Pharmaceutical Substances Syntheses, Patents, Applications - Part 169 ppt

6 mg as hydrochloride Trade Names: D: Sistalgin Cascan; wfm I: Sistalgin Bracco-comb.; wfm... 4-butoxyphenol 3-rnorpholino- Pmmocaine Trade Numes: I : Proctofoam HC Anusol Warner-La

Pramiverine P 1681

' 3 3 n3L y L " 3

2 HCI H 2 0 I F ,-NYCH3 - HCI

I

" CH3

I Promirocelom hydrochloride

I Reference (s):

BE 864 269 (Parke Davis & Co.; appl 7.3.1978; USA-prior 3.3.1977)

US 4 145 347 (Parke Davis & Co; 20.3.1979; USA-prior 3.3.1 977)

Butler, D.E.; Nordin, 1.C.; L'Italien, Y.J.; Zweisler, L.; Poschel, P.H.; Mamott, J.G.: J Med Chem (JMCMAR) 27,684 (1984)

Formulation(s): tabl 600 mg (as sulfate)

Trade Name(s):

IJse: antispasmodic RN: 14334-40-8 MF: C,,H,,N MW: 293.45

CN: N-(I -methylethyl)-4,4-diphenylcyclohexanamine

hydrochloride

RN: 14334-41-9 MF: CZIHz7N HCl MW: 329.92 EINECS: 238-284-5

LDjo: 25 mgkg (M, i.v.); 346 mglkg (M, p.0.);

26 mglkg (R, i.v.); 623 mglkg (R, p.0.);

20 mgkg (dog, i.v.); 140 mgkg (dog, p.0.)

diphenyl- methyl vinyl 4.4-diphenyl-2-

acetaldehyde ketone cyclohexen-1 -one

Promiverine

Reference(s):

DE 1 793 61 1 (Merck AG; appl 15.12.1964)

Formulation(s): amp 2 mg12 ml; drg 2 mg; drops 2 mglml; suppos 6 mg (as hydrochloride)

Trade Name(s):

D: Sistalgin (Cascan); wfm I: Sistalgin (Bracco)-comb.;

wfm

1682 P Pramocaine

Pramocaine

(Pramoxine)

ATC: C05AD07 Use: local anesthetic RN: 140-65-8 MF: C,,H,,NO, MW: 293.41 EINECS: 205-425-7

LDso: 79 mgkg (M, i.v.)

CN: 4-[3-(4-butoxyphenoxy)propyl]morpholine

hydrochloride

RN: 637-58-1 MF: C,,HnN03 HC1 MW: 329.87 EINECS: 21 1-293-1

LDso: 79.5 mglkg (M, i.v.); 1050 mgkg (M, p.0.)

Reference(s):

US 2 870 151 (Abbott; 1959; prior 1954)

Wilson, J.W et al.: J Org Chem (JOCEAH) 16, 792 (1951)

4-butoxyphenol 3-rnorpholino-

Pmmocaine

Trade Nume(s):

I ) : Proctofoam HC Anusol (Warner-Lambert) Prax (Ferndale) (Trommsdorffl-comb.; wfm Caladryl (Warner-Lambert) Proctofoam (Schwarz) F: Tronothane (Abbott) Cortane-B OTIC (Blansett) Promasone (Ferndale)

USA: Analpram-HC (Ferndale) Epifoam (Schwarz)

propyl chloride

Pranlukast

(ONO-1078; RS-411; SB-205312)

ATC: R03DC02 Use: antiallergic, antiasthmatic, leukotriene D,-antagonist RN: 103177-37-3 MF: C27HuNs04 MW: 481.51

CN: N-[4-oxo-2-(1H-tetrazol-5-yl)-4H-l-benzopyran-8-yl]-4-(4-phenylbutoxy)benzamide

hydrate (2:l)

RN: 150821-03-7 MF: C2,H2,N504 1/2H20 MW: 981.04

monosodium salt

RN: 103 180-28-5 MF: C,,H,,N,NaO, MW: 503.49

NaN3

NO2 0 1 NH3 NO, pyridinivm chloride

@CN

O M ,

/

ethyl 8-nitro-4- 2-cyano-8- 8-nitro-2-(tetro-

0 x 0 - l -benzopyran- nitro- l-benzo- zol-5-yl)-1 -benzo-

h

synthesis of I1

NH H N ' ~ ~ ( c ~ ~ ~ c - 0 ~ H ~ C C H ~ O H

0

0

ethyl I -trityl-

carboxylate

Trt:

Reference(s):

a EP 173 516 (0no Pharm.; 1.12.1993; J-prior 22.1 1.1984)

Nakai, H et al.: J Med Chem (JMCMAR) 31, 84-91 (1988)

b EP 0 716 088 (Sumitomo Chem.; appl 23.6.1995; J-prior 23.6.1994)

synthesis of intermediates type 11:

W O 9 532 199 (SmithKline Beecham; appl 30.1 1.1995; GB-prior 21.5.1994)

combination with PAF-antagonisls:

EP 469 477 (Hoffmann-La Roche; appl 26.7.199 1 ; USA-prior 2.8.1990)

Formulation(s): cps 112.5 mg (as hydrate)

Trade Name(s):

Pranoprofen

RN: 52549-17-4 MF: Cl,H,,NO, MW: 255.27

LD,,: 447 mglkg (M, p.0.);

59.5 mglkg (R, p.0.)

CN: a-methyl-5H-[I]benzopyrano~2,3-b]pyridine-7-acetic acid

ATC: MOlAE Use: anti-inflammatory, analgesic

1684 P Pranoprofen

POCI,

HCI

5H-[l]benzo- pyrano[2.3-b]- pyridine

5H-[I Ibenzopyrono- cyanide

[2.3-b]pyridine (11)

methyl iodide

Reference(s):

FR 2 193 593 (Yoshitomi; appl 19.7.1973; J-prior 21.7.1972, 13.1.1973,3.4.1973)

DOS 2 337 052 (Yoshitomi; appl 20.7.1973; J-prior 21.7.1972, 13.1.1973,3.4.1973)

US 3 931 205 (Yoshitorni; 6.1.1976; appl 18.7.1973; J-prior 21.7.1972)

HCI

r 4

synthesis q f 5-hydroxy-5H-[1 Jbenzopyrano[2,3-blpyridine:

Mann, F.G.; Reid, J.A.: J Chem Soc (JCSOA9) 1952, 2057

COOH

~ r a n o ~ r o f e n '

Formulation(s): cps 75 mg

Trade Name(s):

J: Niflan (Yoshitomi; 1981)

Prasterone P 1685

Use: anabolic, androgen RN: 53-43-0 MF: C,,H,,O, MW: 288.43 EINECS: 200-175-5

LD,,: >10 g k g (M, p.0.);

>10 glkg (R, p.0.)

CN: (3fl)-3-hydroxyandrost-5-en-17-one

H3 1 NH20H HCI, pyridine, C2H50H

2 S0Cl2

b

1 hydroxylamine hydrochloride

2 thionyl chloride 16-dehydropregnenolone

ocetate

( cf pregnenolone synthesis)

1 Prasterone

1 NH20H

2 POCI3, pyridine

b

1 hydroxylamine

2 phosphoryl chloride pregnenolone ocetate

(9 v.)

1 OH-

2 HOCl

n *

H H

Reference (s):

Ullmanns Encykl Tech Chem., 4 Aufl., Vol 13, 30

from cholesterol:

Ullmanns Encykl Tech Chem., 3 Aufl., Vol 8,648

Rosenkranz, G et al.: J Org Chem (JOCEAH) 21,520 (1956)

US 2 335 61 6 (Parke Davis; 1943; prior 1941)

Formulation(s): amp 200 mglml

1686 P Prasterone enanthate

Trade N a m e ( ~ ) :

D: Gero Hormetten (Hormon- Gyno Hormetten (Hormon- I: Gynodlan (Schering, as

Chemie; as sulfate)-comb.; Chemie; as sulfate)-comb.; valerate)

GB: Diandrone (Organon); wfm

Use: androgen RN: 23983-43-9 MF: C26H4001 MW: 400.60 EINECS: 245-970-8

CN: (3P)-3-[(I-oxoheptyl)oxy]androst-5-en-17-one

prasterone

(9 v.1

enanthic anhydride I Prosterone enonthate

Reference(s):

ZA 686 1 12 (Schering AG; appl 20.9.1968; D-prior 4.10.1967)

GB 1 246 639 (Schering AG; valid from 30.9.1968; D-prior 4.10.1967)

altertmtive synthesis:

DOS 2 534 91 1 (Schering AG; appl 1.8.1975)

use against psoriasis:

DOS 2 147 309 (Schering AG; appl 17.9.1971)

Form~dation(s): amp 200 mg in comb with estradiol valerate

Trade Name(s):

Pravastatin

(Eptastatin)

ATC: ClOAA03 Use: cholesterol depressant, HMG-CoA- reductase inhibitor

RN: 81093-37-0 MF: C,,H,,O, MW: 424.53

CN: [IS-[lẵS*,GS*),2a,6a,8~(R*),8aa]]-1,2,6,7,8,8a-hexahydro-P,6,6-trihydroxy-2-methyl-8-(2-methyl-l- oxobutoxy)-1-naphthaleneheptanoic acid

monosodium salt

RN: 81 131-70-6 MF: C,,H,,NaO, MW: 446.52

LD,,,: 201 1 m g k g (M, ịv.); 8939 mglkg (M, p.0.);

440 mglkg (R, ịv.); >12 g k g (R, p.0.)

Pravastatin P 1687

hydroxylation by Mucor hiemolis or P

coccineus, R solani,

H3C

Nocardia

Reference(s):

DE 3 122 499 (Sankyo; appl 5.6.1981; J-prior 6.6.1980, 8.9.1980, 19.9.1980, 22.8.1980)

US 4 346 227 (Sankyo; 24.8.1982; appl 5.6.1981; J-prior 6.6.1980, 22.8.1980, 11.3.1980)

Serizawa, N et al.: J Antibiot (JANTAJ) 36, 604 (1983)

mevastatin

asymmetric synthesis:

Daniewski, A.R et al.: J Org Chem (JOCEAH) 57, 7133 (1992)

Provostatin

pharmaceutical fortnulation with increased s t a b i l i ~ :

EP 336 298 (Squibb; appl 30.3.1989; USA-prior 31.3.1988)

combination with coenzyme Q10:

US 4933 165 (Merck & Co.; 12.6.1990; appl 8.1 1.1989)

US 4 929 437 (Merck & Co.; 29.5.1990; appl 2.2.1989)

mevastatin (compactin):

The Merck Index, 1 lth Ed., 6088 (Rahway 1989)

Endo, A.: J Med Chem (JMCMAR) 28,401 (1985)

new production process:

EP 877 089 (Gist-Brocades, EP-prior 7.5.1997)

WO 9 736 996 (Gist-Brocades; appl 21.3.1997; EP-prior 28.3.1996)

WO 9 845 410 (Yungjin; appl 30.6.1997; KR-prior 10.4.1997)

EP 776 974 (Sankyo; appl 29.11.1996; J-prior 29.1 1.1995)

conversion of compactin by Actinomadura:

WO 9 640 863 (MIT; appl 4.6.1996; USA-prior 7.6.1995)

hydroxylation by Saccharopolysopra hirsuta:

EP 649 907 (Bristo-Myers Squibb; appl 18.10.1994; USA-prior 22.10.1993)

use for slowing progression of atherosclerosis:

EP 671 170 (Bristol-Myers Squibb; appl 21.2.1995; USA-prior 11.3.1994)

use for preventing restinosis:

EP 459 453 (Squibb & Sons; appl 29.5.1991; USA-prior 31.5.1990)

Formulation(s): tabl 5 mg, 10 mg, 20 mg (as sodium salt)

Trade Name(s):

D: Liprevil (Schwarz/Sanol) GB: Lipostat (Bristol-Myers Selectin (Bristol-Myers

Pravasin (Bristol-Myers I: Aplactin (Mead Johnson) J: Mevalotin (Sankyo; 1989)

Vasten (Specia; RhGne- Sanaprav (Sankyo Pharma)

Poulenc Rorer; 199 1)

Prazepam ATC: NO5BA11

Use: tranquilizer

RN: 2955-38-6 MF: C,9H17CIN20 MW: 324.81 EINECS: 220-975-8

LD,,,: 2300 mglkg (M, p.0.);

>4 glkg (R, p.0.);

>4 glkg (dog, p.0.)

CN: 7-chloro-l-(cyclopropylmethyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

P

CI

/

alanate 2-amino-5-chloro- cyclapropane-

benzophenone carbonyl chloride

oxide

benzophenone

HZN-NHZ hydrozine

0

phthalimidoacetyl chloride

6

cl$2

Prazepam

1 NOH

Br

-b

1 sodium hydride

2 cyclopropylmethyl bromide 7-chloro-2-0x0-5-

phenyl-2.3-dihydro-

1 H-1.4-benzodiazepine

Praziauantel P 1689

Reference(s):

a DAS 1 229 098 (Warner-Lambert; appl 24.2.1964; USA-prior 1.3.1963)

US 3 192 199 (F H McMillan, J Pattison; 29.6.1965; appl 1.3.1963)

b US 3 192 200 (H M Wuest; 29.6.1965; prior 5.3.1963)

alternative synthesis:

Inaba, S et al.: Chem Pharm Bull (CPBTAL) 17, 1263 (1969)

Formulation(s): drops 15 mglml; tabl 10 mg, 20 mg, 40 mg

Trade Name(s):

D: Demetrin (Godecke; Parke GB: Centrax (Parke Davis); USA: Centrax (Parke Davis);

Mono-Demetrin (Godecke; I: Prazene (Parke Davis) Verstran (Parke Davis;

F: Lysanxia (Parke Davis) J: Prazepam (Sumitomo

Chem.)

Use: anthelmintic RN: 55268-74-1 MF: C,,HXN2O2 MW: 312.41 EINECS: 259-559-6

LD,,: 2454 mglkg (M, p.0.);

2840 mglkg (R, p.0.);

>200 mglkg (dog, p.0.)

CN: 2-(cyclohexylcarbony1)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one

cC;':: ,'

l-ominomethyl-

1,2.3,4-tetrahydro

isoquinoline

@

+

isoauinoline

+ C ' ~

- 4

cyciohexonecorbonyl chloride

N-cyclohexylcorbonyl- ominomethyl)-l.2,3,4- tetrahydroisoquinoline

chloroocetyl

1690 P Prazosin

Reference(s):

DOS 2 457 971 (E Merck Patent GmbH; appl 7.12.1974)

DOS 2 362 539 (E Merck Patcnt GmbH; appl 17.12.1973)

DOS 2 504 250 (E Merck Patent GmbH; appl 1.2.1975)

DOS 3 01 1 156 (E Merck Patent GmbH; appl 22.3.1980)

Formulation(s): f c tabl 150 mg, 600 mg; tabl 500 mg

Trade Name(s):

D: Biltricide (Bayer) Cysticide (Merck) I: Biltrizide (Bayer) Cesol (Merck) F: Biltricide (Bayer Pharrna) USA: Biltricide (Bayer)

Use: antihypertensive, a,-adrcncrgic blocker

RN: 19216-56-9 MF: C,yH21N504 MW: 383.41 EINECS: 242-885-8

LD,,,: >400 mglkg (M, i.v.); >4 glkg (M, p.0.)

CN: I-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbony1)piper~ine

monohydrochloride

RN: 19237-84-4 MF: C,yH21N504 HCl MW: 419.87 ETNECS: 242-903-4

L D , : 92 mgkg (M, i.v.); 5 glkg (M, p.0.);

73 mglkg (R, i.v.); 1950 mgkg (R, p.0.);

r700 mglkg (dog, p.0.)

2-ornino-4.5-di- sodium 2,4-dihydroxy-6,7-

rnethoxybenzoic cyanate dirnethoxyquinazoline

odd

2,4-dichloro-6.7- dirnethoxyquinazoline (I)

4-omino-2-chloro-

6,7-dimethoxy-

quinozoline

i Prazosin

Reference(s):

US 3 5 11 836 (Pfizer; 12.5.1970; appl 13.12.1967; prior 6.8.1965,7.6.1966)

US 3 635 979 (Pfizer; 18.1.1972; prior 6.8.1965,7.6.1966, 13.12.1967)

US 3 663 706 (Pfizer; 16.5.1972; prior 6.8.1965, 13.12.1967, 12.5.1970)

DAS 1 620 138 (Pfizer; appl 2.7.1966; USA-prior 6.7.1965,7.6.1966)