Professional Documents
Culture Documents
CNG NGHIP HO
DC
CNG NGHIP BO CH
CN SN XUT NGUYN
LIU
K S CN HO DC
o to cc trng HKT,
H TNG HP (SP)
DC S
o to ti cc trng H
Dc
i hc Y Dc
- i tng hc mn ho dc:
+ Y, bc s (dc l: au ci g?, dc lc: mnh hay yu?)
+ Dc s (ho dc)
+ K s, c nhn (ho dc v k thut tng hp)
- Ngi hc ho dc phi hc:
+ Hc nhm thuc tc dng ln cc bnh
+ Hc v bnh (Khi nim, nhm thuc tr bnh )
+ Phi bit phng php iu ch n (SX nguyn liu)
-1-
-4-
-5-
- Thuc: l cht c tc dng iu tr, d phng, chn on bnh dng cho ngi
hoc ng vt
- Dc l hc thc nghim: trn ng vt
- Dc l hc lm sng: trn ngi
* Dc l hc:
- Dc lc hc: nghin cu tc ng ca thuc trn c th sng. Tc dng chnh,
tc dng ph.
- Dc ng hc: nghin cu tc ng ca c th n thuc. S phn ca thuc
trong c th.
- Dc l thi khc: nh hng ca nhp sinh hc trong ngy, trong nm.
- Dc l di truyn: tnh cm th ca tng c th, gia nh chng tc do tnh di
truyn.
- Dc l cnh gic: nghin cu, nh gi 1 cch c h thng cc c hi lin
quan n vic dng thuc ca cng ng.
Trong phm vi chng trnh chng ta ch nghin cu v Dc lc hc v
Dc ng hc c khi nim c bn v s phn ca thuc trong c th.
- Vn chuyn thuc vo c th
- Hp thu
- Phn b
- Chuyn ho, tc dng
- Thi tr
Nhm nh hng kt hp cng tc nghin cu tm kim thuc mi cng nh iu
ch cc hp cht lm thuc, nhng hp cht c hot tnh sinh hc.
1.3.2. S phn ca thuc trong c th
1.3.2.1. Hp thu ca thuc
Thuc
Hp thu
Mu
Mng sinh hc
T bo
Ni tc dng
Phn phi
3 yu t nh hng n hp thu
1.3.2.1.1. Cu to v c trng ca mng sinh hc
- Cu to: Mng sinh hc c cu to bng lp lipit vi hai hng phn t, c cu
trc mm, th lng c qunh, c cc anbumin vn chuyn c qua mng.
- c trng ca mng: C kh nng nhanh chng thay i cu trc, cc phn t
anbumin nh ang bi c trong mng, cu trc khng gian bin i ti mc l
trong mng to thnh nhng rnh cc phn t c kch thc nh, cc cht ho
tan, cc ion c th i qua c. Th th hoc enzym c th bm c vo.
1.3.2.1.2. Tnh cht ho l ca phn t thuc v tc dng pH ti s hp thu
- S vn chuyn ca thuc qua mng ph thuc vo:
-6-
+ Cu to lipit ca mng.
+ H s phn b lipit-nc.
- Mc ion ho nh hng n h s phn b lipit-nc. Mc ion ho c
biu th bng hng s phn ly Kd. Mi lin h gia Kd v pH c Henderson
Hasselbach tnh nh sau:
+ Vi trng hp axit:
axit ko phan ly
pKd = pH + log
+ Vi trng hp baz:
-7-
-8-
Mt da
5. Cy ghp di da
Tnh mch
Tim
vo
( intrathecal)
Trong mng bng
Vo mng phi
Vo mng khp
Vo ty xng
Vo mng tim
Di da
-12-
- Kh epoxit
- Kh cc hp cht d vng
4. Thy phn
- Thy phn este.
- Thy phn amit.
- Thy phn azit
5. Hidrat ha
6.ng phn ha.
7.Cc phn ng lin hp
- ng vng
- M vng
- N- cacboxyl ha
- Dime ha
- Chuyn ti amit
- Decacboxyl ha
1.3.2.4.1. Nhng phn ng chuyn ha ( ging ha pha I).
1.3.2.4.1.1. Phn ng oxi ha thng qua enzim li ni bo ( microsoma
oxidations)
Hnh thc chuyn ha sinh hc ca thuc ph bin nht l oxi ha, cn chuyn
ha bng kh ha th t c ngha hn.
- Enzim microsoma l enzim oxi ha nhiu chc nng ( mixed function
oxidase)
- Monooxigluose
- iu kin c th oxi ha l phi c O2 v NADPH ( nicotinadenindinucleotit-phosphat).
- Microsoma-hidroxylase.
Cc loi phn ng oxi ha thng qua enzim microsoma:
a. Hidroxyl ha nhn thm:
CH3
CH3
NHCOCH2NH(CH3)2
NHCOCH2NH(CH3)2
CH3
CH3
OH
lidocaine
m-hidroxi-lidocaine
acetanilide
paracetamol
O
C2H5
HN
C2H5
HN
CH(CH3)CH(OH)CH3
O
CH(CH3)(CH2)2CH3
HN
O
Pentabarbital
-13-
c. To epoxi
Benzpirenepoxi
Benzpiren
d. N-deankyl ha
CH3
O
H
N
+ HCHO
N
Cl
Cl
nordiazepame
diazepame
e. O-deankyl ha
CH3
CH3
N
+ HCHO
H3OC
OH
HO
morphine
codeine
phenaxetin
paracetamol + CH3CHO
f. S-deankyl ha
-14-
OH
SCH3
SH
N
+ HCHO
N
H
N
H
S-metyltiopurin
nor-S-metyltiopurin
g. Oxi-dezamin ha
CH2CH(CH3)NH2
CH2COCH3
amphetamine
+ NH3
phenylaxeton
h. N-oxit ha
N
H3C
H3 C
3-metyl-piridin-N-oxi
i. S-oxit ha
O
S
(CH2)3N(CH3)2
Cl
(CH2)3N(CH3)2
Chlorpromazine-S-oxid
Chlorpromazine
j. Dehalogen ha
F3C
CH
Br
F3CCH2-OH
F3C-COOH
Cl
halothan
k. Oxi ha etanol
CH3CH2OH
CH3CHO
-15-
CH3CHO
CH3CH2OH
NADH + H
NAD
CH3CHO
NADH + H
NAD
CH2CH2NH2
HO
d. Thm ha
CO
CoA
CO
O2
H2O
FAD
FADH2
CoA
NH2
NH2
N N
SO2NH2
H2N
N N
SO2NH2 + H2N
sulfanilamide
(co hoat tinh)
prontosil
NH2
triaminobenzen
CHOH
CH (CH2)OH
H2N
CHOH
NH - COCHCl2
NH - COCHCl2
axetophenon
CH(OH)CH3
1-phenyletanol
-16-
CH (CH2)OH
COO(CH2)2N(C2H5)2
+H2O
COOH + HO(CH2)2N(C2H5)2
H2N
procaine
axit p-aminobanzoic
CONH(CH2)2N(C2H5)2
H2O
H2N
COOH
+ H2N(CH 2)2N(C2H5)2
axit p-aminobanzoic
procainamide
CONHNH2
isonicotin hidrazide
COOH
+ H2N - NH2
axit isonicotinic
Enzim
UDP
glucuronid
transferase
Sunfo tranferase
Metyl tranferase
Acyl tranferase
Glutation S- tranferase
Nhm phn ng
-OH,-COOH,-NH2,-SH
-OH,-NH2,-SO2NH2
-OH,-NH2
-OH,-NH2,-SO2NH2
-COOH
Epoxit
-OH
Cc nhm chc khc
SO2NHR
+ CH3COOH
+ H2SO4
C 6H5OSO3H
-17-
H3COCHN
SO2NHR
CH3
C6H5CH2Cl
OCHN
CH3
OCHN
CH - COOH
+
HS
CH - COOH
H2C
C6H5H2CS
(N-acetyl-cystein)
H2C
C6H4
CONHCH2COOH
H2NCH2COOH
C6H4
OH
OH
acid salicyluric
Acid salicylic
CH(OH)CH2NH2
HO
HO
CH(OH)CH2NH2
H3CO
Nor-metanephrine
Nor-adrenaline
COOH
COOH
O
COOC6H5
eter glucuronic
este glucuronic
NHC6H5
DX N-glucuronid
-18-
-19-
-20-
C hai loi tng tc thuc, khc nhau ni v cch thc m cc cht tng
tc vi nhau:
+ Tc dng tng h (interference, interation) xy ra trong mi trng in vivo
do tng tc sinh hc gia cc thuc c cc protein (acceptor, receptor, enzim)
tham gia.
+ tng tc tng k (incompatibility) l tng tc in vivo, hoc gia hai dng
bo ch hoc gia nhng hot cht trong lc chng hp thu trong c th, tng
k l tng tc thun ty ha l, khng cn c s tham gia ca t chc sng
(nh protein). Tng k l i khng ha hc (cc thuc axit khng trn ln
cc thuc baz, thuc l protein khi gp mui kim loi s kt ta hoc mt tc
dng)
- i khng do nh hng ti dc ng hc.
+ Cn tr hp thuc qua ng tiu ha.
+ Cm ng enzim chuyn ha thuc gan.
Thuc gy cm ng Cytocrom P 450 khin nhiu thuc khc chuyn ha mnh
qua gan (tng thanh thi) v lm mt tc dng.
+ Cn tr hp thu qua ng thn.
1.3.3.1.6. Tc dng hip ng.
Thuc A c tc dng l m, thuc B c tc dng l n, lc A kt hp vi B
xy ra 2 trng hp:
Tc dng = m+ n l hip ng cng (additive effect).
Tc dng > m+ n l hip ng vt mc (synegism).
C khi A khng c tc dng ging B nhng A vn lm tng tc dng ca B th
ni A lm tng tim lc (potentiation) ca B.
Tc dng hip ng c 2 loi sau:
- Hip ng do nh hng ti dc ng hc.
+ nh hng ti hp thu
+ y nhau ra khi protein- huyt tng.
+ ngn cn chuyn ha
+ gim thi tr
- Hip ng cng receptor
Khi dng cc khng sinh cng nhm vi nhauth hip ng nh mt php
cng:
- Hip ng trc tip nhng khc receptor.
Hai thuc A v B tc dng ln receptor khc nhau nhng cng c tc dng
dc l ging nhau.
V d: phi hp thuc h huyt p vi thuc li tiu cha cao huyt p cng
l hip ng trc tip. Aspirin dng cng dn xut coumarin ( nh warfarine)
lm tng tc dng chng ng mu: aspirin chng kt dnh tiu cu cn
Warfarin c ch tng hp cc yu t ng mu.
- Hip ng gin tip.
Thuc A c tc dng ph, lm hn ch hot tnh ti a ca n. Dng thuc B
loi tc dng ph ca A. Ta ni B l hip ng gin tip ca A. V d: dng
-21-
-22-
CONH - NH2
CONH - NH - CH(CH3)3
isoniazide
iproniazide
COO(CH2)2N(C2H5)2
H2N
CON(CH2)2N(C2H5)2
procainamide
procaine
R=CH3 : tolbutamide
R=Cl : chlorpropamide
t1/2 = 4 - 8h
t1/2= 35h
Noradrenaline
Adrenaline
Isoprenaline
1
58
270
0,014
1,3
0,33
-24-
C2H5
HO
C
HO
OH
C
HO
C2 H5
C
C
trans-dietylstilboestrol
C2H5
C2H5
cis-dietylstilboestrol
-25-
-27-
-29-
+ Cc thuc gan c.
+Cc thuc cha bnh Parkinson.
2.2.1. CC THUC GY T
2.2.1.1. I CNG:
a, nh ngha: l thuc lm mt cm gic mt vng c th ti ch dng thuc m
cc chc phn hot ng khng b nh hng.
b, Tiu chun ca mt thuc gy t tt: gy t c, phc hi li sau khi dng
thuc, thi gian va cho mc ch gy t.
c, Lin quan cu trc v tc dng:
i b phn cc thuc t c cu trc ging lidocaine.
Theo Logren (1948) gm 3 phn: thn m, thn nc, chui trung gian
(xem bng 2.1).
d, Tc dng dc l:
Tc dng ti ch, tc dng trn cc si thn kinh trung ng, thn kinh thc
vt. C cc loi gy t sau:
+ Gy t b mt ( bi v thm thuc ti ch).
+ Gy t thm nhim (tim di da).
+ Gy t dn truyn (tim vo cnh ng dn truyn ca thn kinh ).
Tc dng ton thn (khi thuc i vo vng tun hon).
Bng 2.1. Cu trc cc hp cht c tc dng gy t.
-31-
Cng thc
Phn thn m
Phn thn nc
Loi nhm
Tn
nc
este
-32-
Este
Cocaine (2-1)
thuc u tin
pht hin v s
dng
Procaine (2-2)
anilit
Lidocaine (2-4)
uretan
Diperodone (25)
Xeton
Dyclonine
6)
ete
Pranocaine (27)
(2-
CH3
H2N
C6H5COO
cocaine
Procaine
(novocain)
lidocaine
* Phng php tng hp procaine (2-2) (phi thuc): c 3 con ng tng hp:
O2 N
CH 3
2-8
COCl
O 2N
C
COOH
O 2N
2-10
COOC 2 H5
O 2N
2-9
2-14
B
COOCH 2CH2 Cl H N
2
O2 N
2-11
COOH
2-15
2-13
O 2N
2-12
H 2N
procaine
(Novocain, Ethocaine, Syncaine)
-33-
COOC 2 H 5
H 2N
CH3
+
ClCOCH 2Cl
CH3
NH2
NH-COCH2Cl
CH3
NH(CH5) 2
CH3
NH-COCH2N(C2H 5) 2
CH3
* Mt s hp cht gy t khc
CH3
NH
H
N
CO
2.2.2. CC THUC M.
2.2.2.1. I CNG.
a, nh ngha: thuc lm cho con ngi v ng vt mt ht tnh cm v mi cm
gic. Vi liu iu tr, thuc khng nh hng ti h h hp, tun hon v c th
phc hi sau khi dng thuc.
b, iu kin ca mt thuc m tt: mnh, khi mo ngn, khng chy n nu
dng kh.
2.2.2.2. CC THUC M DNG THEO NG H HP.
Bng 2-2: Cc thuc m dng theo ng h hp.
CH2
N=N=O
CH2=CH2
H2C CH2
Dinitrogen oxit
Etylen
C2H5OC2H5
CHCl3
CCl2=CHCl
Dietyl ete (ETE M)
Cloroform
Tricloetylen
CF3-CHClBr
CH2=CH-O-CH=CH2
CF3-CH2-O-CH=CH2
Halothane
Divinyl ete
Fluroxen
(Fluothane)
(Vinydon)
(Fluromar)
CHCl2-CF3-O-CH3
CHClF-CF2O-CHF2
CHF2-CHCl-O-CHF2
Methoxyfluraen
Enflurane
Isoflurane
(Metofane)
(Ethrane)
(Forane)
2.2.2.3. CC THUC GY M THEO NG TNH MCH.
- C hi mi n vi cc nh phu thut khi H.Wesse (1932) tm ra hexobarbital
(thuc ng, tim).
- u im: Lm m nhanh, phng tin gy m n gin (tim).
-34-
+ H2C
CN
CN
C
COOC2H 5
COOC2H 5
2-23
2-22
1. CH3ONa
2. CH3Br
H
N
H5C2OOC
CH3
CH 3 NH-CONH 2
C
N
H
NC
1. NH2 - CO - NH2
2. H2O/H+
C
2-1 9
C
H3C
2-24
H3C
COOC2H5
H2N
+
H2N
COOC2H5
R1
C
H
N
C
C
R2
C S
C
N
H
2-21
2-22
2-23
thialbarbital
inactin
thiopantal
H 3C
O 2N
Cl
N
F
midazolam (2-24)
flunitrazepam (2-23)
-35-
CN
C
COOC2H 5
NH
COCl
+
CO
O
O2N
O2N
2-25
NH2
C2H5OH
NH2CH2COOC2H5
H2SO4
O
O2N
F
2-26
CH3
O
NH
1. NaOCH3
N
O2N
2. (CH3)2SO4
O2N
2-23
2-27
-36-
CH2NO 2
Cl
NO2
H
N
NXCH3
H
N
Cl
2-30
H3C
CH2
2-31
H3C
CH3 -C(OC2H5 )3
N
CH
N
-H 2 /MnO 2
Cl
Cl
F
2-32
2-24
-37-
CH2
Cl
F
H2N
NH2
NH2
H2NOH
NOH
Cl
Cl
F
2-34
2-33
CH2Cl
NH-COCH2Cl
ClCH2COCl
NaOH
HCl
NOH
Cl
Cl
F
2-35
2-36
H
N
NHCH3
NHCH3
H2NCH3
N
Cl
Cl
2-37
2-38
-38-
CH3
N
HN
OCH3
C2 H5
O
(H5C2)2NOCH2CO
2-42
2-43
Cl
O
NHCH3
2-45
2-46
-39-
N HC
COOC 2H5
2-44
CH3
N(C2H5 ) 2
+ ClCH 2CN
CH NH2
CH NHCH 2CN
2-47
CH3
CH N CH 2CN
HCOOH/NEt 3
C2 H5OOCH
CHO
CH3
CHO
CH N
CH CN
CHO
NaOCH 3
2-49
2-48
SH
S
CH3
CH3
NH2
CH
CH N
NaSCN
NaOCH3
CH3
2-51
2-50
CH
H2SO4 -HNO3
H2NOC
NC
CH3
CH3
C
N
CH N
CH N
CH
H 5C2OOC
H2NOC
2-44
2-52
BrMg
Cl
O
NH
H2O
CN
2-53
Cl
Br 2
Cl
O
C
CH 3NH 2/H 2O
Br
HO
2-55
2-54
H
CH3
Cl N+
CH3
Cl
CH3
HN
C
HO
HO
2-56
2-57
-40-
Cl
H2C
NHCH3
+
2-45
CN
O
piperidin.HCl
KCN
OK
N
N
2-59
2-58
MgBr
2-46
2.2.3. CC THUC GY NG
2.2.3.1. I CNG
- nh ngha: l thuc c ch thn kinh trung ng to gic ng sinh l.
An thn ng m cht
C ch chung ca thuc ng: c ch cc chc phn ca h li m
vai tr dn dt v chn lc nhng thng tin t ngoi bin vo v no. Thuc
ng cn lm tng tch ly axit -aminobutyric (GABA) (cht c ch tin
synap no) v glyxin (cng l cht c ch).
2.2.3.2. NHM THUC NG (AN THN)
Gm cc nhm sau: ancol, andehit, dn xut uretan, cc amit, dn
xut barbituric, nhm dioxopiperidin, nhm diazepam v cc nhm khc.
2.2.3.2.1. Cc loi thuc ng loi ancol.
- Thuc ng u tin c pht hin l ancol etylic. Nng trong mu
0,08%: sng khoi; 0,2%: i ng lo o, say; 0,3%: say hon ton, long
chong, phn x ri lon: 0,4%: hon ton mt tri gic; 0,5%: lit trung tm
h hp, ngng tim.
- Cc ancol khc:
-41-
OH
HC
CH2 CH3
HC
CH3
Cl C
CH Cl
CH
CH2
Meparfynol
HO
2-62
Chlorbutanol
Ethchlorvynol
HO
OH
CH3
Cl CH3
CH3
2-61
2-60
Cl
Cl OH
OH
CH3
CH3CH3
OH
CH
3
centalum
CH3
2-64
2-63
phenaglycodol
Polyetylenglycol
2-65
2-70
2-71
Ngoi ra cn c:
CH3
O
Cl 3C
Cl 3C
CH
O
HC
CH3
(CH2OH) 2
Cl 3C
CH
C(CH3)2
HC
NH
OH
OH
H3C
CH3CHO
Cloralformam
it
Cholorhexado
l
Penthricloral
CH3
O
H3C
Paraaldehit
2-72
CHO
(C2H5)2CBrCONHCONH2
2-77
carbomal
(bromadal, Adalin)
(C2H5)2CBrCONHCONHCOCH3
2-78
Acetylcarbomal
(abasin, sedamyl)
2-79
apronalide
(sedormid, isodormid)
Bromisoval
* iu ch carbomal (2-77)
NaOH/C2H5OH
lm nng
SOCl2
(C2H5)2CHCOOH
(C2H5)2C(COONa)2
(C2H5)2C(COOC2H5)2
1800
CO(NH2)2
lm nng
(C2H5)2CHCOCl
H2O/H+
Br2
(C2H5)2C(COOH)2
(C2H5)2CBrCOHlg
(C2H5)2CBrCONHCONH2
propanidid
(Epontol, Sombrevin)
-43-
1
NH
3
NH
2
C O
R1
R2
NH
C O
C
C
NH
2-82
2-83
axit bacbituric
bacbiturat
+ Axit bacbituric
khng c tc dng.
+ Thay 1H C5 bng R1 tc dng gy ng km.
+ Thay 2H C5 bng R1,R2 tc dng gy ng tng nhng R1,R2>6C, R1+R2
<8C th tc dng gim.
+ R1 hoc R2 lin kt kp tc dng gy ng tng.
+ R1 v R2 l mch nhnh hoc mch vng tc dng tng nhng thi gian
tc dng ngn.
-44-
Tn chung
1.
R1
R2
R3
R4
Bit dc
Loi tc dng bn
Phenobarbital (2-84)
etyl
phenyl
Gardenal
barbital (2-85)
etyl
Etyl
Veronal
butobarbital (2-86)
etyl
n-butyl
Soneryl
aprobarbital (2-87)
allyl
allyl
Alonal
2.
amobarbital (2-89)
etyl
isoamyl
Amyltal
heptabarbital (2-90)
etyl
1-cycloheptenyl
Medomin
pentobarbital (2-91)
etyl
1-metyl butyl
Nembutal
cyclobarbital (2-92)
etyl
1-cyclohexenyl
Phanodorm
3.
secobarbital (2-93)
allyl
1-metylbutyl
Imesonal
Hexobarbital (2-94)
metyl
1-cyclohexenyl
CH3
Evipan
-45-
4.
thiopental (2-95)
etyl
1-metylbutyl
Trapanal
thiobarbital (2-96)
allyl
2-cyclohexenyl
Kemithal
* Tc dng dc l:
- Tc dng trn thn kinh: c ch thn kinh trung ng. Ty loi
barbiturat, ty liu lng, cch dng (ung hay tim) hoc ty trng thi ngi
bnh m s c tc dng an thn, gy ng hoc gy m. Barbiturat lm du c
phn ng tm thn gy nn do nhng cn au, c th phi hp tt vi loi thuc
h st gim au.
Vi liu gy m, barbiturat c ch ty sng lm gim phn x a suynap
v n suynap. Liu cao lm gim p lc dch no ty.
- Trn b my h hp: c ch trc tip trung tm h hp hnh no nn
lm gim bin v tn s cc nhp th. Liu cao hy hoi trung tm ny, lm
gim p ng vi CO2.
- Trn b my tun hon: Liu gy m lm gim lu lng tim v h
huyt p, liu c c ch c tim.
*Tc dng ph: Gy nghin (quen thuc), iu ny trc ht biu
hin qua vic tng liu dng, nhng nu s dng lin tc th hnh thnh nn s l
thuc vo thuc.
*Phng php chung tng hp cc barbiturat.
R1X/RONa
2-97
COOR
CN
2-100
CHR1
R2X/RONa
R1X/RONa
CN
2-101
COOR
C
COOR
2-99
COOR
CHR1
R1
R2
COOR
2-98
COOR
CH2
COOR
R2X/RONa
R1
COOR
C
R2
CN
2-102
-46-
O
C
COOR
R1
HN=C(NH2)2
R1
R2
2-99
NC
HN
C=
(N
HC
H
O
C
R1
R2
NH
H2O/H+, nng
R1
NH
C
O
O
2-83
-47-
2-103
NH
C NH
R2
NH
2)
C O
C NH
R2
COOR
NH
NH
2-104
R1
COOR
C
R2
CN
2-102
NH=C(NH2)2
O
C
R1
R2
NH
C O
C
C
NH
C
R1
C NH
R2
NH
2-105
NH
NH
R1
R2
C NH
C
C
H2O/H+/
O
H2O/H+/
R1
R2
NH
C O
C
C
H2O/H+/
NH
O 2-83
-48-
CN
NH
2-107
NH
2-106
NH
-49-
*iu ch hexobarbital(2-94)
-50-
C2H5
C2H5
C2H5
C2H5
N
H
2-116
O
Pyrithyldio
n
dihyprilon
N
H
2-117 methyprylo
n
aminoglutethimide
bemegride
(redimyl)
O
(H3C)2C
NH
2-127
-51-
H 3C
C
H3C
C2H5
H3C
C
O
CH2
NC
C 2H 5
CONH2
NC
H 3C
C2H5
C
CONH2
C
N
H
2-135
H 3C
NC
H3C
CONH2
NH2 N
C2H5
CH
CONH2
NC
NC
O
C2H5
NH
C
N
H
NH
C2H5
C
C
N
H
2-126
Thalidomide (2-137) v rc ri ng nh ca n.
-53-
OH
Cl
CH3
N
Cl
H
N
2-144
OH
Cl
2-143
2-141
H
N
Cl
NH2
Cl
2-142
2H-1,4-benzodiazepin-2-on
I.
-54-
Tn cht v bit dc
R1
R2
Diazepam
(2-141)
(Valium,
Seduxen)
Nordazepam (2-142) (Calmday,
Madar)
Oxazepam
(2-143)(Adumbran,
Serax)
Temazepam
(2-144)(Cerepax,
Levanxol)
Fludiazepam (2-145)(Erispan)
Medazepam
(2-146)(Nobrium,
Rudotel)
Lormetazepam
(2147)(Loramet,Noctamid)
Lorazepam (2-148)(Ativan, Tolid)
Flurazepam
(2-149)(Dalmane,
Dalmadorm)
Prazepam
(2-150)(Centrax,
Verstran)
Flutoprazepam (2-151)(Restas)
CH3
R3 Nm
iu
ch
H 1961
1961
OH
1962
CH3
OH
1962
CH3
CH3
H
H
F
H
1962
1963
CH3
OH
Cl 1963
H
OH
(CH2)2N(C2H5)2 H
Cl 1964
F 1964
1965
1967
-55-
Tn cht v bit dc
R1
R2
R3
Nm
iu
ch
1963
1963
1963
1963
khc ch l
H
H
Cl
F
th
Tn cht v bit dc
R1
R2
R3
R4
R5
Mexazolam(2-163)(Melex)
CH3
Cl
Cl
Nm
iu
ch
1967
Cloxazolam(2-164)(Enadel,Sepazon)
Cl
Cl
1969
Oxazolam(2-165)(Sevenal,Tranquit)
CH3
Cl
1969
Flutazolam(2-166)(Coreminal)
CH2OH
Cl
1969
Haloxazolam(2-167)(Somelin)
Br
1971
Cc dn xut triazolo-1,4-benzodiazepin
Tt
Tn cht v bit dc
R1
R2
Nm iu ch
Estazolam(2-168)(Eurodin,Juloam)
1970
Alprazolam(2-169)(Xanax)
CH3
1970
Triazolam(2-170)(Halcion)
CH3
Cl
1970
Midazolam(2-24)(Dormic,Hypnovel) CH3
1976
-56-
Ghi ch: Trong midazolam th N* thay bng CH2, cc cht c s dng lm thuc
ng l estazolam va midazolam.
Bng 2-5. Cc benzodiazepin c cu trc c bit
I.
Cu trc 1,4-benzodiazepin
2-172
ketazola
m
2-171
lopazolam
clotiazepam
II.
C2H5
CH3
H3CO
N
Cl
H3CO
OCH3
OCH3
2-177
2-178
-57-
-58-
CH3
CH3
O2N
H2N
F
HN
F
Ac
2-123
f lunitrazepam
CH3
H
N
N
OH
O2N
O2N
H2N
F
-59-
N
F
H3C
H3C
N
N
OHN
Cl
OH
Cl
CH2OH
thuy phn
Cl
H3C
Cl
Cl
Cl
2-170
triazolam
OHN
HOH2C
HOH2C
N
OHCl
HOH2C
OH
N
Cl
Cl
CH2OH
Cl
Cl
-60-
thuy phn
O
Cl
H
N
O
OH
thuy phn
Cl
H
O
N C
CH2OH
Cl
(NH2)2CO
H
O
N C
CH2NHCONH2
Cl
2-143
oxazeam
+ H2
nhn thom
H
N
H
N
OH
N
Cl
OH
Cl
OH
Cl
OCH3
NHCH3
NH2
H
N
Cl
Cl
2-140
chlordiazepoxide
NH2
Cl
NH2
Cl
CH2COOH
-61-
-62-
Cl
H2N-OH
N
Cl
2-182
H
N
NH2
1. CH2Cl
OH 2. NaOH
H2O2
Cl
2-183
2-184
CH3
O
N
Cl
2-141
b. C. Stanley (1964)
d. i t 6-cloro-2,4-diphenyl-quinazolin
-63-
-64-
CoCl
ZnCl2
+ 2
N
Cl
Cl
C6H5
OH
Cl
NH2
H(+)
NH2
NH2OH
Cl
NOH
ClCH2COCl
Cl
NOH
CH2Cl
NHCOCH2Cl
NH2CH3
HCl
Cl
Cl
2-194
-65-
NHCH3
Cl
2-140
chlordiazepoxide
NH
CH2Br
Cl
CH2NH(CH2)2OH
NH2(CH2)2OH
Cl
Cl
2-195, X= Cl
2-196, X= H
AcOH
H
N
NH2
CH2 CH
CH3
OH
Cl
O
Cl
2-164
cloxazolam
HN
Cl
H
N
HN
O
CH3
AcOH
Cl
O
OH
CH3
oxazolam
-66-
-67-
- Cu trc khc:
-68-
O
NH
C2H5
NH
O
NH
C2H5
2-84
phenobarbital
(Sevenal, Luminal)
CH3
N
NH
O
2-211
mephobarbital
(Prominal, Mebaral)
C
C2H5
2-212
primidone
(Sertan, Mylepsin)
-69-
NH
O
R3
N
3
4
R1
1
N
H
R2
Tn cht v bit dc
R1
R2
R3
Phenytoin (2-213)
C6H5 C6H5 H
(Dihydan,Dilatin,Zentropil)
mephenytoin (2-214)
C2H5 C6H5 CH3 1934 (1939)
(Insulton,Mesantoin,Sacerno)
Ethotoin (2-215) (Peganone)
H
C6H5 C2H5 1988 (1957)
Nhng im quan trng lin quan gia cu trc v tc dng:
O
R
N
3
5
N1
H
KCN
CH
OH
cc HNO3
benzoin
C6H5
ure/C2H5OH/OH
NHCONH2
O(-)
C
O
chuyn vi
benzilic
C6H5
C6H5
NHCONH2
C
C6H5
O
HN
(C6H5)2C
N(-) Me(+)
H(+)/H2O
C
O
-70-
2-213
phenytoin
COO(-)
0,2-0,6
2-3
Tn cht v bit dc
R1
R2
R3
CH3
Nm
iu
ch
1944
Liu
dng
1
ngy (g)
0,8-1
Trimetadione(2216)(Absentol,
Trimedal,
Tridione, Ptimal)
Paramethadione
(2217)(Paradione)
Dimethadione
(2218)(Eupractone)
Ethadion(2-219)
(Dimedion,Epinyl, Petidion)
Aloxidone (2-220) (Malidone,
Malazol)
CH3
CH3
CH3
C2H5 CH3
1951
0,4-0,6
CH3
CH3
1888
0,9-2,4
CH3
CH3
C2H5
1949
CH3
CH2CH=CH2 1949
-71-
* iu ch Trimetadione(2-216): M.A.Spielman(1951)
* iu ch 2-216,2-217,2-218,2-219,2-220
NH
R1
C
R1
HCN
O (KCN)
CN
C
R2
R2
R1
KSCN
HS=CN S=C=NH
R2
OH
O
H(+)/H2O
R1
C
C
R2
CN
O
R1
Br2/dd NaBr
C
C
R2
NH
O
C
C
R2
O
NH
R1
NH2
NH
S
2-216
2-217
2-218
2-219
2-220
Tn cht v bit dc
R1
R2
R3
Ethasuximide
(2-222)(Ethymal, CH3 C2H5 H
Pemal,Zarcntin)
-72-
Thi
gian
iu
ch(s
dng )
1927
Liu
dng
1
ngy
(g)
0,51,5
mesuximide
(2-223)(Celontin, CH3 C6H5 CH3
Petinutin)
phensuximide
(2- H
C6H5 CH3
224)(Liphene,Milontin,Succitimal)
Morsuximide
(2-225) CH3 C6H5
(Morfolep,Perlepsin)
1951
1951
0,61,2
2-4
1962
0,5-2
C6H5 CH CONHCONH2
R
Tn cht
Phenacemide(2-230)
Neophedan, Phenurone)
R
(Epiclase, H
-73-
Nm
ch
1933
iu Liu dng 1
ngy (g)
0,5-2
Ethyphenacemide(2C2H5
231)(Pheneturide,Benuride,Trinuride)
Chlorphenacemide(2Cl
231)(Comitiadon)
1912
0,6-1
1956
0,5-1
-74-
+Gim au h nhit.
+Gam au chng vim.
2.2.5.2. CC THUC GIM AU MNH
2.2.5.2.1. Morphine v cc dn xut
u im v nhc im ca Morphine
Nguyn liu sn xut Morphine
Thnh phn ca nha thuc phin ch yu l ancaloit, lng ancaloit ton
phn 20-25%, c 25-30 ancaloit.
Cu trc ancaloit thuc phin chia thnh hai nhm
9
10
11
1
14
13
12
6
5
4
3
phenantren
-76-
Tn cht v bit dc
R1
R2
Liu dng 1
ln (mg)
10
120
Morphine(2-244)
H
H
Codeine
(2- CH3
H
245)(Tussipan)
Ethomorphine
(2- C2H5
H
251)(Dionin, Cosylan)
Benzylmorphine(2C6H5CH2
H
252)
Phocodine
(2H
253)(Codylin,Pectolin)
diacetylmorphine(2OCCH3
OCCH3
254)
Thebacone (2-255)
CH3
OCCH3
Bng 2-12. Cc dn xut dihidro-morphinon
20
5
4
Tn cht v bit dc
R1
R2
R3
hidromorphone(2256)
(Dimorphone,Dilandid,Novolaudon)
Hidrocodone (2-257) (Bekadid,
Dicodid, Hycodan)
Oxomorphone(2-258)
Oxycodone(2-259)
(Percodan,
Eucodale)
Metopone(2-260)
Liu
dng 1
ln
(mg)
1,5
CH3
H
CH3
OH
OH
H
H
10
CH3
3,5
-78-
Tn cht v bit dc
Morphine(2-244)
Normorphine(2262)(Desmetylmorphine)
Norcodeine(2-263)(Ndemetylcodeine)
N-allyl norcodeine(2-264)
Nalorphine(2265)(Nalline,Norfin,Anarcon)
Nalorphine
dinicotinate(2266)(Nimelan)
R1
H
H
R2
H
H
R3
CH3
H
CH3
CH3
H
H
H
CH2CH=CH2
CH2CH=CH2
C5H4NCO
C5H4NCO
CH2CH=CH2
Tn cht v bit dc
Naloxone(2-267)(Narcon
Narcan, Narlone)
Naltrexone(2-268)
R1
O
Nalbuphine(2-269)
OH
R2
CH2-CH=CH2
-79-
B
NARCOTINE
2-247
Kt ta
(canxi sunfat v meconat, nha)
Kt tinh
Nc ci
Tinh th mui Gregory clohidrat
morphine v clohidrat codeine
+ NH4OH
+ KOH
+ KOH
CODEINE
2-245
Kt ta hp cht ch
PAPAVERINE
2-248
-80-
Dung dch
THERBAINE
2-246
Bc hi c c dch lc
Ta
Morphine + Narcotine
Dch lc (cn-nc-amoniac)
Papaverin, Therbain, Codeine
Axit axetic
AcOH + benzen
Kt ta
NARCOTINE
2-247
Dch lc
Morphine dng mui
Dung dch nc
Thebaine, Codein
(dng mui)
+ NH 4OH
+ NH 4OH
MORPHINE
2-244
-81-
Ct loi benzen
KOH
PAPAVERINE
2-248
CODEINE
2-247
-82-
CH3
CN
p.u. Braun
BrCN
RO
OH
Thuy phn
RO
2-245, R= CH3
2-244, R= H
OH
2-272, R= H
2-273, R=C H3
N
CH3
RO
2-262, R= H normorphine
2-263, R= CH3 norcodeine
CH3
BrCH2-CH=CH2
2-265, R= H naorphine
2-264, R= CH3 N-allylnorcodeine
RO
OH
Thay nhm metyl trn N bng cc nhm allyl (nalorphine). Xut hin tc
dng i khng lm cht gii c.
*Tng hp cht c tc dng i khng opiat: naloxone (2-267)
- Bn tng hp oxymorphone
-83-
OH
*Bn tng hp metopon (2-260): cht c tc dng gim au mnh, dng c theo
ng ung tt.
-84-
CH3
CH3
CH3
1
2
3
H3CO
5
4
OCH3
H3CO
2-246
H3CO
OR
2-285, R=CH 3
2-288, R= Ac
N
CH3
OR
H3C
2-286
N
CH3
CH3
Br
H3CO
OH H3C
H3CO
2-287
N
OH
Br
2-289
CH3
CH3
H3CO
CH3
2-290, X =Br
2-291, X = H
2-260
metopon
HO
CH3
-85-
-86-
-87-
CH3
E
B
A
C
D
HO
OH
morphine
E
C
A
C
morphinan (I)
phenyl-piperridin (III)
benzomorphan (II)
phenyl-propylamin (IV)
R3
R2
B
A
R1
Tn cht,bit dc
R1
R2
-88-
R3
Tc dng gim
au
Morphinan (2-305)
N-metyl morphinan(2306)
Racemorphan(2307)(Dromoran,Cetarin)
Levorphanol(lisome)(2308)(Levodromoran)
Levallorphan(2309)(Lorphan)
Cyclorphan(2-310)
H
H
H
H
H
CH3
(morphine=1)
0
0,2
OH
CH3
>1
OH
CH3
OH
CH2CH=CH2
15
OH
Butorphanol
(2- OH
OH
311)(Stadol, Torate)
*dng racemic
*tng hp N-methyl morphinan(2-306)
10
-89-
-90-
CH3
CH3
HO
Tn cht, bit dc
Metazocine(2-331), benzomorphan
CH3
Phenazocine(2-332)(Prinadol,Narphen) CH2CH2C6H5
Pentazocine (2-333)(Talwin, Fortral)
CH2CH=C(CH3)2
Cyclazocine(2-334)
Nm
iu
ch
1957
1959
1962
1962
Tc dng gim au
(morphin=1)
0,7
3
0,3
40
-91-
(c)
(b)
(a)
III
I.
Dn
pethidine
xut
1956
0,2
1959
0,2
1960
II. Dn xut ging vi pethidine
1939
1957
R= H
IV. Cc hp cht vng c s cnh 5 hoc 7
1954
-92-
1956
1964
b, ketobemidone(2-345) v bemidone(2-375)
Bn cnh nhng dn xut trn c s normeperidine cn iu ch ra nhng
dn xut c cha nhm th trong nhn thm. Cc nhm th v tr m c tc
dng mnh hn. Ketomidone c tc dng gim au ngang morphine nhng
c tnh v tc dng gy nghin thp hn nhiu.
-93-
CH2CN
(ClCH2CH2)2NCH3
CH3
NC
2-357
H3CO
H3CO
2-372
(ClCH2CH2)2NCH3
C2H5MgBr
H3CO
CH3
C2H5OC
HO
2-374
CH3
C2H5OC
2-345
ketomidone
2-372
HBr
HO
CH3
HOOC
HO
c, Alphaprodine(2-346)
L meperidine ngc
-94-
C2H5OOC
2-375
bemidone
CH3
-95-
Tn cht, bit dc
Methadone(2-395)(Amidon,
Depridol,Poliamidon)
Phenadoxone(2396)(heptalgin,
Heptalin,Supralgin)
Dipipanone(2-397)(Fenidon,
Pamedone,Pipadone)
Isomethadone(2-398)
(isoadonone, Liden)
Imepheptanol(2399)(methadol, Pangerin)
Dextromoramide(2400)(Dimorlin,Jetrium,
Palfium)
Piritramide(2401)(Dipidolor, piridolan)
Diphenoxylate(2-371)
Diarsed,Lomotil,Reasec
D-propoxyphene
(2403)(Darvon,
Develin,
Propox)
Henoperidine
(2344)(Operidine, Lealgin)
Metofoline
(2405)(Versidyne)
Cu trc
R1
C6H5
R2
COC2H5
C6H5
Nm iu Tc
dng
ch ra
gim
au
(morphin=1)
R3
1941
COC2H5
1948
C6H5
COC2H5
1950
C6H5
COC2H5
1948
C6H5
1949
1,5
C6H5
1956
2,5
C6H5
CN
1961
C6H5
CN
1959
C6H5CH2
OCOC2H5
1953
0,2
OH
1960
0,2
1960
0,1
1965
0,2
Tramadol (2-406)(Cripsin)
*Tng hp methadone(2-395)
-96-
CH3
CH2
N
CH3
CH3
2-407
NC
H3C
CH
CH
CH2N(CH3)2
NC
CH3
CH3
CH
CHN(CH3) 2
CH2
Cl(-)
CH3
H3C
2-409
2-408
2-410
1. C2H5MgBr
2. H2O/H(+)
1. C2H5MgBr
2. H2O/H(+)
CH3
C2H5CO
CH
CH3
CH2N(CH3)2
2-398
isomethadone
C2H5CO
CH2
CHN(CH3)2
2-395
methadone
Trong hp cht trung gian 2-410 c iu ch theo phng php c bit sau:
*Tng hp dn
methadone(2-413)
*Tng hp dextromoramide(2-400)
-97-
*Tng hp D-propoxyphene(2-403)
L thuc gim au loi trung bnh, c s dng kh rng ri.
ng phn L khng c tc dng gim au nhng l cht c tc dng gim
ho nn c s dng lm thuc ho vi cc bit dc Novrad, Letusin,
Contratus.
195
9
Propiram(2420)(Algeril)
196
3
0,1
-98-
Fentanyl(2350)(Leptanal,
pentanyl)
Etonitazene(2441)(Opioid)
196
4
80
195
7
1000
Thiambutene(2442)(Grapori,Themalon
)
195
0
-99-
-100-
Meprobamate(2443)(Andaxin,
Miltown,Atraxin,Panediol)
tybamate(2-444)(Benvil,
Solacin)
1951
0,4-1,6
1960
0,2-1
pheprobamate(2445)(Extacol, Gamaquil)
Emylcamate(2446)(Muncital, Striatran)
1960
0,4-1,2
1961
0,6-0,8
Methylpentinolcarbamate(2447)(OblivonC,Trusono,Pentin-C)
1955
0,3-0,6
-101-
Hidroxyzine
(2458)(Atarax, Vistaril)
C6H5
CH
1956
50-100
1957
60-300
1958
150-450
N(CH2)2O(CH2)2OH
Cl
Azacyclonol
(2459)(Ataractan,
Frenquel)
Captodiamine(2460)(Covatix, Suvren)
(C6H5)2C
C6H5
CH
(C6H5)2C
COOH
Cl
N
NH
COOCH2CH2N(C2H5)2
2-457
benactizine
2-462
2-461
Cl
OH
OH
CH
C6H5
H2CH2C
Cl
CH
HOH2CH2C
CH3
C6H5
CH
CH2
Cl
CH
CH2
2-465
buclizine
C6H5
CH
CH2CH2O(CH2)2OH
C6H5
N
2-464
meclizine
2-458
hydroxyzine
2-463
Cl
C6H5
Cl
HN
NCOOCH
CH
NR
-102-
C(CH3)3
CH2NHCH3
COX
COOH
2-476
benoctamine
2-480 X = OH
2-481 X = Cl
2-485 X = NH CH 3
O
N
N
N
N
2-486
Cl
O
N
N
N
(CH2)4
R
O
2-477
buspirone (1970)
(Bespar, Buspar)
2-483 R= H
2-484 R= (CH2)3CN
2-485 R= (CH2)4NH2
O
O
N
NH
N(CH2)4NHCH2CH2NH
N
2-488
2-491
2-489 R= (CH2)4Cl
2-490 R= (CH2)4NH(CH2)2NH2
-103-
-104-
-105-
Tn, bit dc
R1
R2
I. Cc dn xut ca amino-ankyl
Promazine
(2- H
CH2CH2(CH3)2
501)(Sparin,
Verophene)
Chlorpromazine(2 Cl
CH2CH2(CH3)2
-500) (Hibernal,
Thorazine)
methopromazine
OCH3
CH2CH2(CH3)2
(2502)(Mopazine,
Tentone)
acetylpromazine
COCH3
CH2CH2N(CH3)2
(2-503)( Notensil,
Soprintin)
triflupromazine
CF3
CH2CH2N(CH3)2
(2-504)(Nivoman,
Vesprin)
levopromazine (2- OCH3
CH(CH3)2CH2N(CH3)2
505)(Neurcil,
Tisercin)
II. Cc dn xut ca piperidin-ankyl
H C
Thioridazine(2SCH3
N
506)(Mellaril,
H C
Melleril)
3
N
m
i
u
ch
Liu
dng
(mg/ng
y)
195
0
3001000
195
2
300-800
195
2
50-500
195
7
150-200
195
7
100-150
195
7
50-100
195
8
200-600
196
3
75-300
20-30
H3C
Mesoridazine(2507)(Lidanil,Sere
ntil)
SOCH3
pipamazine(2508)(Mometine,
Nausidol)
Cl
196
0
Pericyazine
(2- CN
509)(Neuleptil,
Neulactil)
III. Cc dn xut ca piperazinyl - ankyl
196
0
N
H2C
-106-
Perazine
(2- H
510)(Taxilan,
Teusilan)
Prochlorperazine( Cl
2-511)(Nipodal,
Compazin)
Trifluoperazine
CF3
(2-512)(Stelazine,
Terfluzine)
195
7
50-100
195
7
15-40
195
9
6-20
Thioproperazine(2
-513)(Majeptil,
Vontil)
Butaperazine(2514)(Magalectil,
Randolectil)
Perphenazine(2515)(Fentazin,
Trifalon)
Metofenazate(2516)(Frenolon)
SO2N(CH3)
20-60
195
9
CO(CH2)2C
H3
196
1
30-50
Cl
195
6
8-32
Cl
196
2
50-80
Fluphenazine(2517)(Dapotum,
Prolixin)
CF3
196
0
1-20
196
1
60-120
197
0
10-20
Acetophenazine(2 COCH3
-518)(phentoxate,
Tindal)
Pipotiazine(2SO2N(CH3)
519)(piportil, RP 2
19552)
*c im cu trc :
- khong cch N ca nhn vi N mch nhnh l 3C (khc vi anti-histamin
ch c 2C)
- N mch nhnh phi bc 3
- Gam 1 nhm ankyl mch nhnh th gim tc dng.
- V tr C c nhm th ht in t (Cl, OCH3) tng tc dng an thn
-107-
- Khung phenolthiazin tan trong m, mch nhnh tan trong nc, t l tan
trong m/ nc c vai tr quan trng.
CHLORPROMAZINE
a, Tc dng dc l:
Trn h thn kinh trung ng.
Trn h thn kinh thc vt.
Trn h ni tit .
C tc dng khng histamin nhng yu.
b, Tng tc thuc:
Lm tng tc dng ca thuc ng.
C tc dng i khng vi cc thuc kch thch thn kinh tm thn
(amphetamine)
Khng c tc dng hip ng tng mc.
c, C ch tc dng:
d, Dc ng hc
e, Tc dng khng mong mun
f, p dng lm sng (c tc dng a dng c dng nhiu khoa: tm
thn, khoa sn, gy me, khoa ni, da liu)
g, Chuyn ha:
Chlorpromazine trong c th tm thy 12 loi cht chuyn ha
*Cc phng php chung tng hp cc dn xut ca phenothiazin
-108-
+ K2CO3
- CO2
H2N
Cl
N
H
N
H
COOH
COOH
S + I hoac SCl2
R1-Cl
NaNH2
H
SH
Cl
Cl
+
NH2
Cl
NaOH
O2N
NH2
O2N
Cl
R1
N
NH
O2N
R 1OH
COCH3
S+I
hoac
SCl2
COCl
COCl2
- CO2
S
ClCOOR 1
D
N
H
R
Cl
R1
COOR1
R1Cl, NaH
amin bc 2
+ K2CO3
E
X
Br
R
S
F
X
Cl
Br
HN
R1
G
SH
Cl
Cl
Br
+ Na2S
+
O2N
Br
O2N
Br
H2N
-109-
*Tng hp Thioridazine(2-506)
*Tng hp Mesoridazine(2-507)
-110-
Cu/t 0
nung nng
+
Cl
COOH
nung nng
- CO2
SCH3
SCH3
N
H
NH2
COOH
2-532
S
S + I2
nung nng
N
H
SCH3
N
H
SCH3
2-531
2-533
S
CH3OCl
1. R-COOH (oxh)
2. deaxetyl ha
N
H
SCH3
COCH3
2-531
N
H
SCH3
N
CH3
SCH3
CH2 CH2Cl
2-530
N aN H 2
SCH3
N
H2C
H2C
N
H3C
2-507
mesoridazine
-111-
Tn cht,
dc
bit R1
R2
I. Dn xut amino-ankyl
-112-
Nm
ch
iu Liu
ngy
(mg)
dng
Prothixene
(2- H
543)(Prothixenum)
Chlorprothixene(2- Cl
544)
(Taractan,
Truxal)
II. Dn xut piperazinyl-ankyl
Thiothixene
(2- SO2N(CH3)2
545)(Navane,
Orbinamon)
Clopenthixol (2- Cl
546)(Ciatyl,
Sordinol)
Flupentixol(2CF3
547)(Fluanxol,
Siplarol)
N(CH3)2
1960
N(CH3)2
1960
50-400
1964
6-30
1962
5-50
1963
3-6
-113-
*Tng hp thiothixene(2-545)
-114-
Br
Br
HSO3Cl
C6H5SH/Cu/
COOH
COOH
COOH
2-555, X = SO2Cl
HN(CH3)2
2-557, X = SO2N ( CH 3) 2
2-556, X = SO2N ( CH 3) 2
cc. H2SO4
1. Bu Li
hoac SOCl2
2. CH3COOCH3
SO2N(CH3)2
SO2N(CH3)2
C
CH3
2-558 Y =O
NH2-NH2/NaOH
2-559, X = H 2,
2-560
N aBH 4
p.u Mannich
CH2O/N metyl piperidin
SO2N(CH3)2
H2CH2CN
SO2N(CH3)2
NCH3
HO
C
H
H2CH2CN
NCH3
2-545
POCl3/piridin
- H2O
thiothixene
1. Br-MgCH2CH2Cl
2. HN
3. Ac2O/
N-CH3
(-H2O)
-115-
Nm iu ch
1959
5-15
1959
5-15
Anisoperidone(2565)
1961
40-100
Aceperone(2566)(Acetabutone)
1961
Trifluperidol(2567)(Trisedyl,
Triperidol)
1962
1-2
Paraperidide(2568)(Amiperone)
1962
5-40
1962
5-30
Methylperidide (2570)(Meperidide)
1962
5-40
Fluropipamide
(Dipiperon,Propitan)
1962
20-60
Haloperidide(2-569)
CO
N
Cl
II.
-116-
Spiroperidol
(2571)(Spiperone,
Spiropitan)
1964
0,5-3
1963
0,5-1,5
1964
5-20
1961
100-400
1961
5-60
NH
N
N
C6H5
Benperidol(2572)(glianimon,
Frenactyl)
H
N
NH
Droperidol
573)(Inapsine,
Dridol)
(2-
NH
H3CO
*c dng vo neuroleptanalgezia
HALOPERIDOL l thuc tiu biu ca nhm butirophenol ny:
L thuc an thn kinh a nng, chng thao cung.
Cu trc ha hc haloperidol gn ging vi GABA l cht trung gian ha
hc ca cc qu trnh c ch thn kinh trung ng.
Tc dng an thn mnh l do c ch receptor dopaminegic trung ng.
a, Tc dng dc l: c ch phn x, c ch kch thch tm thn vn ng,
c ch thao cung, c ch hoang tng.
b, Chuyn ha : chuyn ha ch yu qua gan do qu trnh kh ankyl-oxi
ha.
c, Ch nh :
Cc trng thi thao cung, hoang tng, lon tm thn cp v mn, phn
lp.
Chng nn.
-117-
-118-
CH3OH
H
N
NH
HO
H3C
+
HOCH2NHCH2
HOCH2NHCH2OH
HOCH2NH2
+ NH4ClH
CH2
O
(+)
+
HOCH2NHCH2
-H(+)
H3C
H3C
/ H+
2-576 a-e
/ H+
- H 2O
H
N
H2C
H2C
C6H5CH2 H2C
(+)
H3C
(+)
2-578 a-e
Bz:
2-577 a-e
H
N (+)
NH
Bz:
NH2 COOEt
N
1. CH2=CH- CN
2. CH2=CH- CN
3. EtOH/H+
Dickman
Bz-N
OEt
O
Bz
1. H2O/H+
2. X
MgX
Y
-119-
2-580 a-e
-120-
-121-
-122-
O
CH
OH
(p-FC6H4)2HC(H2C)3N
p-FC6H4OC(H2C)3 N
HN
Cl
2-606:f luspirilane
(Imar, redeptin)
liu dng 2-6 mg/tun
2-563: haloperidol
(Haldol, Serenase)
R1
(p-FC6H4)2HC(H2C)3N
R2
N
*Tng hp pimozide(2-607)
-123-
Cl
CF3
b, Cc dn xut ca benzamit
Bng 2.27. Cc thuc an thn nhm benzamit
Tn hp cht (bit R1
dc)
R2
R3
Metoclopamide(2- NH2
613)(Maxolon,
Reliveran)
Sulpiride(2H
614)(dogmatil,
Mirbanil)
Cl
CH2N(C2H5)2 1962
SO2NH2
1964
300800
Sultopride(2615)(Barnetil,
Topral)
SO2C2H5
1968
400600
Tiapride(2H
SO2CH3
CH2N(C2H5)2 1970
616)(Tiaprizal,
Doparid)
Trong sulpiride(2-614) l i din cho nhm ny.
Tc dng:
Sulpiride l thuc an thn c tc dng lng cc (bipolar)
Ch nh
Cnh bo
Tc dng ph
*Tng hp sulpiride (2-614)
100200
-124-
Nm
iu
ch
Liu
dng
ngy
(mg)
10
CH
CH2OH
OCH2
OH
CH
CH2OH
OH
2-618 me phenesin
(Atesin, Myodetensin)
CH3
Cl
OCH2
CH
OCH2
CH
CH2OCOCH2
CH2OCONH2
OH
OH
CH
CH
CH2NH
OH
CH2OCONH2
2-622 phenylramidol
(Elan, Miodar)
OH
2-621 styranmate
(Linaxar, Sinaxar)
CH2OCONH2
CH3CH2CH2
CH3
CH2OCONH
CH(CH3)2
*Tng hp carisoprodol(2-623)S
b, Dn xut ca benzoxazol
H2C
HC CH2
COOH
O
O2N
CH=N N
NH
O
Cl
2-627
dantrolen
(Dantamacrin, Dantrium)
2-626
baclof en
(Baclon, Liosenal)
-126-
*Tng hp dantrolen(2-627)
NX
O2N
CHO
O2N
O
2-635
2-633, X= H
2-634, X= N(+) Cl(-)
CH2
H2N
COOC2H5
H2N
N
H2N
NH
CH2
COOC2H5
O
O
NH2
2-637
CHO
O2N
H2N
NH
N
H
O
2-638
CH
O2N
NH
O
O
2-635
2-638
2-627
dantrolen
-127-
OH
OH
OH
OH
Phehidroxilasa
CH2
CH
Dopamin
- hidroxilase
Tyhidroxilasa
CH2
NH2
CH
COOH
OH
DOPA
- decarboxilasea
CH2
NH2
CH
COOH
NH2
CH
COOH
phenylalamin
phenylalamin
(Phe)
(Phe)
CH2
NH2
COOH
dopamine
3,4-dihiroxi-phenylalamin
(DOPA)
(DA)
OH
OH
CH
MAO
COOH
OH
OH
axit
3,4-dihidroximandulic
(VMA)
OH
OH
PEA-N-metyl
COMT
OH
OH
OH
OCH3
OCH3
transf erase
CH
OH
CH2
NH2
noradrenaline
(NA)
CH
CH
OH
CH2NHCH3
adrenaline
epinef rin
COMT
(A)
OH
MAO
OCH3
CH
OH
CH2OH
3-metoxi-4-hidroxiphenylglicol
MHPG
CH
axit
3-metoxi-4-hidroximandulic
(VMA)
OH
CH2NHCH3
metanef rin
-128-
OH
COOH
a, Levodopa (L-dopa)(2-639)
Tc dng dc l
*Tng hp : c nhiu con ng tng hp, sau y l ba cch trong s :
1. Tng hp L-dopa i t vanillin v hydantion
-129-
2-645, R=H
2-646, R=Br
2-647, R=Cl
-130-
2-642, R=H
2-648, R=COCH3
amantadine
Apmorphine
bromocriptrine
1949
1-20
Cycrimine
655)(Pagitane)
1950
1-20
1957
1-10
1946
10-100
(2-
Biperiden(2656)(Akineton,
Dekinet)
II. Dn xut ca diphenylmetan
Etanautiene(2657)(Antiparkin,
Rigidyl)
-131-
Benztropine(2-658)
(Cobrentin, Cogentin)
1952
1-4
Orphenadrine(2659)(Myophane,
Parekin)
1955
25-200
1947
50-200
Ethopropazine(2661)(Parkisol,
Parsitan)
1952
60-150
Methixene(2662)(Tremaril,
Tremoquil)
1958
5-20
-132-
orphenadrine(2-659),
pridinol
*Tng hp Trihexyphenidyl(2-654) v Cycrimine (2-655)
2-667
Trihexyphenidy
2-655 R=
Cycrimine
-133-
-134-
-135-
75 C
3%NH3/
Doxapram (2-681)
*Tc dng : kch thch h hp, tc dng trc tip n trung khu h hp
(kch thch s thng gi ph nang, tng th tch khng kh lun chuyn,
ci thin cc trao i kh).
*Tng hp doxapram(2-681)
doxapram
Bemegride (2-126): tc dng kch thch trc tip cc trung khu h hp v
tun hon trn hnh no, lm tng nhp tim, tng huyt p, tng bin h
hp.
*Tng hp: xem phn 2.2.3.2.6. thuc ng nhm dn xut dioxopiperazin
2.3.2.CC THUC KCH THN
Lch s pht hin ra:
- D (-)treo-ephedrine(2-688)(Miura,1887)
- D(-)adrenaline(2-689)(Aldrich,Takemine,1901)
- D-(+)amphetamine(2-690)(Edelesno 1867,1927)
2-688
D -(-)ephedrine
(:R; :S)
2-689
D-(-)adrenaline
(:R)1 - epinefrine
-136-
2-690
D-(+)amphetamine
Dexedrin,
Dextroamphetamin
1929
5-15
Fenproporex(2692)(Gacilin, Solvolip)
1966
10-20
Mefenorex(2693)(Doracil, Pondinil)
1966
40-80
Phentermine(2-
1946
20-40
-137-
694)(Duromine,Ionamine)
Phenpentermine(2695)(Liprodne,
Modatrop)
1964
10-20
Chlorphentermine(2696)(Desopimon,
PreState)
1954
50-75
Chlortermine(2697)(Voranil)
1965
25-50
Norpseudoephedrine(2698)(Adiposetten, Thinz)
1927
30
Dimepropion(2699)(Medulor)
1928
50-100
Diethylpropion(2700)(Tenuate, Tepanil)
1928
50-75
Benzphetamine(2701)(Didrex, Inapetyl)
1957
50-150
Clobenzorex(2702)(Dinintel, Rexigen)
1966
30-60
Furfenorex(2703)(Frugal, Frugalan)
1965
80-120
-138-
Fenfluramine(2704)(Ponderax,
Pondimin)
1963
60-120
1944
10-60
Pipradrol(2-706)(Detaril,
Meratran)
1948
3-6
Levophacetoperane(2707)(Lidpran)
1960
15-45
II. Cc piperidin
Methylphenidate(2705)(Centedrin, Ritalin)
III. Cc morfolin
Phenmetrazine(2708)(Gracidin, Preludin)
1958
25-75
1956
70-100
N
H
CH3
Phendimetrazine(2709)(Dietrol, Plegine)
-139-
Fenbutrazate(2710)(Cafilon, Filon)
IV. Cc oxazolin
Aminorex(2711)(Apiquel, Minocil)
1962
50-100
1963
5-10
1913
20-60
1969
1-3
1974
40-80
Clominorex(2-712)
Fluminorex(2-713)
Pemoline(2714)(Cylert,Tradon)
V. Cc cu trc khc
Mazindol(2715)(Sanorex, Teronac)
N
N
HO
Fluoxetine
716)(Prozac)
(2-
Cl
Tng hp phentermine(2-694)
-140-
iu ch chlorphentermine(2-696)
2-720
-
2-696
chlorphentermine
-141-
-142-
COOH
COOH
COOH
HC - NH2
HC - NH2
HC - NH2
CH2
CH2
CH2
OH
phenyl alanin
OH
tirosin
NH2
COOH
CH2
NH2
OH
DOPA
NH2
CH2
CH2
CH2
CH2
CH2
CH2
OH
OH
tiramin
OH
dopamine(DA)
NH2
NH2
CH2
CH2
HC - OH
HC - OH
NH2
CH2
HC - OH
OH
OH
phenyl etanol amin
OH
OH
HO
octopamin
noradrenaline
CH-CH2NHCH3
OH
adrenaline(A)
Hnh 2-11. Qu trnh tng hp adrenaline v cc cht lin quan trong c th.
-143-
195
9
100
Isocarboxazid(2730)(Marplan)
195
9
30
Phenelzine(2-731)(Kalgan,
Nardil, Stinerval)
193
2
30
Pheniprazine(2-732)(Catrol,
Catron, Cavodil)
195
8
Mebanazine(2-733)(Actomol)
195
8
40
Phenoxypropazine(2734)(Drazine)
196
3
15
II. Cc amin
Tranylcypromine(2735)(Parnate,Parnitene,Tylciprin
e)
194
8
30
-144-
Etryptamine(2-736)(Monase)
196
0
45
Pargyline(2-737)(Eudatin,
Eutonyl,Supirdyl)
196
2
25
Clorgiline(2-738)
196
2
20
L-deprenylselegiline(2739)(Eldepryl,Jumex)
196
4
15
-145-
*Tng hp tranulcypromine(2-735)
*Tng hp etryptamine(2-736)
-146-
*Tng hp moclobemide(2-743)
Clomipramine(2-757)
(Hydiphen,Anafranil)
196
1
20-30
Trimipramine
(2-758)(Sapilent,
Stangyl, Surmontil)
196
1
150
-147-
Desipramine(2-759)(Irene,
Norpramin,Pertofran)
196
2
75
Opipramol
(2-760)(Dinsidon,
Insidon, Nisidana)
196
1
100
196
0
100
Nortryptyline(2762)(Allegron,Aventyl,Nortrilen)
196
2
40
Butryptyline
763)(Centrolyse,Evadene,
Evadyne)
(2-
196
2
100
(2-764)(Agedal,
196
5
100
Noxiptiline
Nogdal)
-148-
Amineptine
Manecon)
(2-765)(Survector,
197
0
200
Protryptyline(2-766)(Concordin,
Maximed, Vivactil)
196
2
30
196
2
120
Dothiepin
(2768)(Altapin,Depresym,Prothiade
n)
196
2
100
Dibenzepin
(2-769)(Ansiopax,
Deprex, Noveril)
196
3
100
196
7
250
NH - (CH2)6COOH
Amoxapine
770)(endin,Demolox)
(2-
NH
Cl
O
-149-
Iprindole
(2-771)(Galatur,
Prondol,Tertran)
196
3
90
Bng 2-33. Cc thuc chng trm cm quan trng nht thuc nhm cu trc ba
vng 6-6-6 v bn vng lin hp
Tn
Cng thc cu Nm iu ch
Liu
dng
to
mg/ngy
I. Cc cht ba vng
H3 C
CH3
Dimethacrine(21963
150
772)(Istonil,Linostil)
N
(CH2)3 -N
CH3
CH3
Melitracen(2773)(Dixeran,Trausabun)
Danitracen (2-774)
OH
1963
75
1965
1967
50
CH3
-150-
Maprotiline
776)(Ludiomil)
(2-
1969
100
Bng 2-34. Cc thuc chng trm cm thuc nhm cc cht c cu trc khc nhau
Tn
Cng thc cu to
Nm
Liu
iu
dng
ch
mg/ngy
Tofenacin (2-777)
1963
200
(Elamol, Tofacine)
Zimelidine (2-778)
(Normud, Zelmid)
1972
200
Fluoxetine (2-779)
(Prozac)
1974
50
Nomifensine (2780)
(Alival,
Hostalival,Merital)
1969
150
Trazodone (2-781)
(
Desyrel,
Molipaxin,
Tombran)
1968
150
Caroxazone
(2782) (Timostenil)
1968
450
-151-
Thozalinone
(2783) (Stimsen)
1962
100
Viloxazine (2-784)
(Vivalan)
1969
200
Bupropion (2-785)
(Wellbutrin)
1971
300
C-C-
C-CC-N
C-N
II
-152-
X= O,S,N
IIIa
IIIb X=C,N
Cc hp cht c th xem trong bng 2-32
2.3.3.2.4. Tng hp mt s thuc chng trm cm
Tng hp imipramine (2-756)
* iu ch hp cht 2-789
-153-
-154-
-155-
iu ch trazodone (2-781)
2.3.4.
CC CHT GY RI LON TM THN
nh ngha: cc cht c kh nng gy ra trn ngi bnh thng mt s triu
chng ca bnh lon tm thn v cc o gic c gi l cc cht lon thn
(lon tm thn).
2.3.4.1. Ngun gc ca cc cht lon tm thn:
- a s l c ngun gc t thc vt v phn nhiu l cc hp cht ancaloit.
Bng 2-35. Mt s cht c tc dng lon thn bit
Tn
Cng thc cu to
Nm Liu
iu dng
ch mg/ngy
-156-
Ergotamine (2-829)
H3C
OH
OC-NH
H
N
O
N
Lysergide
(2-830)
(LSD-25,Delysid)
N
H
O
CH2C6H5
1938 0,05-0,1
C2H5
C
O
H
CH3
N
C2H5
CH3
N
H
Ibogain
(Ibagin)
(2-381)
1901 300-400
Harmin (2-832)
1841 300-400
Harmalin
1941 300-400
(2-833)
Psilocibine (2-834)
1958 4-8
Bufotenin (2-835)
1934 15-20
i..v
-157-
Imethyltryptamine
(2-836) (DMT)
1955 50-100
i.v.
1957 50-100
Adrenochrome
838)
1937 20-50
i.v.
(2-
Adrenolutin (2-839)
1949 50-70
Mescalin (2-840)
1896 300-500
Myristicine (2-841)
1909 400-600
Axit ibotennic
842)
1964 70-100
(2-
Muscimol (2-843)
1964 10-15
Tetrahidrokannabinol
(2-844) (THC)
1964 20-30
-158-
Phencylidine (2-46)
CH
1960 10-20
i.v.
2.3.4.2. Tc dng dc l:
Cc cht lon thn u gy cc ri lon tm thn nh: o nh (o th, o thnh),
cm gic xon vn, mt nh hng v khng gian v thi gian, vi n tng
thi gian tri qua nhanh chng, cn sng gp. n tng nh ang bp bnh
bay bng trong v tr, hnh nh c th mo m vi tnh cm gii th nhn cch,
phn i nhn cch, lo u, hi hp.
2.3.4.3. C ch tc dng:
Lm thay i s sn xut, s gii phng cc amin sinh hc (serotonine,
catecholamine, encephaline) hoc thay i tnh cm th ca cc receptor c
hiu vi cc amin ny ti cc vng khc nhau trn h thn kinh trung ng.
-159-
-160-
MC LC
CHNG 1: M S KIN THC CHUNG V HA DC ............................ 1
1.1. Ha dc qu kh, hin ti v tng lai ........................................................ 1
1.2. Cc yu t ha l v cu trc ha hc nh hng n tc dng sinh hc........ 5
1.3. Khi nim v dc l hc ................................................................................... 5
1.4. Tin trnh nghin cu a mt thuc mi vo s dng ................................... 27
CHNG 2: CC THUC TC DNG LN H THN KINH TRUNG NG
2.1. i cng v h thn kinh trung ng v hot ng ca n ........................... 30
2.2. Cc thuc c ch h thn kinh trung ng........................................................ 30
2.2.1. Cc thuc gy t .............................................................................................. 31
2.2.2. Cc thuc m ................................................................................................... 34
2.2.3. Cc thuc gy ng ........................................................................................... 41
2.2.4. Cc thuc cha ng kinh............................................................................... 68
2.2.5. Cc thuc gim au ......................................................................................... 75
2.2.6. Cc thuc tm thn .......................................................................................... 99
2.2.7. Cc thuc gin c ...........................................................................................125
2.2.8. Cc thuc cha bnh Parkinson....................................................................127
2.3. Cc thuc kch thch h thn kinh trung ng .................................................134
2.3.1. Thuc hi sc .................................................................................................134
2.3.2. Thuc kch thn ..............................................................................................136
2.3.3. Thuc chng trm cm ...................................................................................142
2.3.4. Cc cht gy ri lon tm thn ......................................................................156
Ti liu tham kho ....................................................................................................160
-161-