
ω f« z
o
a.
cn
203
Table XV fCONT)
VASOPRESSIN (VAS1VASOPRESSOR RESPONSE
P •d
J3
XJ
C
ω ti
θ' tP
d C
ti
ti JS
> u
<
ti cn c
<e
Λ
O
CO
ti
ti >
c
0
α ti
cn P
cu Md
α <
co
<
rd >
0
u ti
4J u
C 0
0 «U
u ti
«
P
ti ti
o ti
0« □
Q
c
•d
X
ti tP
ti
0
Q
□
CO •
< d
>
ti o!
ti
0
Q tp
6
ΤΓ nin σι n·
M3 lf) lf)
CN r* t£>
fM ©
f* lf) co
f) tn co io o
CN tn *
id fN
O
CN
CN fN σΓΊησΗβοοιηΓ^Ν·ί*»^Ν·Ν·ΐΛ£θΓ^ο^ο<ΝΗ©©\θθ\θ^ΐΛΐΛ»-ι< Π (*l N -< d r-f r-4 (N CN Η (Ν Η Π H Hr4CļHr4fSC4r4fNHfMHCtf4(N ti β
β
M tP o
if)vj,vfh>Ha3(Na\!Ti^'HHkf'ūpjnj>Lnr'h^Na)(7)OHico\otf)r*-oin ncoifionm^Kortr^mr'r-i^rMr-cNincNvocNmojmninnOoifjfnvotn γ4ΗΗ(ΝΗΗΗΗΗΗγ4ΗΗΗΗΗΗΗΗΗΗγ4γ4γ4γ4Ηγ4ΗΗιΗΗγ4 * o
r4 r4 CD tn n tn ο α cn tn
Nt-irjae^OfNr'rroirīnr-NHoiai^docjif© nin^infsiin^tn«tncN'<rrdN»r-iN'Onrd«nfN^r4©
O o © © o © O O
o <0 σ CO ίΤ ©
rd rd fN m
p
Ό Φ Λ rd n 0* »d ed *d >
>
*0 o
aa
CN
N c
cn
CN
O <N
O (N o
CN o
fN o
fN ©
fN o
ro u
>
td
CO s
S ω
o.
X w
s
X
CO
204
Table XVI
VASOPRESSIN (VAS) VASOPRESSOR RESPONSE
Ex. No. Dose mg/kg Max % Inhibition Time (min)
2 30 i.v. 74 120
9 10 i.v. 95 60
17 30 i.v. 50 60
36 30 i.v. 71 60
99 10 i.v. 76 120
210 10 i.v. 78 90
217 30 i.v. 57 90
271 10 i.v. 56 60
274 10 i.v. 59 300
465 10 i.v. 35 90
466 30 i.v. 94 94
467 10 i.v. 65 120
46Θ 10 i.v. 68 30
469 10 i.v. 69 30
470 10 i.v. 87 180
30 p.o. 69 180
471 30 i.v. 35 90
472 30 i.v. 36 90
474 30 i.v. 30 60
476 10 i.v. 73. 30
30 p.o. 19 180
477 10 i.v. 33 180
30 p.o. 92 30
478 10 i.v. 76 120
479 10 i.v. 33 60
30 p.o. 69 90
480 10 i.v. 29 300
481 30 p.o. 53 80
482 10 i.v. 40 60
484 10 i.v. 79 300
30 p.o. 22 180
485 30 i.v. 64 60
48S 30 i.v. 43 60
489 30 i.v. 39 120
490 I0 i.v. 74 90
10 p.o. 65 120
517 10 i.v. 81 90
525 30 i.v. 70 60
527 30 i.v. 35 180
528 30 i.v. 66 300
530 30 i v. 89 120
581 10 i.v. 94 30
30 p.o. 79 30
562 10 i.v 75 180
5S5 10 i.v. 56 30
587 10 i.v. 75 60
589 10 i.v. 65 90
205
Table XVI (continued)
VASOPRESSIN (VAS) VASOPRESSOR RESPONSE
Ex No. Dose mg/kg Max % Inhibition Time (min)
30 p.o. 30 120
590 30 i.v 39 120
592 30 i.v. 37 90
593 30 i.v. 67 60
594 30 i.v. 36 180
595 30 i.v. 44 90
599 30 i.v 36 90
600 30 i.v. 78 60
Oxvtocin Receptor Binding (a) Membrane Preparation
Female Sprague-Dawley rats vveighing approximately 200-250 g are injected intramuscularly (i.m.) vvith 0.3 mg/ kg of body vveight of diethylstilbestrol (DES). The rats are sacrificed 18 hours later under pentobarbital anesthesia. The uteri are dissected out, cleaned of fat and connective iissues and rinsed in 50 ml of normai saline. The tissue pooled from six rats is homogenized in 50 ml of 0.01 mM Tris.HCI, containing 0.5 mM dithiothreitol and 1.0 mM EDTA, adjusted to pH 7.4, using a polytron at setting 6 vvith three passes ol 10 sec each. The homogenate is passed through tvvo (2) layers of cheesecloth and the filtrate centrifuged at 1000 x g for 10 min. The clear supernatant is removed and recentrifuged at 165,000 x g for 30 min. The resulting peliet containing the oxytocin receptors is resuspended in 50.0 mM Tris.HCI containing 5.0 mM MgCI2 at pH 7.4, to give a protein concentration of 2.5 mg/ml of tissue suspension. This preparation is used in subsequent binding assays vvith pH|Oxytocin.
(b) Radioligand Binding
Binding of 3,5-[3H]Oxytocin (pHJOT) to its receptors is done m microtiter plates using pH]OT, at various concentrations, in an assay buffer of 50 0 mM Tris.HCI, pH 7 4 and containing 5.0 mM MgC^, and a mixture ol protease inhibitors: BSA, 0.1 mg; aprotinin, 1 0 mg; 1,10-phenanthrolme. 2.0 mg; trypsin, 10.0 mg; and PMSF, 0.3 mg per 100 mlof buffer solulion. Non-specific binding is determined in the presence of 1.0 uM unlabeled OT The binding reaction is terminated after 60 min., at 22°C, by rapid filtration through glass fiber fitters using a Brandel® ceil harvester (Biomedical Research and Development Laboratories, inc., Gaithersburg, MD). Competition experiments are conducted at equilibrium using 1,0 nM [3H]OT and varying the concentration of the displacing aģents. The concentrations of aģent displacing 50% of [3H]OT at its sites (IC50) are calculated by a Computer assisted LUNDON-2 program (LUNDON SOFTVVARE INC., Ohio, USA).
The results of this assay on representative examples are shovvn in Table XVII.
Table XVII
Oxytocm
Ex No. Dose (μΜ) % Inhibition at 10 μΜ ICso
3 4 6 7 17 36 54 85 93 96 160 10 10 10 10 10 īo 10 10 10 10 10 90 98 92 97 31 67 94 98 87 94 31 0.36 0.66 0.35 0.13 2.45 0.16 0.46 0.06 1.2
205
Table XVII (conlinued)
Oxyloc!n
Ex. No. Dose (μΜ) % Inhibition at 10 μΜ Ιθ50
164 10 67 2.45
210 10 64 4
214 10 64 4
215 10 74 0.57
217 10 37 1.2
274 10 95 1
297 10 76 4
298 10 76 4
416 10 44.6 7.4
417 10 21
418 10 39
419 10 28
420 10 16
429 10 11
430 10 16
431 10 18
432 10 19
433 10 12
435 10 10
436 10 32
441 1 22
443 10 70
444 10 21
448 10 11
449 10 14
450 10 22
451 īo 43
452 10 36
455 10 75 2.9
460 10 77 3.1
461 10 44.6 7.4
462 10 14
463 10 55 8.5
464 10 71 2.4
465 īo 93 0.033
463 10 96 0.26
469 10 96 0.265
470 2.5 92 0.22
471 10 99 0.35
472 10 0
473 īo 20
474 10 18
476 10 94 0.82
477 1.25 97 0.029
478 1.25 97 0.04
479 '0 76 0.15
480 10 98 0.15
48) 10 88 0.24
207
Table XVII (continued)
Oxytocin
Ex. No. Dose (μΜ) % Inhibition at 10 μΜ
462 10 97 0.126
485 10 86 2.2
486 10 18
489 īo 44
490 10 99 0.3
491 10 46
517 10 91 0.32
519 10 97 0.48
520 10 79 2.2
524 īo 84 1.8
525 10 98 0.28
526 īo 97 0.47
527 10 92 0.45
528 10 90 1.17
529 īo 92 0.45
530 īo 99 0.31
538 10 90 0.9
546 10 91 0.99
547 5 97 0.26
580 10 79 2.96
581 10 99 0.2
582 10 96 0.675
583 īo 61 4
584 10 26
585 10 70 4.7
586 īo 61 4.7
587 īo 56 8
588 10 90 2
589 īo 79 2.9
590 10 12
591 10 29
592 10 41
593 10 82 1.1
594 10 19
595 10 49
596 10 86 4
597 10 42
598 10 2
599 10 92 0.35
609 10 66 2.7
664 10 95 1.4
665 10 97 1
666 10 83 2.1
667 10 89 1.6
676 10 32
The compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or basos. These salts include bui are not limited to the follovving: salts vvith inorganic acids such as hydrochioric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as
208 acetic acid, oxalic acid, succinic acid. and maleic acid Oth r salts include salts vvith alkali metāls or alkaline earth metāls, such as sodium, potassium. calcium or magnesium or vvith organic bases. The compounds can also be used in the form of esters, carbamatos and other conventional p'o-drug forms, vvhich, vvhen administered in such form. convert to the active moiatv in vivo When the compounds ai a employed for the above utility, they may be combined vvith one or more pharmaceuticallv acceptable carriers, for miample, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules. dispeisible povvders, granules, or suspensions containing, for example, from about 0.05 to 5% ol suspending aģent, syrups containing, for example, from about 10 to 50% of sugar and elixirs containing, for exampie from about 20 to 50% e'uanol. and the like, or parenterally in Ihe form of sterile injectable solution or suspension containing from about 0 0U to 5% suspending aģent in an isotonic medium. Such pharmaceutical preparations may contain, for example, trom about 0 05 up to about 90% of the active ingredient in combination vvith the carrier, more usually betvveen about 5“; and 60% by vveight.
The effective dosage of active ingredient employed mav vary depending on the particular compound employed, the mode of administration and tho scverity of the condition being treated. Hovvever, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 500 mg/kg of animai body vveight, preterabiy given in divided doses lwo to four times a day, or in sustained release form. For most large mammals the total dailv dosage is from abou: 1 to 100 mg, preferably from about 2 to Θ0 mg. Dosage forms suitable lor internai use comprise from about 0.5 to 5%) mg of the active compound in intimate admixture vvith a solid or līquid pharmaceutically acceptable carrier This dosage regimen may be adjusted to provide the optimal therapeutic response. For examplc. several divided doses mav be administered daily orthe dose may be proportionally reduced as indicated by the exigcncios of tho therapeutic siiuation
These active compounds may be administered orally ar vvell as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch lactose dicalcium phosi;+ate microcrystalline cellulose, sucrose and kaolin, vvhile liquid carriers include sterile vvatci. polyelhylene glycols, nen-iome surfactants and edible oils such as corn, peanut and sesame oils, as ara appropnate to the nature of the aclīve ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation .1 pharmaceutical compositions may be advantageously included, such as flavoring aģents, coloring aģents, preservinu aģents, and antioxidants, forexample, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the stan; Ipoint ol ease of preparation and administration are solid compositions, particularly tablets and hard-lιIIed or liquid-filled capsules. Oral administration of the compounds is preferred.
These active compounds mav also be administered painnleially or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologicallv acceptable salt can be prepared in vvater suitably mixed vvith a surfaetant such as hydroxypiopylcellulose. Dispersions can also be prepared in glycerol, liquid poiyethylene glycols and mixtures thereof in oils Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the grovvth oi microorganisms.
The pharmaceutical forms suilable for iniectable use include sterile aqueous Solutions or dispersions and sterile povvders for the extemporaneous preparation of sterile injeciable Solutions or dispersions. In ali cases, the form must be sterile and must be fluid to the extent thal easy syringabihty exists It must be stable under the conditions of manufacture and storage and must be oreserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, vvater, ethanol, polyol(e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mnhuros thereof. and vegetable oils.

Claims (15)

1. A compound selected from those of the (ormula:
vvherein Y īs a moiety selecterl tiem -(CH2)n- vvherein n n an integer trom 0 to 2,
209 — CΗ Io»·rαIkyI ( C , - C 3) and —C
A-B is a moiety selected from and -H-(CH2)m- vvherein m is an integer Iram t io 2 provided that when v is -(CH2)n- and n is 2, m may also be zsro and vvhen n is zsro, m may also be three. provided also that whon Y s -(CH2)n- and n is 2, m may not bs two; ths moiety represents: (1) fused phenyl or luscd substituted phenyl optionally substituted by one or tvvo substituents selected from (Cļ-C3)lower alkyl, halogen. amino, (C.,-C3)lower aikoxy and (Cļ-C3)lower alkylamino; (2) a 5-membered aromatic (unsaturated) heterocyclic ring having one heieroatom selected from 0, N and S; (3) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (4) a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having tvvo nitrogen atoms; (5) a 5-mcmbered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with eilher one oxygen or one sulfur atom; vvherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C,-C,3)lower alkyl. hengon or (C,-C3)loweralkoxy;
the moiety:
is a five membered aromatici unsaturated) (used nitrogen containing heterocyclic ring vvherein D, E and F are selected from carbon and nitrogen and vvherein the caihon atoms may be optionally substituted by a substituent selected from halogen, (C1-C2)lower alkyl, hydroxy. CCc:t-, COCF3,
210
Ο
II
-C-0- I α»· r α I It y I ( C, -c3) .
b(CH2),O /“λ “(CHj),-0-1 o»ir α I k jr t(C,-C3) , “(CHa),OH, (I —C- I o»· r αIk yl (C,-C, f=\
-(CHj),- *
{CH,),- H
-CHO, amino, (Cļ-C3)lower alkcxy (C,-C3) lovver alkylar’ino. CONH lovver alkyl(Cļ-C3) and-CON[lower alkyl(CļC3)]2; q is one or tvvo; Rb 's īndepcndently selected from īiydrogen, -CH3 or -C2HS;
R3 is a moiety ot the formula
II — C - A r vvherein Ar is a moiety selected from the group consislir-ļ of vvherein X is selected from 0. S. NH. NCH3 and NCOCHR4 is selected from hydrogcn lovver alkvIfCļ -C3). -CO-lc ver alkyl(Cļ-C3),
21t
-SO2k>wer alkyl(C,-C3); R1 and R2 are independontly selected from hydrogen, (Cļ-C3)lower alkyl, (Cļ-C3)lower alkoxy and halogen; R5 is selected Irom hydrogen. (C, -C-,)lower alkyl, (C,-C3)lower alkoxy and halogen;
R® is selected from (a) moieties of the formula
-NCOAr ' , -CON A r ' , -NC
CH2Ar' , -NCONA r ’,
-CHjCOAr', -N CO- ( C H )„-cyc I ο α I Ic y I ;
-NHSO2-lower alkyl(C, -C8) straight or branched,
-NHSO2-iower aikenyl(C, -C8) straight or branched wherein cycloalkyl is delined as C3 to C6 cycloalkyl, ;yclohexenyl or cyclopentenyl; Ra is independenlly selected from hydrogen, -CH-,. -C2HS.
212 /~λ
-(ΟΗ,,,-Ν^Ο
-(CH2)q-O lovver alkyl(C,-C2j. and -CH2CH2OH q is one or two; and Ft,, Raand Rb areas hereinbefore defined;
(b) a moiety of the formula vvherein R2 is as hereinbefore delined:
(c) a moiety of the formula:
vvherein J is Ra, lovver alkyl(C,-Cs) branched or unbranched, lower alkenyl(C,-C8) branched or unbranched, O-lovver a!kyl(C-, -C8) branched or unbranched. -O-lovver alkenyl(C1-Ca) branched or unbranched, tetrahydrofuran, tetrahydrothīophene. or -CH2-K vvherein K is iC,-C3) lovver alkoxy, haiogen, tetrahydrofuran, tetrahydrothiophene or the heterocvclic ring moiety
-N \ _ /
G— Fl vvherein D', E‘, F and G are seleclod from caibon or nhrogen and vvherein the carbon atoms may be optionally substituted vvith haiogen, (Cļ-C-jlov/er alkyl. hydioxy. -CO-lower alkyl(C,-C3), CHO, (C,-C3)lower alkoxy, -CO2-lower alkyl(C,-C3), and R;i aud Rb are as hereinbefore defined;
(d) a moiety of the formula:
vvherein Rc is selected from haiogen. (C,-C3' fc.vcr .'dkyL -O~iower aikyl(C1-C3), OH,
213
II
-O-C-lo»tr aIkyI(
-Cjļ.-S-loiir α I k y I (C,-C,), •NH(CH,)q-CON
-o-(ch2)3n^ /Rb and Ra, Rb are as hereinbefore delmed; vvherein Ar is setecled irom moielies of the formula vvherein W' is selected from O. S NH, N-lower alkyi<C,-C3), N-CO-lower alkyl(C,-C3) and NSO2lower alkyl (Crc3>;
R4' is selected from hydrogen lovver alkyl(C,-C3) -COlovver alkyl(C.,-C3),
-SO2lower alkyl(C,-C3): R1 and H2’ are independenily selecled from hydrogen, (C,-C3)lower alkyl, (C,-C3) lovver alkoxy and halogen: R5' ts selected Irom hydroqen, (C, -C3)lower alkyl, (Cļ-C^lovver alkoxy and halogen; R7 is selected from hydrogcn lovver alkyl(C,-C3), halogen, O-lovver alkyl(C,-C3) and CF3;
Reand Raare independently solecledfrom hydrogen lovver afkyl(C-,-C3), -S-loweralkyl(C1-C3), halogen, -NHlovver alkyl(C,-C3).-OCF3. -OH -CM, -S-CF,. -NO,, -NH2, O-loweralkyl(CrC3),
214
-0-C-(C,-CJ)Ig, ,aVk^\ and CF3 and;
R’° is selected from hydrogen halogen and lovver a:ky!(C,-C3), and the pharmaceutically acceptable salts, esters and pro-drug forms thereof
2. A compound according to Claim 1 selected from those of the formulae:
vvherein the moiety is selected from a phenyl, thiophene furan, pyrrolc or pyridine ring vvherein the phenyl ring may be optionally substituted vvith one or tvvo substituents selected from (C,-C3) lovver alkyi, halogen, amino, (C,-C3) lovver alkoxy and (Cļ-C3) lovver aikylamino.
R3 is the moiety:
o i!
-CAr vvherein Ar is the moiety:
R5
R® is selected from (a) moieties of the formula:
215 i* i’
-MCOAr', -COMAr'
Γ Γ f
-HCOCHjAr·, -MCOHAf'
-NHSO2-lower alkyl(C,-Cs) straight or branched,
-NHSO2-lower alkenyl(C·,-Ca) straight or branched.
vvherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independently se· lected from hydrogen, -CH3, -C2H5, •(CH2)q-O-lower alkyl(C,-C3), -CH2CH2OH; q is one or tvvo; Rļ, is independently selected trom hydrogen -CH3 and -C2H5;
(b) a moiety of the formula:
-N-CO J wherein J is Ra, lovver alkyl(C,-C8) branched or unbranched, lovver alkenyl(C,-C8) branched or unbranched, O-lovver alkyl(C.,-C8) branched or unbranched -O-lower atkenyl(C,-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or -CH2-K vvherein K is (C,-C3) lovver alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene orthe heterocyciic ring moiety:
216 vvherein D'( EP and G are selected from carbon or nitrogen and vvherein the carbon atoms may be optionally substituted vvith halogen, (C1-C3)lower alkyl. hydroxy, -CO-lovver alkyl(C-,-C3), CHO, (Ci-C3)Iower alkoxy, -CO2-lower aikyl(Cļ -C3), and Ra and Rb are as hereinbefore defined; R1 and R2 are independentty selected from hydrogen, (C-ļ-C3)lower alkyl. (C-, -C3) lovver alkoxy and halogen;
(c) a moiety of the formula:
-M-COCHAr’ vvherein Ro is selected from halogen (Ct-C3) lovver alkyl, -O-lovver alkyl(Cļ-C3), OH,
-0-c-lor., Ο Ik, | (c,-C,) .-S-I .r α I lty I (C,-C3) , and Ra, Rb are as hereinbefore defined; and Ar' is selected from the moieties:
vvherein X is selected from O. S. NH, NCH3, NCOCH3;
R5 and R5' are independenlly selected trom hydrogen. (C,-C3)loweralkyl, (C1-C3)loweralkoxy, and halogen; R7 is seiected from hydrogen, lovver alkyl(C,-C3), halogen, O-lovver alkyl(Cļ-C3) and CF3;
R8 and R9are independenlly selected Irom hydrogen, lovver alkyl(C1-C3), -S-loweralkyl(Cļ-C3), halogen, -NHloweralkyl(C1-C3), -OCF3, -OH, -CN. -S-CF3, -NO2, -NH2, O-lovver alk^ļC,^),
-O-C-lover α I k y I ( C , - C 3 ) .
and CF3;
R11 is selected from hydrogen, halogen, (C1-C3)fowei alkyl. hydroxy, COCI3, COCF3,
217
If
-c-0-io..r oikrKc^Cj).
-(ch,),h
-(CH,),
N 0.
v_y
-(CH,),-O-Ik.tr o lkyl(C,-Cj), tl — c- l.«.r » I k jr I (C,-Cj) .
ΓΣΣ*· / \ I \
CH,-k. Z.H , -CHj-M Ζ,Ν z=\
CHO, and (Cļ-C3)lower alkoxy: q is one or tvvo.
W' is selected from 0, S, NH, N-lower alkyl(C., -C3), NCO-lower alkyl(C1-ca) and NSO2-loweralkyt(C1-C3), and the pharmaceutically acceptable salts thereof
3. A compound according to Ciaim 1 selected trom those of the formulae:
wherein m is one or tvvo; and the moiety:
is selected from a phenyl, thiophene, furan, pyrrole and pyridine ring; R3 is the moiety:
o
II
-CA r vvherein Ar is the moiety:
218
R6 is selected from (a) moieties of the formula:
HCOAf1,
-COHA r
R, R, R.
I I I*
-MCOCHjAr' , -HCOHAr ' ,
-CHjCOAr' , -HCO-(CHj),-eyeloalkyl;
-NHS02-lower alkyl(C,-C8) straight or branched,
-NHS02-lower alkenvifCļ-Cg) straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independently se lectedfrom hydrogen, -CH3, -C2H5, ^R t» k
r~\ _*
-(CH2)q-0-lower alkyl(C,-C3), -CH2CH2OH; q is one or tvvo:
219
Rb is independently selected from hydrogen. -CH3 and -C2H5;
(b) a moiety of the formula:
-N-CO J wherein J is Ra, lovver alkyl(C,-Cs) branched or unbranched, lovver alkenyl(C1-C8) branched or unbranched, O-lower alkyl(C,-C8) branched or unbranched -O-lovver alkenyl(C,-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or -CH2-K vvherein K is (C,-C3) lovver alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
wherein D', Ε', P and G are selected Irom carbon or nitrogen and vvherein the carbon atoms may be optionally substituted vvith halogen, (C1-C3)lower alkyl, hydroxy, -CO-lower aH^lfCļ-C^, CHO, (Cļ-C3)lower alkoxy, -CO2-lower alkyi(C1-C3), and Ra and Rb are as hereinbefore defined; R1 and R2 are independently selected from hydrogen, (C1-C3)loweralkyl, (C,-C3) lowcr alkoxy and halogen;
(c) a moiety of the formula:
-N-COCHA r 1 vvherein Re is selected from halogen, (C-, -C3) lovver alkyI, -O-lovver alkyl(C1 -C3), OH,
II
-O-C-low.r α I ky I (C,-C3) ,-S-lower ο I ky I (C,-C,),
-S-(CH2)2-N/Rb and Ra, Rb are as hereinbefore defined; Ar' is selected from the moieties:
220 vvherein X is seiected irom 0. S, NH. NCH3, NCOCH3;
vvherein R5 and R5' are independently seiected Irom hydrogen (C1-C3)lower alkyl, (Cļ-C^lovver aikoxy, and halogen;
R7 is seiected (rom hydrogen, lower alkyl(C1-C3), halogen, O-lower alkyl(C1-C3) and CF3;
R8and R9are independently seiected Irom hydrogen, lower alkyl(Cļ-C3), -S-loweralkyl(Cļ-C3), halogen, -NH· lovver alkyl(C,-C3), -OCF3. -OH, -CN. -S-CF3, -NO2, -NH2, O-lower alkyl(C,-C3),
0 I
-0 - C - I o w e r α I k y I ( C , - C , ) , and CF3;
R11 is seiected from hydrogen, halogen, (Cļ-C^lovver alkyl. hydroxy, COCI3, COCF3,
-C-O-I.».r . I kr I ( C,-C ,). -(CH,),-lt^
-(CH,) -o-li».r « I hr I (C,-C,).
r=\
-c- l...r , -CHj-H^M .
/—\
ΓΛ
-(CH,),- It II
CHO, and (C1-C3)loweralkoxy; q is one or tvvo:
R12 is seiected from hydrogen, (C,-C3)lower alkyl, halogen and (C,-C3)lower alkoxy; W' is seiected from 0, S, NH, N-lower alkyl(Cļ-C3), NCO-lower alkyl(C,-C3) or NSO2-loweralkyl(C1-C3), and the pharmaceutically acceptable salts thereol.
4. A compound according to Claim 1 seiected (rom thosa of the formulae:
221
R3 is the moiety:
o
II
-CA r vvherein Ar is the moiety:
-NHSO2-lower alkyl(C,-C8) straight or branched,
-NHSO2-lower alkenyl(C,-C8) straight or branched, vvherein cycloalkyl is defined as C3 to C6 cyclonikyl, cyclohexenyl or cyclopentenyl; Rg is independently selected from hydrogen, -CH3, -C2H5,
222 o
-(CH2)q-O-lower alkyl(C,-C3), -CH2CH2OH; q is one or two; Rb is independently selected from hydrogen, -CH3 and -C2H5; and (b) a moiety of the formula:
-N -CO J vvherein J is Ra, lovver alkyl(Cļ-C8) branched or unbranched, lovver alkenvtfCļ-Ca) branched or unbranched, O-lower alkyl(C.,-C8) branched or unbranched, O-lower alken/lfCļ-Ca) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or -CH2-K vvherein K is (C,-C3) lovver alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
vvherein D', E', F' and G are selected from carbon or nitrogen and vvherein the carbon atoms may be optionally substituted vvith halogen, (C1-C3)iower alkyl, hydroxy. -CO-lower alkyl(Ci-C3), CHO, (Cļ-C3)lower alkoxy, -CO2-lower alkvKCļ-Cj), and Ra and Rb are as hereinbefore defined; R1 and R2 are independently selected from hydrogen, (Cļ-C3)lower alkyl, (C.,-C3) lovver alkoxy and halogen;
(c) a moiety of the formula:
-N-COCHAr' vvherein Ro is selected from halogen, (Cļ-C3) lovver alkyI, -O-lower alkyl{C1-C3), OH,
223
II
-O-C-lo.er ο I k y I ( C , - C j ) . - S - I o w . r ο I k y I ( C, - C , ) ,
-s-(ch2 ) 2-n;
-NH ( CH2)q-C0N
-o-(ch2)2n^ /Rb and Ra, flb are as hereinbefore deiined; and Ar' is selected from the moieties:
wherein X is selected Irom O, S, NH, NCH3, NCOCH3:
Rs and R5' are independently selected from hydrogen (C, -C3)lower alkyl, (Cļ-CJlovver alkoxy, and halogen; R7 is selected from hydrogen, lovver alkyl(Č1-C3). halogen, O-lovver alkyl(Cļ-C3) and CF3;
RBand R9ars independently selected from hydrogen, lovver alkyl(C,-C3), -S-lower alkyl(Cļ-C3), halogen, -NHloweralkyl(CrC3), -OCF3, -OH, -CN. -S-CF3, -NOZ, -NH2, O-lovver alkyl(C,-C3),
II
-0 - C - I 0 w e r □ I k y I ( C , - Cj), and CF3;
R11 is selected from hydrogen, halogen, (C,-C3ļlower alkyl, hydroxy, COCI3, COCF3,
224
Ο
Η
-C-O-lewtr αIkγt(Cļ-C5)
-(ch,),h κ·®
-(CH,),- Ν'
Γ~\ * 0 .
(CH,),-Ο-Io»« r aIk f I (C,-C,) — C- I o »·r alk7l{Cļ-Cj)
-CH
-CH
Z
-(CH,),/“Λ (CH,),
CHO, and (C,-C3)loweralkoxy; q is one or two R12 and R13 are independently selected from (C1-C3)tower alkyl, hydrogen, halogen. amino, (C,-C3)lower alkoxy or (C1-C3)lower alkylamino; W' is selected from 0, S, -NH, NH-lower alkyl(C,-C3). NCO-lower alkyl(C.,-C3) or NSO2 lovver alkyl(C,-C3), and the pharmaceutically acceptable salts thereof
5. A compound according to Claim 1 selected Irom Ihose ol the formuiae:
wherein m is one or tvvo; R3 is the moiety:
II
-CA r vvherein Ar is the moiety:
225 so ss
-MCOA r
-COHAr ' , -NCOCHjAr
-NHSO2-lower alkyl(C,-C8) straight or branched,
-NHSO2-loweralkenyl(C1-C8) straight or branched, wherein cycloalkyl is defined as C3 to CB cycloalkyl, cyclohexertyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -C2H5,
SO (ch,;
-(CH2)q-O-lower alkyl(C,-C3), -CH2CH2OH; q is one ortvvo: Rļ, is independently selected trom hydrogen, -CH3 and -C2HS;
226 (b) a moiety of the formula:
-N-COJ vvherein J is Ra, lovver alkyl(C-,-Cs) branched oi unbranched, lovver alkenyl(Ci-C8) branched or unbranched, O-lovver alkyl(C, -C8) branched or unbranched. -O-lovver alkenyl(C,-C3) branched or unbranched, tetrahydrofuran, tetrahydrothiophenc, or -CH,-K vvherein K is (C,-C3) lovver alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
vvherein D', E', F' and G are selected from carbon or nitrogen and vvherein the carbon atoms may be optionally substituted vvith halogen, (C,-C3)lower alkyl hydioxy. -CO-lovver alkvifCļ-Cg), CHO, (C,-C3)lower alkoxy, -CO2-lower all^KC, -C3), and Ra and Rb are as hereinbefore defined; R1 and R2 are independentty selected trom hydrogen, (C,-C3)lower alkyl. (C,-C3) lovvci alkoxy and halogen;
(c) a moiety of the formula:
-H-COCHAr’ I vvherein fl0 is selected from halogen. (C,-C-,) lovver alkyl, -O-lovver alkyl(C,-C3), OH,
II
-0-C-lo«.r ο I ky I ( C,-Cj),-S-Iow»r ο IkyI(C,-C3),
-s-(ch2)2-h^ b
-NH(CH2)-C0N^ b -0-(CHj)jN\
O ' N and Ra, Rb are as hereinbefore delmed: and Ar’ is selected from the moieties
227
R
R wherein X is selected from O. S, NH. NCH3, NOOCH3
R® and Rs’ are independently selecied from hydrogen. (Cļ-C3)lower alkyl, (C1-C3)lower alkoxy, and halogen; R7 is selected from hydrogcn, lovver alkyl(C1 -c3 , haloqen. O-lower alkyl(C1-C3) and CF3;
R8and R9are independenlly selected iromhydrogen. lovver alkyl(C,-C3), -S-loweralkyl(C.|-C3), halogen, -NH· lovver alkyl(C,-C3), -OCF3, -OH, -CN -S-CF3. NO,. -NH,. O-loweralkyl(C1-C3),
-0- C- I ο v e r α I le y l ( C , — C3 ) .
and CF3:
R11 is selected from hydrogen, halogen, (C1-C3iloweralkyl. hydroxy, COCI3, COCF3, o
II
-C-O-I»»«r ·Ikι I (C,-C,) , . -(ch,)
-(CH,),-0-lu«r g I k , I ( C ,-C ,) , -(CH,),OH, r~\
II — c - I»»·r Ik yI(C,-C,)
-(CH,),-N
CHO, and (C.,-C3)loweralkoxy; q is one or tvvo: and W' is selected from 0, S, NH, N-lower alkvKCj-C^, NCOlovver alkyl(C1-C3), or NS02-lower alkyl(C,-C3) R12 and R13 are independently selected from hydrogen, (C,C3)lower alkyl, halogen. amino. (C,-C3)lowor alkoxy or (C,-C3)lower alkylamino, and the pharmaceutically acceptable salts thereof
6. A compound according to Claim t selecied from those ol the lormula:
228 wherein Y is -(CH2)n<
m is one vvhen n is one; and m is one or lwo vvhen is /eio R3 is īhe moiety:
o
II
-CA r vvherein Ar is the moiety:
R 5
R7
R® is selected from (a) moieties ol ihe formula
229
25 -NHS02-lower alkyl(CrC8) straight or branched
- NHSO2-lower alkenyl(C,-C8) straight or branched.
wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; FĻ is independently selected from hydrogen, -CH3, -C2H5,
-(CH2)q-N;
-(CH2)q-N (CH2)q-N \-J
-(CK2)q-O-lovver alkyl(Cļ-C3), -CH2CH2OH'. q is one or tvvo; Rb is independently selected from hydrogen -CH-, and -C2HS; and (b) a moiety of the formula
-N-COJ vvherein J is Ra, lovver alkyl(C,-C3) branched or unbranched, lovver alkenyl(C|-C8) branched or unbranched, O-lovver alkyl(C, -C8) branched or unbranched. O-lovvor alkenvUCļ-Cg) branched or unbranched, tetrahvdrofuran, tetrahydrothiophene, or -CH2-K vvherein K is (C,-C3) lovver aikoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety
230 wherein D', E', F' and G are selected from carbo;i or mirogon and vvherein the carbon atoms may be optionally substituted vvith halogen. (C,-C?'lower alkyl hydroxy -CO-lovver alkyi(Cļ-C3), CHO, {Cj-CaJIovver alkoxy, -CO2-lower alkyl(C-j-C3k and Ra and Rb are as hereinbefore defined; R1 and R2 are independently selected from hydrogen. (Cļ-Cgjiovver alkyl iCj-Cg) lovver alkc.<y and halogen;
(c) a moiety of the formula
-N-COCHAr* vvherein Rc is selected from haiogen. (Cļ-Οτ) lovver alkyl, -O-lovver alkyl(Cļ-C3), OH,
-O-C-low«r ο I k Τ I ( C ,-C, ) .-S - I o»t r ο I k jr I ( C,-C, ) ,
II
-0-(CH2)2l<y and Ra, Rb are as hereinbefore delined; and Ar' is selected from the moieties wherein X is selected from O S. NH. NCH3 unci NCCNH-,
R5 and R5' are independently seiected Irom nydiogen ;CrC3)lower alkyl, (C1-C3)lower alkoxy, and halogen; R7 is selected Irom hydrogen. Iower dlkyl(C,-C'i, halogen, O-lowef alkyl(C1-C3) and CF3;
R8and R9 are independently selected from hvdrogen. lovror alkvKCļ-Cg), -S-loweralkyl(C1-C3), halogen, -NHlower a!ky l(C-,-C3), -OCF3, -OH. -CN -S-CF-, -NO2. -NH2. O-lower alkyl(Cļ-C3),
231
I!
-0-C-Io» e r ntkyl(Cļ-Cj), and CF3,
R is selected from hydrogen. halogen. (C1-ūalowei alkyl, hydroxy, COCI3, COCF3, o
II
-C-0-I···r ιI z'»
-{CH,),-o-i.».r . ik, i (c,-c,). -{εκ,ΐ,οΗ.
—c- i·»·r ·ιν1τΐ(ε,-ϋ,) , - c h j f=\ Ζ=Λ
-Ν Μ-CHj-K Χ,Λ , -CHx-« , -(CM,),-* ,
Γ=\ ,=λ Ζ~λ
-(CH,) - Κ Ν \_/
CHO, and (Ci-C3)lower alkoxy: q is one or t'vo
R12 is selected from (C,-C3)lower alkyl, hydioqon. halogen. and (CrC3)lower alkoxy; W' Is selected (rom O, S, -NH, N-loweralkyl(C,-C3). NCO-lower alkyl(C,-C3) or NSO2-lower alkyl(C,-C3), and the pharmaceutically acceptable salts thereol
7. A compound according to Claim 1 selected Irom ihose ol :he formula:
R 5 vvherein Y is -(CH2)n, n is one when m one and m is tw v/hen n is zero, R3 is the moiety:
i!
-CA r
232 wherein Ar is the moiety
R5
R7
R6 is selected from moieties of the ioimula:
l· r·
-H COA τ ’ , -COΜ A r ' ί*
-KCOCHjAr‘, -MCORAr‘
-CHjCOAf·,
I i
-HH-C-O-l <»i r «Ikyf(C,-Cj) itretghf «r br«neb«tf,
I I
- HH-C-l ·»·γ β I k J I ( C ,-C |) s t relght ·Γ brOūMep, -IHSOj-littr ιIkj I(C,-C,) · I r f t g h t ·Γ br«««h«4,
- N H-C-O-I · ® · r » I k « n r · { C ļ - - ( } ·Γ hmlld,
II
-HH-C - I · ’i r alkenr'fCj-Cj) streigfct · r trtutHetf,
-NHSO2-lower alkenvh'C, -Cc) m. i;;ht or bmnehed.
R1 and R2 are independentlv seieete-J ho-n hydror:on (C,-r ·., lovver alkyl, (C,-C3)loweralkoxy and halogen; vvherein cycloalkyl is defined as 0, to C? c'.c!o.--ilkyl, cvdohokoi vl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -CgHj.
233
-(ch2 )
-(CHz)q-N
-(CH^-O-lovveralk/NCļ-C^) CH2CH,OH: q is one or lwo
Rb is independsntly selected Irom hyd!ogen. -CH, and -C2H3 and Ar1 is selected from the moieties:
Rs and R5' are independently selected hom hydrogen (C, -C3)lower alkyl, (C1-C3)lower alkoxy, and halogen;
R7 is selected trom hydrogen. lovver nlkvIfCļ-Cj!. halogen, 0-loweraikyl(C1-C3) and CF3;
R® and R8 are independently selected Irom hydiogen. lovver alkyl(C,-C3), -S-lovver alkyl(C1-C3), halogen, -NHloweralkyl(C1-C3), -OCF3, -OH. -CN S-CF3 NO2, -NH2 O-lovver alkyl(CrC3),
II
-0 - C - I o » i r alkyl(C,-Cj).
and CF3;
R11 is selected from hydrogen, halogen iC,-C3)!ower alkyl, hydroxy, COCI3, COCF3, o
II
-C-0-I·
e.r . I k τ I ( C,-C ,) , -(CH,),» zB>
''•Ό
-(CH,),-0-1...r .Ik,I(C,-C,), -(CR,),OH, .°. F=\ F=\ — ¢-1.»»r 0 I k f I ( C ,-C ,) , -ΟΗ,-Κ^^,Χ . -CHj-k^^Z /ΗζΛ /-\
-CH,-k. . -CH,-kv<k , -(C«,),-M »t, ,
-(CH,),- X N
CHO, (C-|-C3)lower alkoxy and q is one or tvvo:
234
R’2 js selected from (C-,-C3)lower aikvl hydrocfen halogen, and (Cļ-C3)lower alkoxy; W is selected from O, S, -NH, N-lower alkyl(C,-C3). NCO-lov/'v -ilkyl(C,-č·,), or NSOa-lower alkyl(C1-C3); and the pharmaceutically acceptable salts thereof
8.
A compound according to Claim sclcvled from hose o( Ihc lormulae:
R3 is the moiety:
-C* r vvherein Ar is the moiety
235 i ’ i
-NCOAr ' , -CONAr
-NCOCHjAr'
R, Rk
Γ i
-NCOKAr'.
-CHjCOAr· , -HCO-(CHj),-eireleelkrl;
-NHSO2-loweralkyl(C1-C6i slraighl or branched.
-NHSO2-lower alkcnyl(C,-C5i slraighl or branched, wherein cycloalkyl is defined as C; to C6 cycloalkyl, cyciohexenyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -C.,H5.
+
-(CH2)q-O-lower alkyl(C,-C3), -CH3CH2OH. q is one or lwo. Rb is independently selecled from !iydrogen -CH3 and -C2H5; and (b) a moiety of the formula
-N-CO J vvherein J is Ra, lovver alkyl(C,-C i branched or unbranched, lovver alkenyl(C,-C8) branched or unbranched, O-lovver alkyl(C,-C8) branched oi unbranched -O-lovver alkonyl(C1-C3) branched or unbranched, tetrahydrofuran, tetrahydrothiophcnc. or ,-K vvherein K is (C, -C3; lovver alkoxy, haiogen, tetrahydroluran, tetrahydrothiophene or the heterocycl'e ung moiely
236 vzherein D‘, E', F' and G are selcc' * ! from carbon or nitrogen and vzherein the carbon atoms may be optionally substituted vzith halogen ļC,- i wer ·ilb., hydroxv -CO-lower aU^C,-^), CHO, (Cļ-C3)lower alkoxy, -CO2-lower alkyl(CrC·,) and Α , n d Rb me as herembofors defined; R1 and R2 are independently selected from hydrogen, (C1-C-,)lowei a1'-. -C,-C-.! vjvver alkoxy and halogen;
(c) a moiety of the formula:
-N-COCHA r ' vvherein Rc is selected from halogen. iG, -C3) lovver alkyl, -O-lovver alkyi(C,-C3), OH,
-4-C-l.v.r 0 |ky I (Cļ-Cj) ,-S-f o..r ο 1 Ic r I ( C , - C 3 ) ,
S-( CH, ) 2-fC
-NH(CH2) -Cūli >-(CHj)2 and Ra, Rb are as hereinbefore eeimed: and Ar’ is selected from the meim m vzherein X is selected from O. NCM and NCOCH3;
R5 and R5' are independentlv s ··· ; ed [·,.· hvdrogen 'C, -C3)lower alkyl, (C,-C3)lower alkoxy, and halogen; R7 is selected from hydrogen · alkvl G ,-c3). hak. ;en. O-lovver alkyl(C,-C3) and CF3;
R8and R9are independontly so··· ‘- d from hvdrogen lovver alkyl(C,-C3), -S-loweralkyl(C1-C3), halogen, -NHlovver alkyl(Ci-C3),-OCF3 -Oh ‘1 -S-GI; NO2, -MH9. O-lovver alkyl(C.,-C3),
237 o
I!
-)-C - I ow e r π I It y I ( C , -C3 .
and CF3;
R” is selected trom hydrogen. h·-gen. rc.-C3) lovver alkyl. hydroxy, COCI3, COCF3,
II
- C — 0 — I 0 » ,r 0 Ikr ι (c,-c,), -(CH,),H ' CHll,~ v_? ' _/·
-(CH,),-0-1CT, r 0 Ik, I (C,-C,) , -(CH,),0H,
-CH, — c- 1 Ο»·Γ ο I k y I (C,-C,) , -CHj-N^z^N
-(CH,), r~\
N HR
CHO, and (C1-C3)lov;erajkoxy q is one or tvvo: R12 and R13 are independently selected trom (C1-C3)lower alkyl, hydrogen, halogen, amino iC,-C3)lower aikoxy or (C,-C3)lower alkylamino; W is selected from O, S, -NH, N-lower alky!(C,-C3), NCC-iovver alkyi(C,-C3) or NSO2 lovver alkyl(C,-C3), and the pharmaceutically acceptable salts thereof
β. Apharmaceutical composition useful for Irealmg diseases characterized by excess rēnai reabsorption of wateras well as congestive heart farlure, liver emhosis, ncphrotic syndrome, Central nervous system injuries, lung disease and hyponatremia in a mammai comi msing a suitable pharmaceutical carrier and an effective amount of a compound of Claim 1
10. A compound as claimed m any oru; of claims 1 10 8 tor use in treating diseases characterized by excess rēnai reabsorption of vvater as vvell as con cnstive hearl lailure. liver cirrhosis, nephrotic syndrome, Central nervous svstem injuries, lung disease and hypc:iHl;emia in a mammai
11. A process for preparing a compound o1 the lormuia:
A —S
238 vvherein Y is a moiety selected from 'CH2)n- vvherein π is an mieger from 0 to 2, — CH I ο Λ » r α I k y I ( C ,-Cj) and -C~ ;
A-B is a moiety selected Irom vvherein m is an integer from 1 to 2 m 0/1000 that whon Y is -(CH2)n- and n is 2. m may also be zero and vvhen n Is zero, m may also be three, provirloo ilso that when Y is -rCH2)n- and n Is 2, m may not be tvvo; the moiety represents; (1) fused phenyl or Iuseci, ubstitutec! phenyl oplionally substituted by one or tvvo substituents selected from (Cļ-C3)lower alkyl, haiogen, ario::. (Cļ-C-Jlovver alkoxy or (C1-C3)lower alkylamino; (2) a 5-membered aromatic (unsaturated) heterocyclic ring nnving one heteroatom selected from Ο, N and S; (3) a6-membered aromatic (unsaturated) heterocyclic ring havinn ne nitrogen atom. (4) a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having tvvo nitrogen atom? 5) a 5-mcmbered aromatic (unsaturated) heterocyctic ring having one nitrogen atom together with either one xygen or one sulfur atom: vvherein the 5 or 6-membered heterocyclic rings are optionally substituted by (0-,-0-< -'er alkyl haiogen or (C1-C3)loweralkoxy;
the moiety:
N /
F is a five membered aromaticiunsaluin’cd) fused nitrogen containing heterocyclic ring wherein D, E and F are selected from carbon and nitrogen un i wherom the carbc i atoms may be optionally substituted by a substituent selected from haiogen, (C,-C3)lowe' u:-:yl hydroxy,
II
239
-CHO, amino, (C,-C3) loweralkoxy an iCļ-C-notver alkyi-imino: R3 is a moiety ot the (oimula
I!
— C ~ A r vvherein Ar is a moiety selected from o grouo consisting of and /ΤΤΆ R* vvherein X is selected Irom O. S, NH. NCH3 and NCOCH;
R* is selected from hydrogen. lovver ; i IkvIfC,-C3), -COlotver alkyl(C,-C3),
-SOj-lovver alkyl(Cļ-C3), R1 and R2 n o indepoodenl!y selected irom hydrogen, (C1-C3)lower alkyl, (Cļ-C3)lower alkoxy and halogen;
R5 is selected from hydrogcn. (C,-C- 'ower alkfl. (C, -C3ilowcr alkoxy and halogen;
R® is selected from (a) moieties of the formula
240
R , «b
I I II
-HCOAr’, -C Ο Η A r ' , - N C 0 C Η 2 A r ‘ , - H C Ο Ν A r ' ,
-CHjCOAr’, -NCO-(CHj)n-c y c I ο α I k y I;
0 I I
-NH-C-0-lo»ir αIk y I {C,—C , ) straight or bronchsd,
0 I I
-HH-C·Io»ir α I k y I (C,-C 8 ) straight or branchtd, -NHSOj-low«r alkyl(C,-Cj) straight or bronchsd,
-NH-C-0-Io»»r alk«nyl(Cļ-C>) straight or bronchsd, 0
-NHO-lmir α I k « n f I ( C , - C s, straight or bronchsd,
-NHSO2-tower afkenyl(C3 straight or branched.
wherein cycloalkyl is deiined as lo C6 cycloalkyl cyclohsxenyl or cyclopentenyl; Ra is independently se lected from hydrogen. -CH3. -C< :3
-(CH 2) -N
241
-(CH2)q-H
-(CH2)q-O-lowei alkyltC,-C:i). -C !>CH2OH. q is one or l’.vo;
Rļ, is independently selecled irc ' liydrogon. -CH-). and -C2H5, ’t) and (b) a moiety of tho formula wherein W' is selecled from Ο. n NH, N-lower alkyl(C, -C-; NCO-lovver alkyl(Cļ-C3) and NS02lower alkyl (CvCg),
R4' is selected from hydrogen. Ie ver alkyl(C,-C3), -COlovver alkyl(C,-C3),
242
R
-SO2lower alkyl(C,-C3): R' and are independcntly selected from hydrogen, (C,-C3)lower alkyl, (C,-C3) lovver alkoxy and halocjen; R5 is : 'ecfed from hydrogan, (C, -C3)lower alkyl, (C,-C3) lovver alkoxy and halogen; R7 is selected from h'/drogon Ic or alkylfC,-C3) halogen, O-lowsralkyl(C,-C3) and CF3;
R8and R9 are independenlly seie- dod from hydrogen lovver alkyl(C1 -C3), -S-loweralkyl(C.,-C3), halogen, -NHlower alkvKCļ-C^.-OCF-, -OH - '.M. -S-CF3. -NO2. -NH2, O-lower aikyl(Cļ-C3),
-0 - C - I o * e r ο I k y I ( C , - C , ) , and CF3; and
Ri° is selected from hydrogon. halogen and lovver alkyl(C,-C3): vvhich comprises reacting a compound ot the tormulae;
--Γ and
E vvith a compound of the formula
A r-C-Q vvherein Q is a halogen or an ar7ating group, vvhich results from conversion of an aryl carboxylic acid to a mixed anhydride or from activafi i with a peptide eoupimg reaģent, to give compounds of the Formula i.
12. The compound according 'o Cla i 1 N-i<l-!5H-pyrrcici2,l-c][1.4|benzodiazep'm-10(11H)ylcarbonyl)phenyl] -2,4-dichlorobenzamide
13. The compound according to Claim 1 [4-(5H-pyrroloļ2 1 -cļ[l ,4ļbenzodiazepin-l0(11ļļ)-ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methylbon/amido.
14. The compound according to Claim : N-[4-ļ[3-|idimetbyiaminolmethyl]-5H-pyrrolo[2,1-c][1,4] benzodiazepin-10 (11H)-yllcarbonylJ-3-chiorophcnyiļ-5 ,icio-2-melhylbon/ai mele
243
15. The use ofa compound as claimed in my oneof claims 1 loē in the manufacture of a medicament for the treatment of disease characterised by exccss nal reabsorption ol vvater, congestive heart failure, liver cirrhosis, nephrotic syndrome, Central nervous systom »·' .nies, lung disease and/or hyponatremia.
Patentansprūche
1. Verbindung, ausgevvāhll aus |enen n i Formel worin Y ein Anteil ist, der ausgewahi‘ ist aus -(CH2)n- vvorm n eine ganze Zahl von Null bis 2 ist,
I ii
- CHnied./. I kyl· (C. -C. ) und - C - ;
A-B ein Anteil ist, der ausgevvāhlt isi ius
-(CH2)mŅ- und -N-(CH2)mR3 R1 vvorin m eine ganze Zahl von 1 bis l ist, mit der MaOgabc. da3. vvenn Y lūr -(CH2)n- steht und n 2 bedeutet, m auch Null sein kann und. vvenn n N;;1 ist, m auch drai sein kann, mit der vveiteren MaBgabe, daB, wenn Y tūr -(CH2)n- steht und n 2 bedeutet m n :ht zvvei sein kann der Anteil darstellt: (1) fusioniertes Phenyl cdc< iusīonicrtes, substituicrtes Phcnyl, gegebenenfalls substituiert durch einen oder zvvei Substituenton ausgcvvahli uus (C,-C3)-nied.Alkyl Halogen, Amino, (C1-C3)-nied.Alkoxy und (C,-C3)nied.Alkylamino; (2) einen 5-glibdnrun aromatischen (ungesāttigten) heterocyclischen Ring mit einem HeteroAtom ausgevvāhlt aus Ο, N und S il einen 6-gliedrigon arcmatischen (ungesāttigten) heterocyclischen Ring mit einem Stickstoffatom: (4) einen 0-00- 6-gliedngen aromalischen (ungesāttigten) heterocyclischen Ring mit zvvei Stickstoffatomen; (5) einen 5-gliednuen aromalischen (ungesāttigten) heterocyclischen Ring, der ein Stickstoffatom zusammen mit entvveder cmc: - Sauerstoff· oder einem Schvvefelatom hat; worin die 5- oder 6-gliedrigen heterocyclischen Ringe gcgebonenl. Us substituiert sind durch (C, -C3)-nied,Alkyl, Halogen oder (C^-C^-nied.Alkoxy; der Anteil:
244 ein fūnfgliedriger aromatischer turiūc ittigter) fusionrerter Stīckstotf-naltiger heterocyclischer Ring ist, worin D, t und F ausgevvāhlt sind aus Kohlcnstund Stickstoff. und worin die Kohlenstoffaīome gegebenenfalls substituiert sein konnen durch einen Subsiitucn’ un ausc;ewāhit aus Halogen, (C,-C3)-nied.Alkyl, Hydroxy, COCI3, COCF3,
It
-C-O-nied.Alkvl C -c ) Rb (CH2)qN Rb (CH2)q-Nx
Γ\ (CH2)q-N O,
- (CH2 ) q-O-nied. \ikyl (C2 -C) ) , -(CH2 ) qOH, fi /=\
-C-nied.Alkyl(C -C ) , -CH -Ν N, -CH -Ν λ 2 77 2 x 7
N
-CH, -N l)
Κ -Ν N ‘ -7 (CH:)q-N NR,
-CHO, Amino, (C,-C3 )-niod.Ainoxy ' .-,-C3;-nicd Aiky-ainuic. CONK-med.Alkyl (Οη-Ο3) und -CONfnied.AlkvkC,C3)]2; A eins oder zwci is’: unabi. ugig ausgcwāh!t isl aus VVassorstolf, -CH3 oder -C2H5 ;
R3 ein Anteii der Forinel ist, worin Ar ein Anteii ist. der ausgc-/?ihlt ist aus dei Gruppn bestehend aus
245 und
X worin X ausgevvāhlt ist aus O, S, NH, NCH3 und NCOCH3; R4 ausgevvāhlt ist aus VVasserstoff, nied.Alkyl(C.|-C3}, -CO-niad.AlkvKCļ-Cg),
-SO2-nied.Alkyl (C,-C3); R1 und R2 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C1-C3)-nied.Alkyl, (C,-C3)-nied.Alkoxy und Halogen; R5 ausgevvāhlt ist aus VVasserstoff, (C,-C3)-nied. Alkyl, (C1-C3)-nied.Alkoxy und Halogen;
R® ausgevvāhlt ist aus (a) Anteilen der Formel:
I
-NCOAr
Ķa Ra Rb
1“ 1“ l t
-CONAr’, -NCOCH Ar’, -NCONAr',
-CH2COAri,
-NCO-(CH2)n-Cycloalkyl;
246
R
R
-NHSO2-nied.A!kyl(C1-Cg), gerade oder verzvveigt,
-NHSOg-nied.Aikenļ/liC-ļ-C^), gerade oder verzvveigt, vvorin Cycloalkyl definiert ist als C3- bis C6-Cycloalkyl, Cyclohexenyl oder Cyclopentenyl; Ra unabhāngig ausgevvāhlt ist aus VVasserstoff, -CH3, -C2H5,
-(chz),-n
-(CH2)q-O-nied.Alkyl(C1-C3)und -CH2CH2OH; q eins oder zwei ist; und R1, R2 und Rb die hierin zuvor angegebene Bedeutung haben;
(b) einem Anteil der Formel:
vvorin R2 die hierin zuvor angegebene Bedeutung hat;
(c) einem Anteil der Formel
247 worin J fūr Ra, nied.Alkyl(C,-C8), verzvveigt oder nicht verzweigt, nied.Alkenyl(C,-C8), verzvveigt oder nicht verzvveigt, O-nied.Alkyl (C, -C3), verzweigt oder nicht verzvveigt, -O-nied.Alkenyl(C1-Ca), verzweigt oder nicht verzweigt, Tetrahydrofuran, Tetrahydrothiophen, oder -CH2-K steht, worin K (C,-C3)-nied.Alkoxy, Halogen, Tetrahydrofuran, Tetrahydrothiophen oder der heterocyclische Ringanteil:
ί x E \ _ / G—Fl ist, worin D', E‘, F1 und G ausgevvāhlt sind aus Kohlenstoff oder Stickstoff, und worin die Kohlenstoffatome gegebenenfalls substituiert sein konnen durch Halogen, (Cļ-Cgļ-nied.AHotl, Hydroxy, -CO-nied.Alkyl (C,-C3), CHO, (C1-C3)-nied.Alkoxy, -CO2 -nied.A!kyl(C1-C3), und Ra und Rb die hierin zuvor angegebena Bedeutung haben;
(d) einem Anteil der Formel:
-N-COCHAr
R, vvorin Ro ausgewāhlt ist aus Halogen, (C-ļ-C3)-nied.Alkyl, -O-nied.Alkyl(C1-C3), OH, ii
-O-C-nied.Alkyl(C1-C,)-, -S-nied.Alkyl(C1 -C, ) ,
-S-(CH2)2-N Rb , -O- (CH2) 2n Rb und Ra, Rb die hierin zuvor angegebene Bedeutung haben; vvorin Ar1 ausgevvāhlt ist aus Anteilen der Formel:
248 vvorin W'ausgevvāhlt ist aus O, 5, NH, N-nied.Alkyi(C^C3), N-CO-nied.Alkyl(C1‘C3) und NSC2 'nied.Alkyl (C-, Co);
R4’ ausgevvāhlt ist aus VVasserstoff, nied,Alkyi(C1-C3 ), -CO-nied.Alkyl(C1-C3),
TR·.
-SO2-nied.Alkyl (0,-03); H1 und R2' unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C,-C3)-nied. Alkyl, (C,-C3) -nied.Alkoxy und Halogen; R5' ausgevvāhlt ist aus VVasserstoff, (C,-C3)nied.Alkyl, (C,-C3)-nied. Alkoxy und Halogen; R7 ausgevvāhlt ist aus VVasserstoff, nied. Alkyl(C, -C3), Halogen, O-nied.Alkyl (C,-C3)und cf3;
R® und R9 unabhāngig voneinander ausgevvāhlt sind aus VVassersloif, nied.Alkyl(C,-C3), -S-nied.Alkyl(C,C3), Halogen, -NH-nied.Alkyl(C,-C3), -OCF3 , -OH, -CN, -S-CF3, -NO2, -NH2, O-nied.Alkyl(C,-C3),
-O-iļ- (Cļ -C3 ) -nied.Alkyl, und CF3 und
R'° ausgevvāhlt ist aus VVasserstoff, Halogen und nied.Alkyl(C,-C3), und die pharmazeutisch akzeptablen Saize, Ester und Pro-Crug-Formen davon.
2. Verbindung nach Anspruch 1, ausgevvāhlt aus jenen der Formein:
249 ausgewšhlt ist aus einem Phenyl-, Thiophen-, Furan-, Pyrrol- oder Pyridinring, worin der Phenylring gegebenenfalls substituiert sein kann mit einem oder zwei Substituenten ausgewāhlt aus (C, -C3)-nied. Alkyl, Halogen, Amino, (C, C3)-nied.Alkoxy und (C1-C3)-nied.Alkylamino,
R3 der Anteil
II
-CAr ist, worin Ar der Anteil:
RS ist, Rs ausgevvāhlt ist aus (a) Anteilen der Formel:
la •NCOAr' i“
-CONAr1
-NCOCHj Ar 1
Ķb
-NCONAr1
-CH2 COAr1 * *
-NCO- (CH ! n-CycloaIkyl; I* ί’ ΖΤλ — M —SO.—\ , X> , -X-S0,CH.—. O
250
8-0
-NHSO2-nied.Alkyl(C-,-C5), gerade oder verzvveigt,
-NHSO2-nied.Alkenyl(C1-Cg), gerade oder verzvveigt, worin Cycloalkyl als C3- bis C6-Cycioalkyl, -Cycfohexenyl oder -Cyclopentenyl definiert ist; FĻ unabhāngig ausgevvāhlt ist aus VVasserstoff, -CH3-, -C2HS, [CH
-Z q \
Rb
- (CH,
Rk
-<CH2)q-(CH2)
-(GH2)q-O-med.Alkyl(C1-C3), -CH2CH2OH; q eins oder zwei ist; Rb unabhāngig ausgevvāhlt ist aus VVasserstoff, -CH3 und -C2Hs;
(b) einem Anteil der Formel
Rb
- N - C O J worin J lūr Ra, nied.Alkyl(C,-Ca), verzvveigt oder nicht verzvveigt, nied.Alkenyl(C1-C8), verzvveigt oder nicht verzvveigt, O-nied.Alkyl (C^Cg), verzvveigt oder nicht verzvveigt, -O-nied.Alkenyl(C,-C8), verzvveigt oder nicht verzweigt, Tetrahydrofuran, Tetrahydrothiophen, oder -CH2-K steht, vvorin K (C1-Ca)-nied.Alkoxy, Halogen, Tetrahydrofuran, Tetrahydrothiophen oder der heterocyclische Ringanteil:
Dl ,
-Z Z' ist, vvorin D', E', F' und G ausgevvāhlt sind aus Kohienstoff oder Stickstoff, und vvorin die Kohlenstotfatome gegebenenfalls substituiert sein konnen mit Halogen, (C1-C3)-nied.Alkyl, Hydroxy, -CO-nied.AlkvKCļ-Cg), CHO, (C-|-C3)-nied.Alkoxy, -CO2 -nied.Alkyl(C1-C3), und Ra und Rb die hierin zuvor angegebene Bedeutung haben; R1 und R2 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C, -C3)-nied.Alkyl, (CrC3)nied.Alkoxy und Halogen;
(c) einem Anteil der Formel:
251 vvorin Rc ausgevvāhlt ist aus Halogen, (Cļ-CjJ-nied.Alkvl, -O-nied.Alkyl(C,-C3), OH,
II
-O-C-nied. Alkyl (Cx -C3 ) -, -S-nied. Alkyl -C3 ) , Rb 'Rb und Ra, Rb die hierin zuvor angegebene Bedeutung haben; und Ar' ausgevvāhlt ist aus den Anteilen:
R
R vvorin X ausgevvāhlt ist aus O, S, NH, NCH3, NCOCH3;
R5 und R5' unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C, -C3)-nied. Alkyl, (C,-C3)-nied. Alkoxy und Halogen;
R7 ausgevvāhlt ist aus VVasserstoff, nied.AlkvKCļ-Cs). Halogen, O-nied.AlkviiCļ-Oj) und CF3;
R8 und R8 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, nied AlkvifCļ-Cg), -S-nied.AlkvifCļC3), Halogen, -NH-nied.Alkyl(C,-C3), -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, O-nied.Alkyl(C,-C3),
O
II
-O-C-nied.Alkyl(Cx-C3), und CF3, und
R11 ausgevvāhlt ist aus VVasserstoff, Halogen, (C1-C3)-nied.Alkyl, Hydroxy, COCI3, COCF3,
252
Ο
II
Rb
- C-O-nied.Alkyl(C, -C3 ) , (CH, ) qN;
•Rj-(CH2)q-N , -(CHjg-N.
(CHJg-N 0,
-(CH2 )q-O-nied.Alkyl(C1 -C3) , -(CH2)q0H, μ /=\
-C-nied.Alkyl(C1-C3 ) , -CH2-Ν , -CH2 -N \/ N
NR.
CHO und (C1-C3)-nied.Alkoxy; q eins oder zvvei ist;
W‘ ausgevvāhlt ist aus O, S, NH, N-med.Alkyl{C,-C3), NCO-nied.Alkyl(C,-C3) und NSO2 -nied.Alkyl(C1-C3), und die pharmazeutisch akzeptablen Salze davon.
3. Verbindung nach Anspruch 1, ausgevvāhlt aus jenen der Formeln:
vvorin m eins oder zwei ist; und der Anteil:
ausgevvāhlt ist aus einem Phenyl-, Thiophen-, Furan-, Pyrrol- und Pyridin-Ring; R3 der Anteii
-CAr ist, vvorin Ar der Anteil:
253 >o ist,
R® ausgevvāhlt ist aus (a) Anteilen der Formel:
\\_o 5 oder re
Ra Rv-, ia r
-NCOAr1, -CONAr1, -NCOCHjAr1, -NCONAr1 ,
-CHjCOAr1, -NCO-(CH2)n-Cycloalkyl;
-NHSO2-nied.Alkyl(C1-C8), gerade oder verzweigt,
-NHSO2-nied Alkenyl(C1-C8), gerade oder verzweigt, vvorin Cycloalkyl als C3- bis C6-Cycloalkyl, -Cyclohexenyl odsr -Cyclopentenyl definiert ist; Ra unabhāngig 40 ausgevvāhlt ist aus VVasserstoff, -CH3-, -C2H5, (CH2)q-N ^Rb
-(CH,)
- (CH, ,-N
-(CH2)q-O-nied.Alkyl(C1-C3), -CH2CH2OH; q eins oder zwei ist; Rb unabhāngig ausgewāhlt ist aus VVasserstoff, -CH3 und -C2H3 l
55 (b) einem Anteil der Formel
254 vvorin J fūr Ra, nisd.AlkvHC^Cg), verzvveigt oder nicht verzvveigt, nied.Alkenyl(Cļ-C8), verzvveigt oder nierīt verzweigt, O-nied.Alkyl(C1-Ca), verzweigt oder nicht verzvveigt, *O-nied.Alkenyi(C,-C8), verzvveigt oder nicht verzvveigt, Tetrahydrofuran, Tetrahydrothiophen, oder -CH2-K steht, vvorin K (C.|-C3)-nied.Alkoxy, Haiogen, Tetrahydrofuran, Tetrahydrothiophen oder der heterocyclische Ringanteil:
ist, vvorin D', E', F' und G ausgevvāhlt sind aus Kohlenstoff oder Stickstoff, und vvorin die Kohlenstoffatome gegebenenfalls substituiert sein konnen mit Haiogen, (C1-C3)-nied.Alkyl, Hydroxy, -CO-nied.Alkyl(C1-C3), CHO, (Ci-C3)-nied.Alkoxy, -CO2 -nied.Alkyl(C-,-C3), und Ra und Rb die hierin zuvor angegebene Bedeutung haben; R1 und R2 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C,-C3) -nied.Alkyi, (Ο,-Οβ)nied.Alkoxy und Haiogen;
(c) einem Anteil der Formel:
I
-N-COCHAr'
R, vvorin Ro ausgevvāhlt ist aus Haiogen, (C,-C3)-nied.Alkyl, -O-nied.AlkvifCļ-C^, OH
O
II
-O-C-nied.Alkyl (C2 -C3),-S-nied.Alkyl(Cļ-C3 ) ,
-S-(CH2)2-N
Rb-NH(CH2)q-CON
-O-(CH2 )2 N und Ra, Rb die hierin zuvor angegebene Bedeutung haben; Ar' ausgevvāhlt ist aus den Anteilen:
255 vvorin X ausgevvāhlt ist aus O, S, NH, NCH3, NCOCH3;
vvorin Rs und R5’ unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C, -C3)-nied, Alkyl, (C,-C3)-nied. Alkoxy und Halogen;
R7 ausgevvāhlt ist aus VVasserstoff, nied.Alkyl(C1-C3), Halogen, Ο-ηίθό.Α^γΙ(0·|-03) und CF3;
R® und R9 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, nied.Alkyl(C1-C3), -S-nied.AlkvHC,C3), Halogen, -NH-nied.Alkyl(C,-C3), -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, O-nied.Alkyl(C,-C3),
II
-O-C-nied.Alkyl(C -C ), und CF3,
R ausgewāhlt ist aus VVasserstoff, Halogen, (C.,-C3)-nied.Alkyl, Hydroxy, COCI3, COCF3,
O
II
- C-O-nied.Alkyl(C1-C3) , -(CH2)qN^ Rb Rb
- (CH2 )q-N
- (CH2 )q-N.
(CH2 ) q-O-nied. Alkyl (C2-C, ), -(CH2)q0H,
-C-nied.Alkyl(C1-C3 ) , -CH2-N^N , -CH2 -N^
-<CH,>q
CHO und (Ο,-Ο^-ηίβό.Α^οχγ; q eins oderzvvei isl;
R'2 ausgevvāhlt ist aus VVasserstoff, (C,-C3)-nied.AlkyI, Halogen und (C^C^-nied.Alkozv; W' ausgevvāhlt ist aus O, S, NH, N-nied.Alkyl(Cļ-C3), NCO-nied.Alf^rKCļ-Cjj) oder NSO2-nīed.Alkyl(C1-C3), und die pharmazeutisch akzeptablen Salze davon.
4. Verbindung nach Anspruch 1, ausgevvāhlt aus jenen der Formeln;
256
-ρ und vvorin R3 der Anteīl
II
-CAr ist, vvorin Ar der Anteil:
V—R1 oder isl, R6 ausgevvāhlt ist aus (a) Anteilen der Formeln:
ΚΙ'
Ni
R-NCOAr', -CONAr’, -NCOCH^Ar’, -NCONAr1,
-CH2COAr', -NCO-(CH2)n-Cycloalkyl;
Rl
I a
-N-SO.
-n-so2-ch2
R.O _
-X -P
-‘ī ιΊι r,
-H-r -
-NHSO2-nied.Alkyl(C1-C8). gerade oder verzvveigt, -NHSO2-nied.Aikenyl(C1-C8), gerade oder verzvveigt,
257 worin Cycloalkyl definiert ist ais C3- bis C6-Cycloalkyl, Cyclohexenyl oder Cyclopentenyl; Ra unabhāngig ausgevvāhlt ist aus VVasserstoff, -CH3, -C2H5, b
-(CH2)q-O-nied.Alkyl(C1-C3)und -CH2CH2OH; q ains oder zwei ist; Rb unabhāngig ausgevvāhlt ist aus VVasserstoff, -CH3 und -C2H5 ; und (b) einem Anteil der Formel:
-N-C 0 J worin J fūr Ra, nied.Alkyl(C,-C8), verzweigt oder nicht verzweigt, nied.AIkenvKCļ-Ce), verzvveigt oder nicht verzweigt, O-nied.AlkvKCļ-Ca), verzvveigt oder nicht verzvveigt, -O-nied.Alkenyl(C,-C8), verzvveigt oder nicht verzvveigt, Tetrahydrofuran, Tetrahydrothiophen, oder -CH2-K steht, vvorin K (C,-C3)-nied.Alkoxy, Haiogen, Tetrahydrofuran, Tetrahydrothiophen oder der heterocyclische Ringanteil:
ist, vvorin D‘, E', F1 und G ausgavvāhlt sind aus Kohlenstoff oder Stickstoff, und vvorin die Kohlenstoffatome gegebenenfalls substituiert sein konnen mit Haiogen, (C1-C3)-nied.Alkyl, Hydroxy, -CO-nied.Alkyl(C1-C3), CHO, (C,-C3)-nied.Alkoxy, -CO2 -nied.Alkyl(C-|-C3), und Ra und Rb die hierin zuvor angegebene Bedeutung haben; R’ und R2 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C1-C3)-nied.Alkyl, (C.|-C3)nied.Alkoxy und Haiogen;
(c) einem Anteil der Formel:
-N-COCHAr'
R, vvorin Rcausgewāhlt ist aus Haiogen, (C,-C3)-nied. Alkyl, -O-nied.Alkyl(C1-C3), OH,
258
Ο
-O-C-nied.Alkyl(Οχ -C3)-, -S-nied.Alkyl(Cx-C3 ) , /Rb
-S-(CH ) -N
Rb
-NH(CH2)g-CON
-0-(CH2)2 N ^b Rb und Ra, Rb die hierin zuvor angegebene Bedeutung haben; und Ar' ausgevvāhlt ist aus den Anteilen:
vvorin X ausgevvāhlt ist aus O, S, NH, NCH3, NCOCH3;
R5und R5’ unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C,-C3) -nied.Alkyl, (C1-C3)-niad.Alkoxy und Halogen;
R7 ausgevvāhlt ist aus VVasserstoff, nied.Alkyl(C1-C3), Halogen, O-nied.Alkyl(C.,-C3) und CF3;
R8 und R9 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, nied.Alkyl(Ci-C3), -S-nied.AH^C,C3), Halogen, -NH-nied.Alkyl (C,-C3), -OCF3 , -OH, -CN, -S-CF3, -NO2, -NH2, O-nied.Alkyl(CrC3),
-O-C-nied.Alkyl(Cq-C3), und CF3,
R” ausgevvāhlt ist aus VVasserstoff, Halogen, (Cļ-C^-nied Alkyl, Hydroxy, COCI3, COCF3,
259
- C-O-nied.Alkyl(Cļ-C3 (CH2)qN;
Rb
- (CH2 )q-Ņ
-(CHJq-N.
, '(CH, )„-’-V/
-(CH2)q-O-nied.Alkyl(Cl-C, ) , -(CH2)qOH,
-C-nied.Alkyl (C2-C3 ) , -CH2-N^N , -CH2 -N^
CHO und (C.|-C3)-nied.Alkoxy; q eins oder zwei ist;
R12 und R13 unabhāngig voneinander ausgewāhlt sind aus (C-,-C3)-nied.Alkyl, VVasserstoff, Halogen, Amino, (C,-C3)-nied.Alkoxy oder (Cļ-C^-nied.-AlkvIamino; W' ausgevvāhlt ist aus O, S, -NH. NH-nied.Alkyl(C1-C3), NCO-nied.Alkyl(C,-C3) oder NSO2-nied.Alkyl(C1-C3), und die pharmazeutisch akzeptablen Salze davon.
5. Verbindung nach Anspruch 1, ausgevvāhlt aus jenen der Formeln:
vvorin m eins oder zwei ist;
R3 der Anteil
-^Ar ist, vvorin Ar der Anteil:
R 5
260 ist, R6 ausgevvāhlt ist aus (a) Anieilen der Formeln:
R,
R*b
I “ I “ | “ ļ
-NCOAr', -CONAr', -NCOCH2Ar', -NCONAr',
Ra
I
-CH COAr’, -NCO-(CH )n-Cycloalkyl;
-N-SO, -CH,
-NHSO2-nied.Alkyl(C1-C8), gerade oder verzvveigt,
-NHSO2-nied.Alkenyl(C1-C8), gerade oder verzvveigt, vvorin Cycloalkyl definiert ist als C3- bis C6-Cycloalkyl, Cyclohexenyl oder Cyclopentenyl; Ra unabhāngig ausgevvāhlt ist aus VVasserstoff, -CH3, -C2Hg,
-(CHJ -H
-(CHJ -H
-(CH, ) -N 0
-(CH2)q-O-nied Alkyl(Ci-C3) und -CH2CH2OH; q eins oder zvvei ist: Rb unabhāngig ausgevvāhlt ist aus VVasserstoit, -CH3 una -C2H5 , (b) einem Anteīl der Formei:
-N-C O J vvorin J fūr Ra, nied.Alkyl(C,-Cs), verzvveigt oder nicht verzvveigt, nied.Alkonyl(C1-Ca), verzvveigt oder nicht verzvveigt, O-nied.Alkyl(C,-C8), verzvveigt oder nicht verzvveigt, -C-nied.AIkenvUCļ-Cg), verzvveigt oder nicht verzvveigt, Tetrahydrofuran, Tetrahydrothiophen, oder -CH2-K steht. vvorin K (C1-C3)-nied.Alkoxy, Halogen, Tetrahydrofuran, Tetrahydrothiophen cder der heterocyciische Ringanteil:
2S1 x E \ _ / G—F' ist, vvorin D', E', F' und G ausgevvāhlt sind aus Kohlenstoff oder Stickstoff, und vvorin die Kohlenstoffatome gegebenenfalls substituiert sein konnen mit Halogen, (C,-C3)-nied.Alkyl, Hydroxy, -CO-nied.Alkyl (C,-C3), CHO, (C1-C3)-nied.Alkoxy, -CO2 -nied.Alkyl(C1-C3), und Ra und Rb die hierin zuvor angegebene Bedeutung haben; R1 und R2 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C,-C3)-nied.Alkyl, (C,-C3)nied,Alkoxy und Halogen;
(c) einem Anteil der Formel:
IS Ra
-N-COCHAr' vvorin Rc ausgevvāhlt ist aus Halogen, (C,-C3)-nied.Alkyl, -O-nied.Alkyl(C,-C3), OH,
II
-O-C-nied.Alkyl(C2 -C3 ) -, -S-nied.Alkyl(C1 -C3 ),
-S-(CH > -N Rb Rb
-NH(CH2)q-CON
-o-(ch2 Rb /Rb
N \
Rb und Ra, Rb die hierin zuvor angegebene Bedeutung haben; und Ar' ausgevvāhlt ist aus den Anteilen:
SO
SS vvorin X ausgevvāhlt ist aus 0, S, NH, NCH3, NCOCH3,
R5 und R5' unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C, -C3)-nied. AlkyI, (C, -C3)-nied. Alkoxy und Halogen;
fl7 ausgevvāhlt ist aus VVasserstoff, nied.Alkyl(C,-C3), Halogen, O-nied.Alkyl(C,-C3) und CF3;
R® und R3 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, nied.Alkyl(C,-C3), -S-nied.Alkyl(C,C3), Halogen, -NH-nied.Alkyl(C,-C3), -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, O-nied.Alkyl (C,-C3),
262 b-nied.Alkyl(C, -C3) und CF3,
R11 ausgevvāhlt ist aus VVasserstoff, Halogen, (C1-C3)-nied.Alkyi, Hydroxy, COCI3, COCF3, >0
II
Rb >s
- C-0-nied. Alkyl (C\ -C3 ) , -(CH2)qN'
Rb (CH2)q-N /, -(CH2)q- r~\ , -(CH2)q-N O, (CH2)q-O-nied.Alkyl(C2-C3), -(CH2)q0H, /=\
C-nied.Alkyl(C3-C3), -CH2-Ν Ν , -CH2-N '''m '
-Ν N, /A
CH2-N^N, -oh2
- (CH2 )q(CH2)q-N
CHO und (C,-C3)-nied.Alkoxy; q eins oder zwei ist; und W ausgevvāhlt ist aus 0, S, NH, N-nied.Alkyl(C,-C3), NCO-nied.AlkvHCļ-CgJoder NSO2 -nied.Alkyl(C,-C3);
R’2 und R13 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C1-C3)-nied.Alkyl, Halogen, Amino, (Cļ-C3)-nied.Alkoxy oder (C1-C3)-nied.-Alkylamino, und die pharmazeutisch akzeptablen Salze davon.
6. Verbindung nach Anspruch 1, ausgevvāhlt aus jenen der Formel vvorin Y fūr -(CH2)n steht;
m eins ist, vvenn n eins ist; und m eins oder zwei ist, wenn n Null ist; R3 der Anteil:
263 ο
-£ατ ist, vvorin Ar dsr Anteil ist, R6 ausgevvāhlt ist aus (a) Anteilen der Formel:
Ra la
CONAr' Ra l
- NCOCH, Ar 1
Ra Rt-, (a |b -NCONAr1
1'
-NCO-(CH2)n-CycIoalkyl;
-NCOAr',
-CH2 COAr Ra I Λ -n-so2
-NHSO2-nied.Alkyl(C1-C8), gerade oder verzvveigt,
-NHSO2-nied.Alkenyl(C1-C8), gerade oder verzvveigt, vvorin Cycloalkyl definiert ist als C3- bis Cs-Cycloalkyl, Cyclohexenyl oder Cyclopentenyl; Ra unabhāngig ausgevvāhlt ist aus VVasserstoff, -CH3, -C2H5,
-(C H 2)q-N “ b Rb (CHz)N
264
-(CH2)q-O-nied.Alkyl(C-ļ-C3), -CHgCHgOH; q airis odar zvvei ist; Rb unabhāngig ausgevvāhlt ist aus VVasserstoff, -CH3 und -C2H5 ; und (b) einem Anteil der Formel:
-N-C 0 J vvorin J tūr Ra, med.Alkyl(C,-Cg), verzvveigt oder nicht verzvveigt, nied.AIkenvIfCļ-Cg), verzvveigt oder nicht verzvveigt, O-nied.AlkvKCļ-Cg), verzvveigt oder nicht verzvveigt, -O-nied.Alkenyl(C1-Ca), verzvveigt oder nicht verzvveigt, Tetrahydrofuran, Tetrahydrothiophen, oder -CH2-K steht, vvorin K (C1-C3)-nied.Alkoxy, Halogen, Tetrahydrofuran, Tetrahydrothiophen oder der heterocyclische Ringanleil:
G —F ist, vvorin D', E', F' und G ausgevvāhlt sind aus Kohlenstoff oder Stickstoff, und vvorin die Kohlenstcffatame gegebenenfalls substiutiert sein konnen mit Halogen, (C-ļ-C3)-nied.Alkyl, Hydroxy, -CO-nied.A^lļCļ-Cj), CHO, (C1-C3)-nied.Alkoxy, -C02 -nied.Alkyl (CpC^, und Ra und Rb die hierin zuvorangegebene Bedeutung haben; R1 und R2 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C-,-C3)-nied.Alkyl, (0·,-03)nied.Alkoxy und Halogen;
(c) einem Anteil der Formel:
-N-COCHAr vvorin Rc ausgevvāhlt ist aus Halogen, (C1-C3)-nied.Alkyl, -O-nied.Alkyl(C,-C3), CH,
265
-S-(CH).-N Rb
-NH(CH2)q-CON Rb Rb
-o- (ch2 )2n Rb und Ra, Rb die hierin zuvor angegebene Bedeutung haben; und Ar' ausgewāhlt ist aus den Anteilen;
R vvorin X ausgevvāhlt ist aus O, S, NH, NCH3, NCOCH3;
Rs und Rs' unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C, -C3)-nied. Alkyl, (C,-C3)-nied. Alkoxy und Halogen;
R7 ausgevvāhlt ist aus VVasserstoff, nied.Alkyl(C1-C3), Halogen O-nied.Alkyl (C-, -C3) und CF3;
R8 und R9 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, nied.Alkyl(C.,-C3), -S-nied.Alkyl(C,C3), Halogen, -NH-nied.Alkyl(C,-C3), -OCF3 , -OH, -CN, -S-CF3 , -NO2, -NH2, O-nied.Alkyl (CrC3),
O
-O-^-nied.Alk/l(C, -C3) , und CF3,
Rit ausgevvāhlt ist aus VVasserstoff, Halogen, (C-,-C3)-nied.ArKyl, Hydroxy, COCi3, COCF3,
266
-(CH2)qN;
- C-O-nied.Alkyl(Cx-C3 (CH2 )q-Ņ (CH2 )q-Ņ (CH2 >qN\
0, (CH2)g-O-nied.Alkyl(C2-C3), -(CH2)qOH, o
-C-nied.Alkyl(Cx-C3), -CH2-Ν Ν , -CH2- .NR.
-ch2 -n x
Λλ
N, -CH -Ν N, -(CH )a-N /“Λ
-(CH2)q
CHO und (C, -C3 )-nied. Alkoxy; q eins oder zwei ist;
R12 ausgevvāhlt ist aus (C1-C3)-nied.Alkyl, Wasserstoff, Halogen, und (C,-C3)-nied.Alkoxy; W ausgevvāhlt ist ausO, S, -NH, N-nied.Alkyl(CrCa), NCO-nied.Alkyl(C,-C3)oderNS02-nied.Alkyl(C1-C3), und die pharmazeutisch akzeptablen Salze davon.
7. Verbindung nach Anspruch 1, ausgevvāhlt aus jenen der Formel:
R 3 vvorin Y fūr -(CH2)n steht; n eins ist, wenn m eins ist, und m zvvei ist, wenn π Nuil ist; R3 der Anteil:
O tl
-CAr ist, vvorin Ar der Anteil
267
R5
K7 ist,
R6 ausgevvāhlt ist aus Anteilen der Formel:
Ra Ra Ra Ra Rb
I I la la lD
-NCOAr', -CONAr', -NCOCH Ar', -NCONAr', l’l’l ,
-K-p — - 0 i
o il
-NH-C-O-nied.Alkyl(Cx-C8), gerade oder verzvveigt,
H
NH-C-nied.Alkyl(Cļ-C8), gerade oder verzweigt,
-NHSO2-nied.Alkyl(Cļ-CB!, gerade oder verzweigt, ll
-NH-C-O-nied.Alkenyl(Cj-C8), gerade oder verzvveigt,
O
II
-NH-C-nied.AIkenyl(Cļ-C8), gerade oder verzvveigt,
-NHSO2-nied.Alkenyl(C1-Cs), gerade oder verzweigt, R' und R2 unabhāngig voneinander ausgevvāhlt sind aus VVassersioii, (C,-C3)-niea.Alkyl, (C,-C3)-nied.Alkoxy und Halogen; vvorin Cycloaikyl definiert ist als C3- bis C6Cycloalkyl, Cyclohexenyl oder Cvcicpentenvl; R, unabhāngig ausgevvāhlt ist aus VVasserstoff, -CH3, -C2H5,
268
-(CHz)q-N ( ch2 ) q-N;
(CHz)q-N
-(CH2)q-O-nied.Alkyl(C1-C3)und -CH2CH2OH; q eins oder zwei ist; Rb unabhāngig ausgevvāhlt ist aus VVasserstoff, -CH3 und -C2H5 ; und Ar' ausgevvāhlt ist aus den Anteiien:
vvorin R5 und R5’ unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C,-C3)-nied.Alkyl, (C, -C3)-nied. Alkoxy und Halogen;
R7 ausgevvāhlt ist aus VVasserstoff, nied.Alkyl(C,-C3), Halogen, O-nied.Alkyl(C,-C3)und CF3;
R8 und R3 unabhāngig voneinander ausgevvāhlt sind aus
VVasserstoff, nied.Alkyl(C,-C3), -S-nied.Alkyl(C,-C3), Halogen, -NH-nied.Alkyl(C.|-C3), -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, O-nied.Alkyl (C,-C3),
-O-C-nied.Alkyl(C,-Cj), und CF3,
R” ausgevvāhlt ist aus VVasserstoff, Halogen, (C1-C3)-nied.Alkyl, Hydroxy, COCI3, COCF3,
- (CH2 ) q-O-nied.Alkyl (CL -C, ) , - (CH2 ) qOH,
269 ° /=λ
-C-nied.Alkyl(C,-C,), -CH -Ν Ν , -CH,-N
-(CH2)q-N ./A r~\
NR.
CHO und (C,-C3)-nied.Alkoxy und q eins oder zwei ist;
R'2 ausgevvāhlt ist aus (C1-C3)-nied.Alkyl, VVasserstoff, Halogen, und (C1-Ca)-nied.Alkoxy; W ausgevvāhlt ist aus O, S, -NH, N-nied.Alkyl(Cļ-C3), NCO-nied.Alkyl(C.,-C3)oder NSO2-nied.Alkyl(C,-C3), und die pharmazeutisch akzeptablen Salze davon
8. Verbindung nach Anspruch 1, ausgevvāhlt aus jenen der Formeln:
und vvorin R3 der Anteil;
li
-CAr ist, vvorin Ar der Anteil:
// ist, R6 ausgevvāhlt ist aus (a) Anteilen der Formeln:
Ra Ra Ra Ra Rļ-,
L la ra l i°
-NCOAr', -CONAr1 , -NCOCH, Ar', -NCONAr',
270
-NHSOg-nied.AlkviiC-ļ-Cg), gerade oder verzvveigt,
-NHSO2-nied.Alkenyl{C1-C0)l gerade oder verzweigt, vvorin Cycloalkyl definiert ist als C3- bis C6-Cycloalkyl, Cyclohexenyl oder Cyclopentenyl; Ra unabhāngig ausgevvāhlt ist aus VVasserstoff, -CH3, -C2HS, ~(ch2) -n;
-(CHz)q-N (CHJ ~N \_y
-(CH2)q-O-nied.Alkyl(C1-C3), -CH2CH2OH; q eins oder zwei ist; Rb unabhāngig ausgevvāhlt ist aus VVasserstoff, -CH3 und -C2H5 ; und (b) einem Anteil der Formel:
-N-C vvorin J fūr Ra, nied.AlkviļCļ-Cg), verzvveigt oder nicht verzvveigt, nied.Alkenyl(Ci-Ce), verzvveigt oder nicht verzvveigt, O-nied.Alkyl(Ci-Ce), verzvveigt oder nicht verzvveigt, -O-nied.Alkenyl(C,-C8), verzvveigt oder nicht verzweigt, Tetrahydrofuran, Tetrahydrothiophen, oder -CH2-K steht, worin K (Cļ-C^-nied.AlkoKV, Halogen, Tetrahydrcfuran, Tetrahydrothiophen oder der hetercc'/clische Ringanteil:
271 ist, vvorin D', E‘, F' und G ausgevvāhlt sind aus Kohlenstoff oder Stickstoff, und vvorin die Kohlenstoffatome gegebenenfalls substituiert sein konnen mit Haiogen, (Cļ-Cjj-nied.Alkvl, Hydroxy, -CO-nied.Alkyl(C1-C3), CHO, (C1-C3)-nied.Alkoxy, -CO2 -nied.Alkyl (Ο,-Ο3), und Ra und Rb die hierin zuvor angegebene Bedeutung haben; R1 und R2 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C,-Cg)-nied.Alkyl, (C,-C3)nied.Alkoxy und Haiogen;
(c) einem Anteil der Formel:
-N-COCHAr'
R, vvorin Roausgewāhlt ist aus Haiogen, (C1-C3)-nied.Alkyl, -O-nied.Alkyl (C,-C3). OH,
O ll
-O-C-nied.Alkyl(C2-C3)-, -S-nied.Alkyl(C3-C3),
-O- !ch2 )2n
Rb Rb und Ra, Rb die hierin zuvor angegebene Bedeutung haben; und Ar' ausgevvāhlt ist aus den Anteilen:
s
R
W vvorin X ausgevvāhlt ist aus O, S, NH, NCH3 und NCOCH3;
R5 und R5’ unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C, -C3)-nied. Alkyl, (C, -C3)-nied. Alkoxy und Haiogen;
R7 ausgevvāhlt ist aus VVasserstoff, nied.Alkyl(C,-C3), Haiogen, O-nied.Alkyl(C1-C3)und CF3;
R8 und R9 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, nied.Alkyl(C1-C3), -S-nied.Alkyl(C1C3), Haiogen, -NH-nied.Alkyl(C,-C3), -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, O-nied.Alkyl(C,-C3), li
-O-C-nied.Alkyl(C3 -C3), und CF3,
R11 ausgevvāhlt ist aus VVasserstoff, Haiogen, (C1-C3)-nied.Alkyl, Hydroxy, COCI3, COCF3,
272
Ο
II
- C-O-nied.Alkyl(C -C )
-(CH2 )q-Ņ
-(CH2)q-N
-Rb 'Rb (CH2 )q-O-nied.Alkyl(C2 -C, ) , -(CH2 )qOH,
-N^^^N , -CH,
-C-nied.Alkyl(C -C ) , -CH,-t/^Sī , -CH,-ī/^ 1 3 2 2 \
-(CH2)q-Ņ
T~\
NR.
CHO und (C,-C3)-nied.Alkoxy; q eins oder zwei ist;
R12 und R13 unabhāngig voneinander ausgevvāhlt sind aus (C1-C3)-nied.Alkyl, VVasserstoff, Halogen, Amino, (C1-Ca)-nied.Alkoxy oder (C1-C3)-nied.Alkylamino; W ausgevvāhlt ist aus O, S, -NH, N-nied.Alkyl(C,-C3), NCO-nied.Alkyl(C1-C3)oder NSO2-nied.Alkyl(C,-C3), und die pharmazeutisch akzeptablen Salze davon.
9. Pharmazeutische Zusammensetzung, die zur Behandlung von Krankheiten geeignet ist, die gekennzeichnet sind durch ūbermāSige Reabsorption von VVasser durch die Nieren sovvie Stauungsinsuffizienz des Herzens, Leberzirrhose, Nephrose-Syndrom, Verietzungen des Zentralnervensystems, Lungenerkrankung und Hyponatrāmis bei einem Sāuger, vvelche einen geeigneten pharmazeutischen Trāger und eine vvirksame Menge einer Verbindung nach Anspruch 1 umfaCt.
10. Verbindung nach einem der Anspruche 1 bis Θ zur Vervvendung bei der Behandlung von Krankheiten, die gekennzeichnet sind durch eine ūbermāSige Reabsorption von VVasser durch die Nieren sovvie Stauungsinsuffizienz des Herzens, Leberzirrhose, Nepnrose-3yndrom, Verietzungen des Zentralnervensystems, Lungenerkrankung und Hyponatrāmie bei einem Sāuger.
11. Verfahren zur Herstellung einer Verbindung der Formel:
vvorin Y ein Anleii ist, der ausgevvāhlt ist aus -iCH2)n-, vvorin n eine garize Zani von Nuii bis 2 ist, - CHnied.AlkvifCļ-C-) und
II
- C - ;
273
A-B ein Anteil ist, der ausgevvāhlt ist aus
-(CH2)mŅ- und -Ņ-(CH2)mvvorin m eine ganze Zahl von 1 bis 2 ist, mit der MaBgabe, da(3, wenn Y fūr -(CH2)n- steht und n 2 bedeutet, m auch Null sein kann und, wenn n Null ist, m auch drei sein kann, mit der weiteren MaBgabe, daB, wenn Y fūr
10 (CH2)n- steht und n 2 bedeutet, m nicht zwei sein kann; der Anteil darstellt: (1) fusioniertes Phenyl oder fusioniertes, substituiertes Phenyl, gegebenenfalls substituiert durch einen oder zwei Substituenten ausgevvāhlt aus (C1-C3)-nied.Alkyl, Halogen, Amino, (C1-C3)-nied.Alkoxy oder (C-, -C3)nied.Alkylamino; (2) einen 5-gliedrigen aromatischen (ungesāttigten) heterocyclischen Ring mit einem HeteroAtom ausgewāhlt aus 0, N und S; (3) einen 6-giiedrigen aromatischen (ungesāttigten) heterocyclischen Ring mit einem Stickstoffatom; (4) einen 5- oder 6-gliedrigen aromatischen (ungesāttigten) heterocyclischen Ring mit zwei Stickstoffatomen; (5) einen 5- gliedrigen aromatischen (ungesāttigten) heterocyclischen Ring, der ein Stickstoffatom zusammen mit entvveder einem Sauerstoff- oder einem Schvvefelatom hat; worin die 5- oder 6-gliedrigen heterocyclischen Ringe gegebenenfalls substituiert sind durch (CvC^-nied.Alkvl, Halogen oder (Cļ-C3)-nied.Alkoxy; der Anteil:
,Λ ein fūnfgliedriger aromatischer (ungesāttigter) fusionierter Stickstoff-hāltiger heterocyclischer Ring ist, worin D, E und F ausgevvāhlt sind aus Kohlenstoff und Stickstoff, und vvorin die Kohlenstoffatome gegebenenfalls substituiert
40 sein konnen durch einen Substituenten ausgevvāhlt aus Halogen, (C.,-C3)-nied.Alkyl, Hydroxy,
O
II
-C-nied . Al)cyl (C; -C3 ) ,
-CHO, Amino, (C,-C3)-nied.Alkoxy und (C.,-C3)-nied.Alkylamino; R3 ein Anteil der Formel so 0
II
- C - Ar ist, vvorin Ar ein Anteil ist, der ausgevvāhlt ist aus der Gruppe bestehend aus 55
274
V vvorin X ausgevvāhlt ist aus O, S, NH, NCH3 und NCOCH3;
R4 ausgevvāhlt ist aus VVasserstoff, nied.Alkyl(C,-C3), -CO-med,Alkyl(C1-C3),
-SO2-nied.Alkyl (C,-C3); R1 und R2 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C.,-C3)-nied.Alkyl, (C,-C3)-nied.Alkoxy und Haiogen;
R5 ausgevvāhlt ist aus VVasserstoff, (C,-C3)-nied.Alkyl, (C1-C3)-nied.Alkoxy und Haiogen;
R6 ausgevvāhlt ist aus (a) Anteilen der Formel:
la
-NCOAr1
-CONAr1
-NCOCHj Ar' (ā
-NCO
It
-CH2 COAr',
-NCO(CH2 ) n-Cycloalk:yl ;
275 ο
II
-NH-C-O-nied.Alkyl(C2-C8 ) , gerade oder verzweigt, i
-NH-C-nied.Alkyl(C2-C9), gerade oder verzweigt,
-NHSO2-nied.Alkyl(C2-C ), gerade oder verzweigt, li
-NH-C-O-nied.Alkenyl(C -Ca), gerade oder verzweigt, (I
-NH-C-nied.Alkenyl(Cx-CB), gerade oder verzvveigt,
-NHSOg-nied.AIkenvIfCļ-Cg), gerade oder verzvveigt, vvorin Cycloalkyl definiert ist als C3- bis C6-Cycloalkyl, Cyclohexenyl oder Cyclopentenyl; Ra unabhāngig ausgevvāhlt ist aus VVasserstoff, -CH3, -C2H5,
-(CK,),-»
-(CH2)q-O-nied,Alkyl(C1-C3)und -CH2CH2OH; q eins oder zvvei ist; Rb unabhāngig ausgevvāhlt ist aus VVasserstoff, -CH3 und -C2H5; und (b) einem Anteii der Formel:
\ _ /
Ν —N.
vvorin Ar1 ausgevvāhlt ist aus den Anteilen der Formel:
276 vvorin W ausgevvāhlt ist aus O, S, NH, N-nied.Alkyl(C1-C3), NCO-nied.Alkyl (C,-C3)und NSO2-nied.Alkyl(C,-C3); R4' ausgevvāhlt ist aus VVasserstoff, nīed.Alkyt(C, -C3), -CO-nied.Alkyl(C,-C3)
-SO2 -nied.Alkyl (0,-0.,); R1' und R2' unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, (C,-C3) -nied. Alkyl, (C,-C3)-nied.Alkoxy und Halogen; R5'ausgevvāhlt ist aus VVasserstoff, (C,-C3)-nied.Alkyl, (C,-C3)-nied.Alkoxy und Halogen;
R7 ausgevvāhlt ist aus VVasserstoff, nied.Alkyl(C,-C3), Halogen, O-nied.Alkyl(C,-C3)und CF3;
R8 und R9 unabhāngig voneinander ausgevvāhlt sind aus VVasserstoff, nied.Alkyl(C1-C3), -S-nied.Alkyl(C,-C3), Halogen, -NH-nied.Alkyl(C,-C3), -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, O-nied.Alkyl(C,-C3),
O
II
-0-C-nied.Alkyl(03 -C3), und CF3 und
R’° ausgevvāhlt ist aus VVasserstoff, Halogen und nied.Alkyl(C,-C3); vvelches die Umsetzung einer Verbindung der Formeln:
O
II
Ar-C-Q
277 umfaBt, vvorin Q ein Halogen oder eine aktivierende Gruppe ist, vvelche sich aus der Umvvandlung einer Arylcarbonsāure in ein gemischtes Anhydrid oder aus der Aktivierung mit einem Peptid-Kupplungsreagens ergibt, zum Erhalt von Verbindungen der Formel I.
12. Verbindung nach Anspruch 1,
N-[4-(5H-Pyrrolo[2,1 -c][ 1,4]benzodiazepin-10( 11 H)-ylcarbonyl)phenyl]-2,4-dichlorbenzamid.
13. Verbindung nach Anspruch 1,
N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-lO(11H)-ylcarbonyl)-3-chlorphenyl]-5-fluor-2-methylbenzamid.
14. Verbindung nach Anspruch 1,
N-[4-[[3-((Dimethylamino)-methyl-15H-pyrrolo(2,1 -c][1,4ļbenzodiazepin-10(11 H)-ylļ-carbonyl]-3-chlorphenylļ5-f1uor-2-methylbenzamid.
15. Vervvendung einer Verbindung nach einem der Anspruche 1 bis 8 bei der Herstellung eines Medikaments zur Behandlung einer Krankheit, die gekennzeichnet ist durch ūbermāflige Reabsorption von VVasser durch die Nieren, Stauungsinsuffizienz des Herzens, Leberzirrhose, Nephrose-Syndrom, Verletzungen des Zentralnervensystems, Lungenerkrankung und/oder Hyponatrāmie.
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FI943543A0 (fi) 1994-07-28
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RU94027583A (ru) 1996-07-20
LV12497A (en) 2000-06-20
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