Biochemistry Involving Carbon-Fluorine Bonds - ACS Publications

10 Preparation and Physiological Evaluation of Some New Fluorinated Volatile Anesthetics DONALD D. DENSON, EDWARD T. UYENO, ROBERT L. SIMON, JR., and HOWARD M. PETERS

Downloaded by TUFTS UNIV on October 15, 2016 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0028.ch010

Stanford Research Institute, 333 Ravenswood Ave., Menlo Park, Calif. 94025

Although several adequate fluorinated anesthetics are in clinical use today, all have disadvantages and possible hazards. We are synthesizing and evaluating fluorinated ethers for use as volatile anesthetics. Since these compounds are "inert" gases, they exert their biologic effects without undergoing any chemical transformation during administration, residence in the body, and elimination from the body. It is hoped they will provide the advantages of currently available fluorinated anesthetics but preclude their disadvantages (1). In discussing volatile anesthetics, it is important to understand the difference between analgesia, narcosis, and anesthesia. Analgesia (Stage I) is the loss of pain or numbing of sensory nerves without loss of consciousness. Narcosis (Stage II) is a reversible state of analgesia accompanied by stupor or unconsciousness. Surgical anesthesia (Stage III) is the reversible loss of all modalities of sensation and loss of consciousness. The planes of surgical anesthesia in humans (2) are: Plane 1: Swallowing reflex lost; respiration regular; muscle relaxation minimal Plane 2: Muscle relaxation increased Plane 3: Muscle relaxation further increased and suitable for intraabdominal surgery Plane 4: Skeletal muscle relaxation complete; possible cyanosis; blood and pulse pressure falls; pulse rate increases The level below Plane 4 of surgical anesthesia is respiratory arrest (Stage IV). While planes 1-3 of surgical anesthesia are the most important, some consideration must be given to the 190 Filler; Biochemistry Involving Carbon-Fluorine Bonds ACS Symposium Series; American Chemical Society: Washington, DC, 1976.

10.

DENSON

E T

Fluorinated

AL.

dangerous a s p e c t s o f Stage l e v e l s must be c a r e f u l l y without

adverse

Volatile

I I I , Plane

avoided

191

Anesthetics

4, and S t a g e

i f the patient

IV.

These

i s to survive

affects.

Thus the major o b j e c t i v e s

of successful

a n e s t h e s i a (_2) a r e

to: (1)

Alleviate

(2)

Block mentation

(3)

Relax

(4)

Preclude adverse

anxiety


tages

that

than

to alleviate

resulting

from

the fear

effects

fluorinated

ethers

important

While

(1) t h e y

muscle r e l a x a t i o n ,

tion

of myocardial

and (3) t h e y

tissue

Halogenated

as

potential While

to

about

less

have

transition effec-

sensitiza-

to epinephrine.

i n Use

compounds have been u s e d

as a n e s t h e t i c agents

comprehensive

During

study

t h e 1940s,

of fluorocarbons

anesthetics(3).

any number o f f l u o r i n a t e d

anesthetic

advan-

they

p r o v i d e more

1847 w i t h t h e d i s c o v e r y o f c h l o r o f o r m .

Robbins r e p o r t e d the f i r s t

more

activity,

demonstrate

H a z a r d s o f F l u o r i n a t e d A n e s t h e t i c s Now

since

offer

these ethers are

provide a long

b e t w e e n a n a l g e s i a and a n e s t h e s i a , (2) t h e y tive

nerves.

a n e s t h e t i c s i n use today

(as a c l a s s )

hydrocarbons.

advantages:

o r motor

of surgery or anesthesia.

of the f l u o r i n a t e d

fluorinated

nerves.

a n g u i s h and

of pain.

more u n p r e d i c t a b l e i n t e r m s o f b i o l o g i c a l three

or afferent

the mental

t h e m u s c l e s by b l o c k i n g e f f e r e n t

Examination suggests

p a i n by b l o c k i n g s e n s o r y

properties,

eight

wide s c a l e

compounds.

compounds have

clinical

potential

use has been

T h e f o u r compounds u s e d

limited

most o f t e n

are :

All

these

ities

that

Halothane

CF CHBrCl

Methoxyflurane

CH 0CF CHC1

Fluroxene

CF CH OCH=CH

Enflurane

CHF 0CF CHC1F

3

3

2

3

2

2

2

compounds a r e a s s o c i a t e d w i t h a c u t e must be c a r e f u l l y

Halothane acid (5).

considered

i s oxidatively NADPH/0

2

2

and c h r o n i c

metabolized

to t r i f l u o r o a c e t i c

2

CF CHBrCl 3

pathways

toxic-

(1, 4 ) .

Hepatocellular

damage

Filler; Biochemistry Involving Carbon-Fluorine Bonds ACS Symposium Series; American Chemical Society: Washington, DC, 1976.

192

BIOCHEMISTRY INVOLVING C A R B O N - F L U O R I N E BONDS

This transformation if

any t o x i c

aberrant

metabolic

implicated

h e p a t o c e l l u l a r damage

i n producing

production

o f few,

capa-

( 1 ) . Halothane i s

an u n p r e d i c t a b l e

a n d i n some c a s e s

rine

harmless with

I t i s q u i t e p o s s i b l e however t h a t

pathways produce r e a c t i v e i n t e r m e d i a t e s

ble of i n f l i c t i n g

(1),

i s probably

intermediates.

postanesthetic

s e n s i t i z e s myocardial

tissue

to

hepatitis epineph-

(6) . Methoxyflurane produces f r e e f l u o r i d e

i o n on metabolism ( 5 ) .

NADPH CH 0CF CHC1


3

2

CH OCF CH OH + C I " 3

2

2

2

\ Urinary Metabolites

H0CH CC1 H

CH 0 + H0CF CC1 H 2

In f a c t lized, These

2

2

2

s i n c e 60-80% o f a l l absorbed m e t h o x y f l u r a n e relatively

high

serum f l u o r i d e

levels

t o the high output

expected.

renal failure

This nephrotoxicity i s further complicated p h é n o b a r b i t a l may

sensitize

Fluroxene

i s metabolized

humans t o t r i f l u o r a c e t i c CF CH 0CH 3

= CH

2

H i g h serum f l u o r i d e s

·*

2

cell

syndrome ( 4 ) .

by t h e o b s e r v a t i o n

a t h r e e f o l d o r greater extent of

methoxyflurane metabolism t o f l u o r i d e

in

i s metabo-

c a n be

l e v e l s a r e o f t e n h i g h enough t o cause r e n a l t u b u l a r

damage, g i v i n g r i s e

that

+ 2F'

2

ion (4).

i n animals

t o t r i f l u o r o e t h a n o l and

acid (5). CF C0 H + Urinary 3

2

Metabolites

a n d h e p t o c e l l u l a r damage a r e a s s o c i a t e d

its

u s e i n humans.

In a d d i t i o n fluroxene

and

i t i s primarily for this

reason

that

i s extremely i t has been

with

flammable, removed

from c l i n i c a l u s e . Enflurane ion

i s tranformed

CF H0CF CHC1F 2

Although

these

patients

they

normal

-»

2

fluoride reach

Unknown M e t a b o l i t e s

ion levels

a r e r o u t i n e l y low, i n some close t o the

level (2).

exposures t o t r a c e s o f these

be a h a z a r d .

+ F"

80 μ m / l , w h i c h i s d a n g e r o u s l y

fluoride tolerance

Chronic can

t o unknown m e t a b o l i t i e s a n d f l u o r i d e

i n humans ( 5 ) .

According

fluorinated

t o a r e c e n t ASA s t u d y

anesthetics

(7), operating


DENSON

10.

room p e r s o n n e l malformation liver

Fluorinated

ET AL.

Volatile

193

Anesthetics

h a v e shown a n i n c r e a s e i n s p o n t a n e o u s a b o r t i o n ,

of children,

cancer

d i s e a s e , and k i d n e y

i n female

anesthesiologists,

disease.

Synthesis of Fluorinated Ethers While

o n l y a few f l u o r i n a t e d

application, of

cyclic


(8) p a t e n t e d

methyl-l,3-dioxolane in

1967.

clinical

A n example o f a c l a s s

diether anesthetics i s 4,5-dihalo-2,2-(bis)trifluoro-

methyl-1,3-dioxolanes,

Gilbert

ethers are i n actual

o t h e r s have shown p r o m i s e .

Terrell

1.

the use o f the parent

2,2-(bis)trifluoro-

1 (X = Y = H) a s a n i n h a l a t i o n a n e s t h e t i c

a n d Moore (9) t h e n

patented

t h e u s e o f 4,5-

dihalosubstituted-2,2-(bis)trifluoromethy1-1,3-dioxolanes

1 in

1973.

~ Gilbert

(8).

While

Terrell

found

h i s m a t e r i a l t o be more p o t e n t

a r e more p o t e n t

than

has l i m i t e d

Our

that the halosubstituted materials

the parent

compound

( 9 ) ; 1,3-dioxolane

anesthetic properties (10).

experience

i n the conversion o f carbonates

formals

l e d us t o i n v e s t i g a t e

equally

as potent,

anesthetics.

halothane

no d e f i n i t i v e A n e s t h e t i c I n d e x d a t a a r e p r o v i d e d by

e t aJL., i t a p p e a r s

itself

than

the p o s s i b i l i t i e s

b u t more s t a b l e ,

Our approach i s based

cyclic

to difluoro-

of preparing

diether inhalation

on t h e f o l l o w i n g r e a c t i o n :

Ο Cat.

Δ Because o f t h e ready

availability

ease o f p r e p a r i n g a host

R-0-CF -0-R 2

of the starting

o f halogenated

analogs,

material, the t h e apparent


194

BIOCHEMISTRY INVOLVING

success as

C A R B O N - F L U O R I N E BONDS

of the 4 , 5 - d i h a l o - 2 , 2 - ( b i s ) t r i f l u o r o m e t h y l - 1 , 3 - d i o x o l a n e s

a n e s t h e t i c s ( 9 ) , we

carbonate,

initiated

our i n v e s t i g a t i o n

using

ethylene

2.

2

We

extended


include

the conversion

the p r e p a r a t i o n of

of carbonates

to difluoroformals to

4,5-dihalo-2,2-difluoro-1,3-dioxolanes:

where X and Y a r e h a l o g e n s

Ethylene

carbonate,

2, c a n be c h l o r i n a t e d t o g i v e

3, and 4 , 5 - d i c h l o r o e t h y l e n e

carbonate,

2

3

Monochloroethylene vinylidene

carbonate,

carbonate,

4-chloro,

4.

4

3, c a n be d e h y d r o h a l o g e n a t e d

5, a s shown b e l o w ( 1 1 ) .

CI Ο

+

>=

(C H ) N 2

5

3

*Ο

*0'

3

5

0


to

10.

Vinylidene

carbonate,

halogenated


Fluorinated

DENSON E T A L .

Volatile

5, c a n be c o n v e r t e d t o a number o f o t h e r

derivatives

a s shown i n Scheme 1.

8

Compounds

^7,

7

and £

are readily

polyhydrogenfluoride/pyridine (12).

o b t a i n e d by t h e u s e o f

reagent,

Straightforward hydrobromination

affords

compounds 10 and 11.

c a n be p r e p a r e d ethylene The

195

Anesthetics

A similar

a s d e s c r i b e d by O l a h e t a l . o r b r o m i n a t i o n (11) series of derivatives

from t h e d e h y d r o h a l o g e n a t i o n

of 4,5-dichloro-

c a r b o n a t e , 4^. fluorination

much e x c i t i n g

reactions

and u s e f u l

dichloroethylene

of these carbonates

chemistry.

carbonate,

have

The f l u o r i n a t i o n

4, f o r example,

led to

o f 4,5-

gives three products:



196

BIOCHEMISTRY

INVOLVING

CARBON-FLUORINE

BONDS

14

The

product

lyst/SF

4

results

mixture

ratio. i n the

ratio

An

i s extremely

increase of >

formation of

0.5

as the major p r o d u c t .

1,3-dioxolane,

^4,

suggests

that

t r i f l u o r o - 1 , 3 - d i o x o l a n e , ^3, f o l l o w e d by

r e a c t i o n a s we carbonate,

will

see

4

ratio

from

ΊΛ

i s an

i n the

4-chloro-2,2,5-

a dehydrochlorination addition

important

fluorination

reaction.

finding

in

The

this

of 4-chloroethylene

3.

B e c a u s e we

observed

the monochlorinated totally

formation of

results

halogen

4,5-dichloroethylene carbonate,

The

the c a t a -

The c h l o r i n a t e d - u n s a t u r a t e d

the

a hydrogen f l u o r i d e

unsaturated-1,3-dioxolane,

on

4-chloro-2,2,5-trifluoro-l,3-

d i o x o l a n e , J^3,

reaction

dependent

i n the c a t a l y s t / S F

we

began o u r

d e r i v a t i v e 3 u s i n g an H F / S F

unexpected

result

2,2,5-trifluoro-1,3-dioxolane,

3

exchange i n the 4,

was 13,

4

fluorination

of

investigation

of

ratio

of

0.45.

the formation of 4-chloroas the o n l y i s o l a t e d

product.

13


10.

DENSON

For t h i s be

Fluorinated

ET AL.

compound t o form,

occurring.

halogen

There

Volatile

197

Anesthetics

a hydrogen s u b s t i t u t i o n

i s no r e p o r t e d e v i d e n c e

exchange o r a d e h y d r o c h l o r i n a t i o n h y d r o g e n

tion

reaction.

tion

a n d o c c u r s w h e t h e r HF o r T i F

precursor results

This result

carbonate

with either

i n no r e a c t i o n .

with SF

i s independent

of the s t a r t i n g

carbonate,

3.

Heating the

c a r b o n a t e , 3^,

f o r 24 h r r e s u l t s

Hydrogen

addi-

concentra-

4

a t 150°C f o r 24 h r

4-chloroethylene

i n t h e absence o f c a t a l y s t

4

4

must

a direct

fluoride

of cat/SF

i s the catalyst.

4

HF o r T i F

Heating

reaction

f o reither

i n recovery

s u b s t i t u t i o n by S F

4

has

b e e n r e p o r t e d by A p p l e q u i s t a n d S e a r l e ( 1 3 ) . Experiments either

conducted

a t lower

d i o x o l a n e , ^15, a s t h e m a j o r


temperatures

resulted i n

no r e a c t i o n o r i n t h e f o r m a t i o n o f 2 , 2 , 5 - t r i f l u o r o - 1 , 3 product.

Cat./100°C

Cl-,

= 0 + SF

A

Cat./125°C

-0' 15

Hydroquinone

A

similar

ethylene prepare

was o b t a i n e d

2,

t o determine

to biological

i n attempts

The o b j e c t i v e o f t h i s

2,2-difluoro-1,3-dioxolane

dioxolane moiety

result

carbonate,

r a t i o was a g a i n m a i n t a i n e d

of the difluoroformal

In these

b e l o w 0.5.

experiments,

t h e HF/SF

4

T h e f o r m a t i o n o f 2,2,4,5-

t e t r a f l u o r o - 1 , 3 - d i o x o l a n e , J^6, was i n d e p e n d e n t t u r e and c a t a l y s t

was t o

f o r c o m p a r i s o n w i t h 1,3-

the contribution

activity.

to fluorinate experiment

o f both

tempera-

concentration.

16

The

hydrogen

substitution

of 4 - c h l o r o e t h y l e n e

reaction

carbonate,

observed

f o r the fluorination

3, i s t h e p r e d o m i n a n t

this

case.

pare

2,2-difluoro-1,3-dioxolane.

reaction i n

We have been u n s u c c e s s f u l i n a l l o u r a t t e m p t s

investigation

t o determine

This reaction

the f e a s i b i l i t y

t o pre-

i s under

of preparing

further this

compound.


198

BIOCHEMISTRY INVOLVING

Structure-Activity The

•

Relationships

major s t r u c t u r e - a c t i v i t y

anesthetics

potency

o f h y d r o c a r b o n s and

i n the

order I >

•

Unsaturation

•

F l u o r i n e a d d i t i o n decreases point

and

Increased an

•

increases

for

volatile

halogen

potency

ethers

Br >

Cl >

increase

F.

potency.

f l a m m a b i l i t y and

of adjacent •


relationships

a r e as f o l l o w s :

Halogenation in

C A R B O N - F L U O R I N E BONDS

potency, increases

boiling stability

atoms.

i n a homologous s e r i e s

increase i n molecular

weight,

and

oil/gas

One

o r more h y d r o g e n atoms a r e

follows

boiling

point,

coefficient. necessary

for

CNS

depression. Since

molecules

oxygen are introduce 16.

not one

c o n t a i n i n g only carbon, u s u a l l y very

potent

chlorine into

These experiments are

fluorine,

hydrogen,

a n e s t h e t i c s , we

and

attempted

to

2,2,4,5-tetrafluoro-1,3-dioxolane, summarized

i n the

following

equations

s

16

Photochemical at

chlorination

room t e m p e r a t u r e

results

of

16

tetrafluoro-1,3-dioxolane, maximum y i e l d ther in

of t h i s

chlorination

the

with

one

significant

Photochemical 16,

with

chlorination excess

of

4-chloro-2,2,4,5products.

to date

results

The

i s 53%.

i n an

i n c r e a s e i n the

4-chloro-2,2,4,5-tetrafluoro-l,3-dioxolane,

oxolane,

of

five

obtained

r e a c t i o n mixture no

e q u i v a l e n t of c h l o r i n e

formation

along with

p r o d u c t , ^17,

of the

by-products,

with

i n the

Fur-

increase desired

17.

2,2,4,5-tetrafluoro-1,3-di-

chlorine results

i n the

4,4,5,5,-tetrachloro-2,2-difluoro-1,3-dioxolane,

formation JL8, a s

the


of major

Fluorinated

DENSON E T A L .

10.

product be

(>95%).

reported

This

Volatile

reaction

i n a future

199

Anesthetics

i s under

publication.

further

s t u d y and w i l l

We do n o t b e l i e v e

4,4,5,5-tetrachloro-2,2-difluoro-1,3-dioxolane, potent

anesthetic

cule.

Generally

since

t h e r e a r e no h y d r o g e n

one o r more h y d r o g e n s

that

18, w i l l

be a

atoms i n t h e m o l e -

are required

f o r CNS

depression. The that atom.


the

structure-activity

relationships

a more p o t e n t member o f t h i s We have a t t e m p t e d

because

weak bond

i n metabolic environments.

determine

how w e l l

structure

reactivity

our c l a s s

reaction

suggest

bromine

potency without

i t i s a thermodynamically However i n a n e f f o r t t o

of d i e t h e r s adheres

r e l a t i o n s h i p s g i v e n above,

f l u o r i n a t e 4,5-dibromoethylene this

contain a

t o maximize a n e s t h e t i c

i n c o r p o r a t i o n o f bromine,

from

p r e s e n t e d above

c l a s s would

c a r b o n a t e , 11.

t o the reported we a t t e m p t e d t o

The major

product

i s 4-bromo-2,2,5-trifluoro-1,3-dioxolane,

19.

11

As

19

i n the case o f the f l u o r i n a t i o n

of 4,5-dichloroethylene

carbonate,

3, we have o b s e r v e d h a l o g e n e x c h a n g e ,

conversion

i s independent

been a b l e t o i s o l a t e

of cat/SF

4

but here

concentration.

t h e u n s a t u r a t e d bromine

this

We h a v e n o t

c o n t a i n i n g 2,2-

d i f l u o r o - 1 , 3 - d i o x o l a n e , 20.

20

Experiments with T i F exchange i n t h e absence in

t h e absence

experiments ethylene 6

f

4

4

of catalyst

involving

a t 1 0 0 ° and 150°C

of SF .

Similarly,

resulted

i n no e x c h a n g e .

the f l u o r i n a t i o n

c a r b o n a t e , 11,

resulted

i n no

e x p e r i m e n t s w i t h SF, Additional

o f b o t h 4,5-dibromo-

and 4 - b r o m o - 5 - f l u o r o e t h y l e n e

carbonate,

are i n progress.


200


Physiological The search

potential

a

by

onto the stance

to the

the

of

the

j a r , and Every

righting

15

the

interval

The

the

but

the

later

m i c e were k e p t on

a pan.

the

(15). not

closed quickly

facilitated

by

gentle into

immediately. was

gently

r o t a t e d and

t o become a n e s t h e t i z e d Since

the

t h a n 5 min

two

sub-

calculated

Stone

j a r was

occurrence

time

(loss

of

i s considered

the of

induction to

represent

anesthetic

l i m i t s was

i n the

The

being

removed

every

15

record The

agents,

u s e d as

tail

a

crite-

latent

In the

toxicity

first

performed to determine

each of

the

another dose-range

e a c h compound were e x p r e s s e d

as

The

by

an

point.

hour

each

5 0

and

three

second

stage,

lower

con-

selected

anesthetic

margin of

(AC

of the

in

was

a n i m a l s were

In the

anesthetic

median l e t h a l

range,

t o chose t h r e e

p o t e n c y and

w h i c h 50%

hours

conducted

Fifteen

medium e f f e c t i v e

an

If

after

administered

concentration

median a n e s t h e t i c c o n c e n t r a t i o n concentration

A

end

i n m i c e was

a n i m a l s were t e s t e d a t

anesthetic

by

minutes.

compounds.

conducted

t o determine the

anesthetized.

was

concentrations.

was

concentration

The

the

was

tested

a dose-range experiment

lethal

three

removed

f o r twenty-four

were s e l e c t e d .

Fifteen

estimated

five

as

test

substances

the

study

of the

centrations.

The

pinch

stage,

concentrations

concentration.

every

s u b j e c t s were k e p t

e v a l u a t i o n of the

stages.

at

a n a l g e s i a was

considered

j a r , the

The

then

(to righting)

showed a n a l g e s i c r e s p o n s e a h a l f

from the

any

was

minutes,

recovery

Postanesthetic

the

minutes.

appropriate

j a r f o r 10

time of

base of each a n i m a l ' s t a i l

still

aminal

be

The

of

syringe

compound t h a t w o u l d

container

between t h e s e

an

to

j a r was

i n d u c t i o n t i m e f o r known p o t e n t

pressing

tested

from a

amount o f a t e s t

by Ough and

capped

noted.

no

ejected the

glass jar

a m e a s u r e d amount

F i v e m i c e were q u i c k l y d r o p p e d

b o t t l e was

seconds,

s c r e w cap,

and

" a i r " i n the

s u b s t a n c e was

container.

s q u e a k on

two

Initially the

of each t e s t

f o r each animal.

pinching

to

minute,

re-

those

induction.

placed

noted

jar.

f o r each animal

min

optimal

r i o n of

of

r e f l e x ) was

0.5

the

and

the

saturate

similar

A wide-mouth,

methods r e p o r t e d

the

time r e q u i r e d

after

to

" a i r " were e v a l u a t e d .

evaporation

rotation

in this

procedures

i n a s y r i n g e was

concentrations

saturate

the

compound

bottom of

according

(14).

agents synthesized

o x y g e n f o r one

t h a t would

Several


Burgison

flushed with

synthesized

and

anesthetic

were t e s t e d i n m i c e by

described was

Evaluation

safety

of

index. )

i s defined

animals are

concentration

(LC


as

an

expected 5 0

)

is

10.

DENSON

an

E T

Fluorinated

AL.

201

Anesthetics

e s t i m a t e d c o n c e n t r a t i o n by w h i c h 5 0 % o f t h e a n i m a l s a r e

expected to

AC

5 0

to die.

.

safety.

The lower

the A C

5 0

,

the lower

of

LC

safer.

5 0

of

the c o n c e n t r a t i o n o f drug

However, a d r u g

i s not n e c e s s a r i l y

methoxyflurane

(AI) i s the r a t i o

the a n e s t h e t i c index t h e g r e a t e r margin

f o r metabolism.

centration

for

The a n e s t h e t i c i n d e x

The l a r g e r

available

acting

at lower

con-

As a l r e a d y d i s c u s s e d ,

i s nephrotoxic, yet i t s A C

i s about

5 0

half

that

halothane. Before

reviewing are


Volatile

p r e s e n t i n g our p h y s i o l o g i c a l

some d a t a a v a i l a b l e

summarized

i n Table

1 (2, 8 ) .

nephrotoxicity

data are a v a i l a b l e

1,3-dioxolane,

i t i s interesting

larger

than halothane

fluorine,

hydrogen,

reported

by T e r r e l l

noteworthy

that

data,

While

and o x y g e n .

data

for 2,2-(bis)trifluoromethylt o note

that

While

little

i t s AI i s s l i g h t l y

contains only

carbon,

no d e f i n i t i v e A I d a t a a r e

(9) f o r t h e h a l o g e n a t e d very

These

no h e p a t o c e l l u l a r o r

( 8 ) . T h i s molecule

t h e r e was

i t i s worthwhile

f o r other anesthetics.

analogs,

i ti s

increase i n activity.

Table 1 ANESTHETIC POTENCY FOR FLUORINATED

ANESTHETICS

B.P. Anesthetic

(°C)

AC

50

Halothane

0.3

Fluroxene

43

1.2-8

Enflurane

57

2-4

100

0.5

2,2

(Bis)trifluoro-

AI

MAC

5 0

2.74

0.78

105

Methoxyflurane

LC

5 0

0.78

3.50

-

-

0.23 6.0 2.2

-

4.70

2.38

methyl-1,3-dioxolane

We

began o u r p h y s i o l o g i c a l

standard. is

slightly

Table ized

1).

gained rapid

we o b t a i n e d a n A I o f 4.75,

h i g h e r t h a n t h e A I o f 3.50

previously

by p t o s i s

was c h a r a c t e r i z e d

the r i g h t i n g

reflex,

accompanied

by " f l a t

r e c o v e r y t i m e s were o b s e r v e d ,

elimination.

(Rapid e l i m i n a t i o n

lipophilicity.)

At l e t h a l

e a r s were o b s e r v e d

tails."

they maintained

by

i n addition

i s character-

lacrimation.

Once t h e a n i m a l r e it.

indicating

In a d d i t i o n , rapid

halothane

i s often associated with

c o n c e n t r a t i o n s , dark

T a b l e 2 summarizes our f i n d i n g s

t o p t o s i s and

as a which

reported (see

At a n e s t h e t i c concentrations, halothane

during induction

Recovery

e v a l u a t i o n s using halothane

In these experiments

eyes

lower

and b l a n c h e d

lacrimation.

f o r halothane.


202

BIOCHEMISTRY

INVOLVING

CARBON-FLUORINE

BONDS

Table 2 EFFECTS OF HALOTHANE CF -CHBrCl, ON MICE (AI = 4.75) 3

Cone,

No of

Vol

Animals

%


Time, min 0.78

Deaths 0

5

0.83

0

1.00 1.06

15 15

-

7 12

1.03

0

4.00

15

8

15

7.72

3

5.00

15

13

15

8.13

9

15

8.83

12

15

14

anesthetic concentrations of 4,5-dichloro-2,2-difluoro-1,312, minimum h i n d

l e g movement and p t o s i s were

no l a c r i m a t i o n o r c o n v u l s i v e b e h a v i o r .

terized

by t h e a n i m a l s

had

a bouncy g a i t .

for

halothane,

running

Recovery

in circles.

times

elimination

suggests

M i c e were w o b b l y and

Ptosis

than

t h a t , e v e n a t low

a higher

4 , 5 - d i c h l o r o - 2 , 2 - d i f l u o r o - 1 , 3 - d i o x o l a n e , 12.

t r a t i o n s were c h a r a c t e r i z e d by i r r e g u l a r bradycardia.

charac

f o r 1£ were much l o n g e r

i s not n e a r l y as r a p i d

Slower e l i m i n a t i o n

observed,

R e c o v e r y was

a s shown i n T a b l e 3, s u g g e s t i n g

concentrations, halothane. for

Mean Recovery

15

dioxolane, but

Induced

0.94

5.50

At

Induced

before 30 sec before 5 min

as i t i s f o r

lipophilicity L e t h a l concen

respiration

a n d l a c r i m a t i o n were o b s e r v e d

and

apparent

i n a few

animals.

Table 3

EFFECTS OF

:c> |

\ F„ ON MICE

o

/

12

(ΑΙ = 7.88) Cone,

No of

Vol

Animals

%

0.25

Induced

Induced

before 30 sec before 5 min

15

Mean Recovery time, min

0

Deaths

-

0

0.30

15

2

0.63

0

0.35

15

-

13

10.60

0

2.00

15

-

15

60.08

0

2.50

15

-

15

60.47

6

3.00

15

1

15

120

14


10.

DENSON

ET

Anesthetic dioxolane, siveness, animals

Fluorinated

AL.

Volatile

concentrations of 4-chloro-2,2,5-trifluoro-1,3-

13, were c h a r a c t e r i z e d by h y p o a c t i v i t y , s l i g h t ptosis,

and o c c a s i o n a l l a c r i m a t i o n .

often ran i n c i r c l e s

Recovery times,

given

and some l o s t

i n Table

t h e AI d e t e r m i n e d

13^, was a p p r o x i m a t e l y

halothane,

recovery

mos)


times

those

reflexes.

reported

(see Table 3 ) .

t h e same a s t h e A I d e t e r m i n e d

were somewhat

the animals'

longer

f o r 13.

e y e s became e x t r e m e l y

and deep j e r k y r e s p i r a t o r y

breathing

righting

half 12

convul-

recovery the

f o r4-chloro-2,2,5-trifluoro-1,3-

dioxolane,

concentrations,

During

their

4, were a b o u t

for 4,5-dichloro-2,2-difluoro-1,3-dioxolane, Although

203

Anesthetics

response

was

At

dark

for

lethal

(exophthal-

f o l l o w e d by

shallow

and b r a d y c a r d i a .

Table

4

0< .0

C E F F E C T S OF

F

13

(AI Cone,

No. o f

Vol

Animals

%

0.88

15

0.94

15

1.00

=

4.66)

Induced before

Induced

30 s e c

before

Mean R e c o v e r y

5 min

time,

min

Deaths

5

1.95

0

-

13

3.07

0

15

-

14

4.13

0

3.00

15

-

15

15.48

0

4.00

20

-

20

17.78

10

5.00

15

5

15

19.72

12

The

preliminary evaluation of

dioxolane, ptosis

During

shivered

recovery,

the animals

f o r a few m i n u t e s .

those

dioxolane, During

2,2,4,5-tetrafluoro-1,3-

i s summarized i n T a b l e

5.

and t a c h y p n e a were a s s o c i a t e d w i t h

tions.

than

1£,

observed

Recovery

for either

Rapid

hind

anesthetic

ran i n c i r c l e s , times

l e g movement concentraand some

were f a r more

1J2, o r 4 - c h l o r o - 2 , 2 , 5 - t r i f l u o r o - 1 , 3 - d i o x o l a n e ,

induction, lethal

1,3-dioxolane

rapid

4,5-dichloro-2,2-difluoro-1,31£.

concentrations of 2,2,4,5-tetrafluoro-

were c h a r a c t e r i z e d by t h e same o b s e r v a t i o n s


made f o r

204


the

anesthetic concentrations.

During

l e g s were e x t e n d e d and d r a g g e d , front

recovery,

and a n i m a l s

however,

crawled

with

hind their

legs. Table

5

Ο

F^°v E F F E C T S OF

F

ON

2

MICE

0


16 Cone.,

No. o f

Vol

Animals

%

Mean R e c o v e r y

Induced before

Time,

5 min

Deaths

min

4.0

10

2

0.92

0

5.0

5

2

1.42

0

6.0

5

5

2.37

0

5.58

10.0 12.0

Statistical The

Analysis

data

obtained

from the a d m i n i s t r a t i o n o f t h e lower

c e n t r a t i o n s of halothane centage of animals

were a n a l y z e d

The p e r c e n t a g e s

c e n t r a t i o n on l o g a r i t h m i c p r o b a b i l i t y

three

were p l o t t e d p a p e r a s shown

of

induced

at each o f the three

13^, were p l o t t e d .

From t h e g r a p h ,

t o t h e method o f L i t c h f i e l d

i n Table

1,3-dioxolane, the

6.

Since A C

5 0

the A C

5 0

o f e a c h compound and W i l c o x o n

was (16)

of 4,5-dichloro-2,2-difluoro-

12, i s s i g n i f i c a n t l y

former i s considered

inducing

1.

of 4-chloro-2,2,5-trifluoro-1,3-dioxolane,

computed a c c o r d i n g shown

con

i n Figure

4,5-dichloro-2,2-difluoro-1,3-

12, and t h e p e r c e n t a g e

lower c o n c e n t r a t i o n s

as

against

t h e p e r c e n t a g e o f mice a n e s t h e t i z e d a t each o f t h e

lower c o n c e n t r a t i o n s

dioxolane,

con

the per

t h a t were a n e s t h e t i z e d a t e a c h o f t h e t h r e e

lower c o n c e n t r a t i o n s .

Similarly,

by c a l c u l a t i n g

lower than

t o be more p o t e n t

than

that

of

halothane,

the l a t t e r i n

anesthesia.



10.

DENSON E T A L .

Fluorinated

0.2

0.4

VOLUME

PERCENT

2

4

VOLUME

PERCENT

0.6

Volatile

Figure

1

CONCENTRATION

6

10

CONCENTRATION

20

205

Anesthetics

1. Effects of inhalation anesthetics on mice

Figure 2. Effects of high doses of inhahtion anesthetics on mice


206

BIOCHEMISTRY

Table

INVOLVING

CARBON-FLUORINE

BONDS

6

ANESTHETIC POTENCY AND

MARGIN OF

STRUCTURE VS.

SAFETY

ACTIVITY

:t> ^0

X

Compound

Y

AC


Halothane

0.99

4.7

4.75

CI

Cl

0.33

2.6

7.88

13

CI

F

0.88

4.1

4.66

16

F

F

_

_

-

The

that

results

d i e d at

compound.

of the

a d m i n i s t r a t i o n of

the

LC

Further

pound

computing

three

high

the

high

concentrations

percentage of

concentration

p e r c e n t a g e s were p l o t t e d a g a i n s t 2.

From t h e

three

a n a l y s i s showed t h a t

indicating

i s considerably

derived

t h e AI

of

the

higher

levels

of

each

concentrations

as

margin of

than that

listed

than that

s a f e t y of

of

in

Table

4,5-dichloro-2,2-

i s s u b s t a n t i a l l y higher that

of

animals

concentration-response

o f e a c h compound was

5 0

difluoro-1,3-dioxolane halothane,

by

each of the

The

shown i n F i g u r e

curves, 6.

5 0

12

compounds were a n a l y z e d

as

AI

LC

5 0

the

of

new

com-

halothane.

Summary From t h e trends

o x o l a n e s do present. rine

summary o f o u r

data

in structure-activity not

As

contain

could

i s replaced

be

by

6,

we

can

see

some

A l t h o u g h our d i -

b r o m i n e , good a n e s t h e t i c a c t i v i t y

predicted,

fluorine.

chlorine i s replaced

cients will

be

determined

and

activity

increases

new

c l a s s of

potent

The

structure activity

the

The

d e c r e a s e as

Anesthetic

i n Table

relationships.

activity

lipophilicity

by

fluorine

reported as

the

in a

is

d e c r e a s e s as appears

(partition

chlo-

to coeffi-

later publication).

boiling

point

of

the

series

increases. A oped.

volatile

pounds a p p e a r t o f o l l o w t h o s e compounds i n t h i s

c l a s s are

anesthetics

has

r e l a t i o n s h i p s of t h i s reported

being

i n the

prepared

and

more d e t a i l e d p h y s i o l o g i c a l e x a m i n a t i o n s w i l l

been

devel-

c l a s s of

literature. evaluated, be

and

conducted.


com-

Other

10.

DENSON

Fluorinated

E T A L .

Volatile

207

Anesthetics

Acknowledgement s The search

authors

gratefully

by I n s t i t u t e s

Division,

acknowledge t h e support

of Health,

under Grant

General

Medical

of this re

Sciences

Number 5-R01-GM-20082-02.

Discussion Q:

How l o n g d i d y o u o b s e r v e

the animals

f o r evidence

of latent

toxicity? A:

In a l l cases

Q:

A r e t h e compounds s t a b l e t o base?

A:

Y e s ! You c a n c o n v e r t


carbonate are

f o r at least

using

t h e d i f l u o r o f o r m a l group

concentrated

also stable t o mild

Q:

I s t h e r e any s p l i t t i n g

A:

No, a t l e a s t

Q:

The p o s s i b i l i t y on

A:

24 h o u r s .

sulfuric

back t o t h e

T h e s e compounds

acid. out o f carbonyl

we have n o t o b s e r v e d exists

acid.

f o r other

fluoride?

this. isomers.

C a n y o u comment

that?

We c a n n o t

predict

or d e a l i n g with isomers

w h e t h e r we a r e s t u d y i n g one a c t i v e

unknown m i x t u r e s .

a r e present,

We c a n s a y t h a t

we a r e n o t o b s e r v i n g

an a c u t e

isomer

i f other lethal

effect.

Literature Cited 1. Cascorbi, H. F., "Anesthesia Toxicity," in 1974 Annual Refresher Course Lectures, American Society of Anesthesi ologists Annual Meeting, Washington, D. C., October 12-16, 1974, Lecture number 227 and references cited therein. 2. Larsen, Ε. R., "Fluorine Compounds in Anesthesiology," in Fluorine Chemistry Review, P. Tarrant, Vol. 3, pp. 1-44 (1969) and references cited therein. 3. Robbins, J. H., J. Pharmacol. Exptl. Therap. (1946), 86 197. 4. Brown, B. R., Jr., "Enzymes and Anesthesia," in 1974 Annual Refresher Course Lectures, American Society of Anesthesiolo gists Annual Meeting, Washington, D.C., October 12-16, 1974, Lecture Number 225 and references cited therein. 5. Van Dyke, R. A. and Chenoweth, Μ. Β., Anesthesiology (1965), 26, 348. 6. Tucker, W. K., Rackstein, A. D., and Munson, E. S. Brit. J. Anaesth., (1974) 46, 392. 7. Cohen, E., et al., Anesthesiology (1974), 41, 321. 8. Gilbert, Ε. E., (to Allied Chemical Co.), U.S. Pat. 3,314,850 (1967).



208

BIOCHEMISTRY INVOLVING C A R B O N - F L U O R I N E

BONDS

9. Terrell, R. C., and Moore, G. L., (to Airco, Inc.), U.S. Pat. 3,749,791 (1973). 10. Virtue, R. W., Proc. Soc. Exptl. Biol. Med., (1950), 73, 259. 11. (a) Newman, M. S., and Addor, R. W., Amer. Chem. Soc. (1953) 75 1263. (b) Newman, M. S., and Addor, R. W., J. Amer. Chem. Soc., (1955), 77, 3789. 12. Olah, G., Nojima, Μ., and Kerekes, I., Synthesis, (1973) 779. 13. Applequist, D. E., and Searle, R., J. Org. Chem. (1964), 29, 987. 14. Burgison, R. Μ., "Animal Techniques for Evaluating Anesthetic Drug," in Animal and Clinical Pharmacologic Techniques in Drug Evaluation, J. H. Nodine and P. E. Siegler, eds., Yearbook Medical Publishers Inc, Chicago, Ill. (1964), pp. 369-372. 15. Ough, C. S., and Stone, Η., J. Food Sci., (1961), 26, 452. 16. Litchfield, J. T., Jr., and Wilcoxon, F. Α., J. Pharm. Exptl. Ther. (1949), 96, 99.


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