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and

as

For the sake values

of simplicity,

relative

to

that

these

of

H:

steric

A MR(X)

parameters = MR(X)

were

- MR(H)

A B5(X ) = B5(X ) - B5(H ).

Table 3 Ca-antagonistic activity and physicochemical parameters of R3-substituted compounds (II) Me0,

CN

Me

Me0~C-(CH

2 )3N (CH2) 3 0 0 ~

MeOr--- R3

Me PA2

Compd. No.

a) R3

) AMRb) AB5C

~

11-5 H 0.00 0.00 11-6 Me 0.54 0.46 11-7 Et 1.08 0.93 11-8 n-Pr 1.62 1.39 11-4 iso-Pr 1.49 1.40 11-9 n-Bu 2.16 1.86,, 11-10 iso-Bu 2.03 1.86~! II-11 n-Hex 3.24 2.79~! 11-12 , n-Oct 4.32[! 3.72!! II-13 g) n-dodecyl 6.48t) 5.58t) 11-14 benzyl 2.22 2.90 II-15 (CHg)~OMe-0.32~! 1 57f) 11-16 (CH~i~OEt 0.50t) 2 03f) a) b) c) d) e) f) g)

0.00 1.04 2.17 2.49 2.17 3.54 3.45 4.96 6.39 9.27 5.02 3.49 3.81

A c) Obsd.d) Eq. 1 B1 Calcd.(A )e) 0.00 0.52 0.52 0.52 0.90 0.52 0.52 0.52 0.52 0.52 0.52 0.52 0.52

Eq.3

Eq.2 Calcd.(A )e)

5 . 5 6 6.28(-0.72) 6.76 6.91(-0.15) 7.44 7.33 (0.11) 7.79 7.52 (0.27) 8.05 7.49 (0.56) 7 . 2 1 7.50(-0.29) 7.53 7.52 (0.01) 7.46 6.79 (0.67) 5 . 0 6 5.21(-0.15) 5.33 -0.80 6.48 7.48(-1.00) 6.80 6.22 (0.58) 6.68 6.56 (0.12)

Calcd. ( A )e) 5.76 (-0.20) 6.77(-0.01) 7.38 (0.06) 7.46 (0.33) 7.38 (0.67) 7.43(-0.22) 7.45 (0.08) 6.68 (0.78) 5.10(-0.04) -0.49 6.63(-0.15) 7.44(-0.64) 7.35(-0.67)

5.83(-0.27) 6.61 (0.15) 7.15 (0.29) 7.43 (0.36) 7.43 (0.62) 7.47(-0.26) 7.47 (0.06) 6.79 (0.67) 5.11(-0.05) -1.28 6.64(-0.16) 7.48(-0.68) 7.42(-0.74)

From ref. i i unless otherwise noted. Scaled by 0.i and from ref. 12 unless otherwise noted. Calculated from the values cited from a brochure given by Dr. A. Verloop. pA9 values in the KCl-depolarized guinea-pig taenia coli. A~ the difference between observed and calculated values. Estimated from those of closely related substituents, see ref. I0 for the detail. Omitted from the correlation.

In Eqs. because reason

of was

another length

]-3 compound its not

clear,

receptor

but

site

was omitted

deviation an

might

from

extra have

from the c a l c u l a t i o n

the

correlations.

binding

arisen

interaction

due

to

the

The with

increased

of the R 3 chain.

The

quality

satisfactory, shown

(II-]3)

pronounced

in T a b l e

especially

of the

correlation

particularly 3,

large

the

in terms

deviation

in Eqs.

2 and

for

of Eqs.

]-3 was

of the standard alkoxyalkyl

3. We o r i g i n a l l y

by no m e a n s

deviation.

derivatives thought

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379 Table 5 Ca-antagonistic a c t i v i t y and physicochemical parameters of R4-substituted compounds ( I I ) MeO.

7N

Me I

MeO~C-(CH2)3N(CH2)30~ MeO~ - ~ I iso-Pr

R4 PA2

Compd. No.

R4

11-17 11-18 11-19 11-4 11-20 11-21 11-22 11-23 11-24 11-25 11-26 11-27 11-28 11-29 11-30 11-31 11-32 11-33 11-34 11-35 11-36 11-37 11-38 11-39 11-40 11-41 11-42 11-43

H o-Me o-n-Pr o-OMe o-OEt o-F o-Cl o-NO^ o-NH~ m-Me m-t-Bu m-OMe m-F m-Cl m-NO^ m-NH~ m-CF~ m-CH~OH p-Me p-n-Pr p-t-Bu p-OMe p-F p-Cl p-NO; p-NH$ p-CNp-CH20H

11-44 11-45 11-46

2,3-(0Me) 2 2,4-Me^ 2,5-Me~

11-47. 2,6-(0Me)2 II-48!)3,4-(0Me)2 II-49])3,5-(0Me)2 II-501)3 5-Me2

d) AB papa 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1.04 2.49 2.17 2.07 0.35 0.80 1.44 0.97 0.60 1.70

a) ~ para 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.52 1.43 1.82 -0.08 0.21 0.77 0.03 -1.35 -0.30 -I.00

-O.05h ) -O. zoh ) 0.26 1.04~ ) -0.24~ ) -0.04 1.06 n) -0.19 n) -0.04

0.00 1.04 0.00

0.00 0.52 0.00

-0.16h ) -0.32h ) -O.05n ) -O. lOn) O.06n) 0.12n ) 1.08 n) -0.14 n)

0.52 h) 0.00 0.00 0.00

2.07 0.00 0.00

0.00 -0.08 0.00 0.00

0.00

2.07

-0.08

~

a)

0.00 0.52 1.43 -0.08 0.30 0.21 0.77 0.03 -1.35 0.54 1.85 0.03 0.26 0.79 -0.03 -1.14 0.98 -0.91 0.52 1.43 1.82 -0.08 0.21 0.77 0.03 -1.35 -0.30 -1.00

o

0 b)

0.00 -0.12 -0.13 g) -0.16 -0.14 0.17 0.27 0.82 -0.38 -0.07 -0.07 0.06 0.35 0.37 0.70 -0.14 0.47 0 O0g) -0.12 -0 13g) -0.17 -0.16 0.17 0.27 0.82 -0.38 0.69 0.05 g)

II-51i)3,4,5-(0Me)3 -0.02 h) -0.04 h) a) b) c) d) e) f) g) h) i) j)

c) F ortho 0.00 -0.04 -0 06 0.26 0.22 0.43 0.41 0.67 0.02 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

Obsd.

e)

Eq.7

8.19 8.31 7.79 8.05 8.10 7.95 7.69 7.26 8.15 8.48 6.88 9.00 8.29 8.36 8.17 8.13 8.06 8.11 7.61 6.88 6.88 7.64 8.02 7.73 7.39 6.50 7.64 6.56

Calcd.(A )f) 8.50(-0.31) 8.50(-0.19) 7.83(-0.04) 8.16(-0.11) 8.18(-0.08) 7.78 (0.17) 7.56 (0.13) 7.20 (0.06) 7.89 (0.26) 8.41 (0.07) 7.17(-0.29) 8.48 (0.52) 8.35(-0.06) 8.12 (0.24) 8.25(-0.08) 8.04 (0.09) 7.96 (0. i0) 8.17(-0.06) 8.05(-0.44) 6.90(-0.02) 6.79 (0.09) 7.27 (0.37) 8.31(-0.29) 8.04(-0.31) 7.36 (0.03) 6.71(-0.21) 7.72(-0.08) 6.60(-0.04)

8.23 7.97 8.68

8.14 (0.09) 7.83 (0.14) 8.18 (0.50)

7.57 8.35. 10 20@1 9 53J

7.82(-0.25) 7.26 8.46 8.09

9.32 j ) 7.24

Estimated from Eq. 5 taken from ref. 14. Taken from ref. 15 unless otherwise noted. Taken from ref. 16. Calculated from the B5 values presented in a brochure given by Dr. A. Verloop. pA2 values in KCl-depolarized guinea-pig taenia coli unless otherwise noted. A , the difference between observed and calculated values. Estimated from the values for related substituents. Values are the sum of the values for substituents. Omitted from the correlation. pA2 values in KCl-depolarized rabbit thoracic aorta.

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388

Table 7 Ca-antagonistic a c t i v i t y

and physicochemical parameters of R2-substituted

compounds ( I I ) CN

Me

- (CH2)3N(CH2)30 Me

R2 i so-Pr

PA2 Compd. No.

11-52 11-53 11-54 11-55 11-56 11-57 11-58 11-59 11-60 11-61 I I-62 11-63 11-64 11-65 11-66 11-67 11-68 11-69 11-70 II-71 II-72 11-73 11-74 11-75 11-76

a) R2

H o-Me o-OMe o-OEt o-F o-Cl o-Br m-Me m-OMe m-OEt m-F m-Cl m-CONMe 2 p-Me p-iso-Pr p-OMe p-OEt p-F p-Cl p-Br p-NOp p-NH~ p-NHAc p-CONMep 3,4-(OMe)~

Jr

) A MRa meta

b) AL para

Obsd.

c)

Eq. 10 Cal cd. ( A

)d)

0.00 0.56 -0.02 0.38 0.14 0.71 0.86 0.56 -0.02 0.38 O. 14 O.7~e -i.0o ) 0.56 1.53 -0.02 0.38 0.14 0.71 0.86 -0.28 -1.23

0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.46 0.68 1.14 -0.01 0.50 1 83 e) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 O.O0 0.00

0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 O. O0 0.00 0.00 0.81 2.05 1.92 2.74 0.59 1.46 1.76 1.38 0.72

7.59 7.25 7.60 7.53 7.00 7.40 7.60 7.80 8.20 7.84 7.35 7.50 6.64 7.71 7.26 7.64 7.32 8.25 8.04 7.80 7.87 7.15

7.50 (0.09) 7.42(-0.17) 7.50 (0. i0) 7.46 (0.07) 7.50(-0.50) 7.37 (0.03) 7.30 (0.30) 7.77 (0.03) 7.91 (0.29) 7.74 (0. I0) 7.48 ( -0.13 ) 7.73(-0.23) 6.67(-0.03) 7.82(-0.11) 7.13 (0.13) 7.81(-0.17) 7.24 (0.08) 7.83 (0.42) 7.80 (0.24) 7.67 (0.13) 7.93(-0.06) 7.47(-0.32)

-0.97 ~ - I 05e{ -0 04e)

0.00 0.00 0.68

3.03 2.71 1.92

6.76 6.93 7.99

6.74 (0.02) 7.01(-0.08) 8.22(-0.23)

II-77 f) 3,5-(0Me)2

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0.68

0.00

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II-27 f) 3,4,5-(0Me)3

-0.06 e)

0.68

1.92

9.00

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a) b) c) d) e) f) g)

Taken from ref. 12 unless otherwise noted. Taken from a brochure given by Dr. A. Verloop. pA~ values in KCl-depolarized guinea-pig taenia coli. A ~ the d i f f e r e n c e between observed and calculated values. Estimated from those of c l o s e l y related substituents, see ref. 18 f o r the d e t a i l . Omitted from the c o r r e l a t i o n . 2 + 0 . 73A Lpara Estimated from the equation pA2 = - 0.27~ 2 - O.30A Lpara + 2 ( - 0.77A MR~eta+ 1.12A MRmeta) + 7.50.

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394 Table I i Observed and calculated Ca-antagonistic a c t i v i t i e s for the whole set of verapamil analogs ( I I ) CN Me ~-(CH2)3N(CH2)30 I

R

R3

R4

PA2 Compd. No.

R2

R3

R4

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Eq. 12

Calcd. ( A ) a )

Calcd. ( A ) a )

Obsd.

11-52 11-53 11-54 11-55 11-56 11-57 11-58 11-59 11-60 11-61 11-62 11-63 11-64 11-65 11-66 11-67 11-68 11-69 11-70 11-71 11-72 11-73

H o-Me o-OMe o-OEt o-F o-Cl o-Br m-Me m-OMe m-OEt m-F m-Cl m-CONMe 2 p-Me p-iso-Pr p-OMe p-OEt p-F p-Cl p-Br p-N09 p-NH~

iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr

m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe m-OMe

7.59 7.25 7.60 7.53 7.00 7.40 7.60 7.80 8.20 7.84 7.35 7.50 6.64 7.71 7.26 7.64 7.32 8.25 8.04 7.80 7.87 7.15

7.53 (0.06) 7.43(-0.18) 7.53 (0.07) 7.48 (0.05) 7.52(-0.52) 7.37 (0.03) 7.30 (0.30) 7.92(-0.12) 8.11 (0.09) 7.93(-0.09) 7.50(-0.15) 7.89(-0.39) 6.64 (0.00) 7.81(-0.10) 7.04 (0.22) 7.82(-0.18) 7.26 (0.06) 7.84 (0.41) 7.79 (0.25) 7.65 (0.15) 7.93(-0.06) 7.43(-0.28)

7.48 (0.11) 7.39(-0.14) 7.48 (0.12) 7.44 (0.09) 7.48(-0.48) 7.34 (0.06) 7.27 (0.33) 7.86(-0.06) 8.03 (0.17) 7.87(-0.03) 7.46(-0.11) 7.83(-0.33) 6.65(-0.01) 7.82(-0.11) 7.08 (0.18) 7.84(-0.20) 7.27 (0.05) 7.83 (0.42) 7.81 (0.23) 7.68 (0.12) 7.94(-0.07) 7.40(-0.25)

11-74 11-75

p-NHAc p-CONMe2

11-76 11-77 11-27 11-17 11-18 11-19 11-20 11-21 11-22 11-23 11-24 11-25 11-26 11-28 11-29 11-30 11-31 11-32 11-33

3,4-(0Me)2 3,5-(0Me)2 3,4,5-(0Me)3 3,4,5-(0Me)3 3,4,5-(0Me)3 3,4,5-(0Me)3 3,4,5-(0Me)3 3,4,5-(0Me)3 3,4,5-(0Me)3 3,4,5-(0Me) 3 3,4,5-(0Me)3 3,4,5-(0Me)3 3,4,5-(0Me)3 3,4,5-(0Me)3 3,4,5-(0Me)3 3,4,5-(0Me)3 3,4,5-(0Me)3 3,4,5-(0Me)3 3,4,5-(0Me)3

iso-Pr iso-Pr iso-Pr iso-Pr

m-OMe m-OMe m-OMe m-OMe m-OMe H o-Me o-n-Pr o-OEt o-F o-Cl o-NO^ o-NH~ m-Me m-t-Bu m-F m-Cl m-NO^ m-NH~ m-CF~ m-CH~OH

6.74 (0.02) 6.99(-0.06) 8.40(-0.41) . 8 11. (0 77) . 8.40 (0.60) 8.40(-0.21) 8.40(-0.09) 7.93(-0.14) 8.08 (0.02) 7.79 (0.16) 7.68 (0.01) 7.46(-0.20) 7.74 (0.41) 8.34 (0.14) 7.44(-0.56) 8.40(-0.11) 8.25 (0.11) 8.40(-0.23) 7.94 (0.19) 8.16(-0.10) 8.10 (0.01)

6.72 (0.04) 6.98(-0.05) 8.39(-0.40) 8.03 (0 85)

iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr iso-Pr

6.76 6.93 7.99 8 . 88 9.00 8.19 8.31 7.79 8.10 7.95 7.69 7.26 8.15 8.48 6.88 8.29 8.36 8.17 8.13 8.06 8.11

8.39 (0.61) 8.39(-0.20) 8.41(-0.10) 7.96(-0.17) 8.00 (0.10) 7.64 (0.31) 7.54 (0.15) 7.22 (0.04) 7.70 (0.45) 8.33 (0.15) 7.46(-0.58) 8.38(-0.09) 8.25 (0.11) 8.38(-0.21) 7.91 (0.22) 8.16(-0.10) 8.07 (0.04)

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405 Table 16 a -Blocking a c t i v i t y and physicochemical parameters of R4-substituted compounds ( I ) MeO. MeO

CN

H

- (CH 2) 3N(CH 2) 2 0

MeO~so Pr

R4 PA2 Eq.16

Compd. No.

R4

~

a)

I b) ortho

A LC) para

A _meta c) 55

Obsd. Calcd. ( A )

1-114 1-115 1-116 1-117 1-3 1-118 1-119 1-120 1-121 1-122 1-123 1-124 1-125 1-126 1-127 1-128 1-129 1-130 1-131 1-132 1-133 1-134 1-135 1-136 1-137 1-138 1-139 1-140 1-141 1-142 1-143 1-144 1-145 1-146 1-147 1-148~, 1-149 T) 1-150 1-151 a) b) c) d) e) f)

H o-Me o-n-Pr o-t-Bu o-OMe o-OEt o-F o-Cl o-NO^ o-NH~ o-CNz o-OPr o-OBu o-OCH^Ph o-OH z m-Me m-t-Bu m-OMe m-F m-Cl m-NO^ m-NH~ m-CNz m-CF3 p-Me p-n-Pr p-t-Bu p-OMe p-F p-Cl p-NO9 p-NH~ p-CN2,3-(OMe)~ 2,4-(OMe)~ 2,5-(OMe)~ 2,6-(OMe)~ 2-OMe,5-M~ 2-OMe,5-F

0.00 0.52 1.43 1.82 -0.08 0.30 0.21 0.77 0.03 -1.35 -0.30 0.92 1.38 1.48 -0.80 0.54 1.85 0.03 0.26 0.79 -0.03 -1.14 -0.32 0.98 0.52 1.43 1.82 -0.08 0.21 0.77 0.03 -1.35 -0.30 ~ -O.05e! -0.16 e ) -0.05 e) -0.16 e) 0.46 e) 0.18 e)

0.00 0.00 0.00 0.00 1.00 1.00 0.00 0.00 0.00 0.00 0.00 1.00 1.00 1.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1.00 1.00 0.00 1.00 1.00

0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.81 2.86 2.05 1.92 0.59 1.46 1.38 0.72 2.17 0.00 1.92 0.00 0.00 0.00 0.00

0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1.04 2.17 2.07 0.35 0.80 1.44 0.97 0.60 1.61 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2.07 0.00 2.07 0.00 1.04 0.35

7.37 6.57 6.30 5.57 8.42 8.48 7.45 6.91 7.01 6.53 7.44 7.57 7.37 6.90 7.55 6.30 5.37 6.34 7.35 6.63 6.30 5.94 6.11 5.48 6.31 5.23 5.24 5.86 6.36 5.84 5.42 6.26 5.64 5.71 6.04 6.81 6.09 7.34 8.69

d)

7.08 (0.29) 7.01(-0.44) 6.51(-0.21) 6.15(-0.58) 8.03 (0.39) 8.00 (0.48) 7.07 (0.38) 6.92(-0.01) 7.08(-0.07) 6.57(-0.04) 7.06 (0.38) 7.79(-0.22) 7.49(-0.12) 7.41(-0.51) 6.90 (0.65) 6.44(-0.14) 4.95 (0.42) 5.96 (0.38) 6.87 (0.48) 6.47 (0.16) 6.30 (0.00) 6.19(-0.25) 6.73(-0.62) 5.94(-0.46) 6.47(-0.16) 4.62 (0.61) 4.80 (0.44) 5.81 (0.05) 6.68(-0.32) 5.95(-0.11) 6.17(-0.75) 6.10 (0.16) 5.62 (0.02) 5.96(-0.25) 6.75(-0.71) 6.91(-0.10) 7.07 7.41(-0.07) 7.83 (0.86)

~ values for mono-substituted anisoles. Indicator variable which takes the value of one for o-alkoxy groups and zero for others. Taken from a brochure given by Dr. A. Verloop. A , the difference between observed and calculated values. Values are the sum of the values for substituents. Omitted from the correlation.

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