Pharmaceutical Substances Syntheses, Patents, Applications - Part 91 doc

fluoxetine chiral process from benzoylpropionic acid: US 5 936 124 Sepacor Inc.; appl.. antidiabetic combination: EP294 028 Lilly; appl.. pharmaceutical formulation: EP693 281 Lilly;

DE 2 500 110 (Lilly; appl 3.1.1975; USA-prior 10.1.1974)

US 4 018 895 (Lilly; 19.4.1977; USA-prior 10.1.1974)

US 4 194 009 (Lilly; 18.3.1980; USA-prior 15.9.1976)

US 4 314 081 (Lilly; 2.2.1982; USA-prior 10.1.1974)

US 4 584404 (Lilly; 22.4.1986; USA-prior 24.10.1983, 25.1.1978, 10.1.1974)

b US 5 847 214 (Laporte Organics; USA-prior 7.7.1997)

c ES 2 103 680 (Lilly; appl 3.8.1995)

d US 2760 243 (Albemarle Corp.; USA-prior 25.7.1997)

e ES 210 654 (Lilly; appl 24.7.1995)

f EP 529 842 (Teva Pharm.; appl 6.8.1992; IL-prior 27.8.1991)

EP391070 (Orion; appl 1.3.1990; FI-prior 3.3.1989)

EP 380 924 (E Magnone; appl 8.1.1990; I-prior 10.1.1989)

W09 906 362 (Albemarle Corp.; appl 4.8.1998; USA-prior 4.8.1997)

WO 9 856 753 (Albemarle C o p ; appl 12.6.1998; USA-prior 12.6.1997)

ES 2 120 368 (Almirall Prodesfarma; 16.10.1998; appl 14.6.1996)

EP529 842 (TevaPharm.; appl 6.8.1992; IL-prior 27.8.1991)

EP 617 006 (Pliva D.; appl 4.2.1994; HR-prior 5.2.1993)

E3 2 101 655 (Lilly; prior 28.7.1995)

E3 2 101 654 (Lilly; prior 24.7.1995)

ES 2 101 650 (Lilly; prior 29.6.1995)

W09 81 1 054 (Egis Gyogyszergyar; appl 10.9.1997; HU-prior 10.9.1996),

US 5 760 243 (Albemarle Corp.; 2.6.1998; appl 25.7.1996)

ES2 103 680 (Lilly S A,; 16.9.1997; appl 3.8.1995)

ES 2 103 681 (Lilly; 16.9.1997; appl 19.9.1995)

1 synthesis of enantromers

5 US4950 791 (H C Brown, 21.8 1990; prlor 12.6.1989, 30.3.1988)

: US 4 918 242 (Aldnch, 17 4 1990, prlor 12.6.1989, 30.3.1988)

US4918 207 (Aldr~ch; 17.4.1990; prlor 12.6.1989, 30.3.1988)

fluoxetine chiral process from benzoylpropionic acid:

US 5 936 124 (Sepacor Inc.; appl 22.6.1998)

treatment of nicotine withdrawal symptoms:

US 4 940 585 (W E Hapworth; 10.7.1990; appl 17.2.1989)

treatment of appetite and mood disturbances:

WO 8 903 692 (MIT; appl 21.10.1988; USA-prior 15.9.1988; 22.10.1987)

antidiabetic combination:

EP294 028 (Lilly; appl 29.4.1988; USA-prior 4.5.1987)

pharmaceutical formulation:

EP693 281 (Lilly; appl 17.7.1995; E-prior 20.7.1994)

memory improvement:

US4647 591 (Lilly; 3.3.1987; prior 7.10.1985, 21.6.1985)

solid oral composition:

ES 2 103 682 (Lilly; appl 29.9.1995)

analgesic compositions:

EP 193 355 (Lilly; appl 20.2.1986; USA-prior 25.2.1985, 25.7.1986)

EP 193 354 (Lilly; appl 20.2.1986; USA-prior 25.2.1985)

treatment of anxiety:

EP 123 469 (Lilly; appl 6.4.1984; USA-prior 8.4.1983)

novel trarlsdemal formulations:

W09 802 169 (Alza Corp.; appl 15.7.1997; USA-prior 15.7.1996)

902 F Fluoxymesterone

phur~naceuticd formulations:

EP 693 281 (Lilly; appl 17.7.1995; E-prior 20.7.1994)

low dose tablet:

US 5 830 500 (Pentech Pharm.; 3.1 1.1998; appl 22.7.1996; USA-prior 22.7.1996)

Fornzulation(s): cps 1 1.2 mg, 22.4 mg; sol 22.4 mg15 ml; tabl 22.4 mg (as hydrochloride)

Trade Nume(s):

D: Fluctin (Lilly; 1990) GB: Prozac (Lilly; 1989) Prozac (Lilly; 1989) F: Prozac (Lilly; 1989) I: Fluoxeren (Menarini; 1990) USA: Prozac (Dista)

Use: androgen RN: 76-43-7 MF: C2,H2,F03 M W: 336.45 EINECS: 200-96 1 8

LD,,,: 2350 mglkg (M, i.p.)

CN: (1 1 ~,17~)-9-fluoro-l1,17-dihydroxy-l7-methylandrost-4-en-3-one

-

3,17-dioxo-l l g - pyrrolidine

hydroxy-4-androstene

(from 3,17-dioxo-

4-androstene)

1 H ~ C + ~ - C I

1 H3C-CO-NH-Br

2 NaOH

H H 1 p-toluenesulfonyl 1 N-brorno-

Reference(s):

US 2 793 218 (Upjohn; 1957; prior 1955)

US 2 813 881 (Upjohn; 1957; prior 1955)

US 2 837 517 (Upjohn; 1958; prior 1956, 1955)

US 3 029 263 (Upjohn; 10.4.1962; prior 24.12.1959, 22.12.1958,6.6.1958)

DAS 1 037 447 (Ciba, appl 1955; CH-prior 1954)

Heyl, W.F.; Herr, M.E.: J Am Chem Soc (JACSAT) 75, 1918 (1953)

Bernstein, S et al.: J Org Chem (JOCEAH) 19,41 (1954)

Fried, J.; Sabo, E.F.: J Am Chem Soc (JACSAT) 75,2273 (1953); 76, 1455 (1954)

Herr, M.E et al.: J Am Chem Soc (JACSAT) 78, 501 (1956)

Flupentixol F 903

- -alternative synthesis

US 3 118 880 (Ciba; 21.1.1964; CH-prior 26.5.1954)

Formulation(s): tabl 1 mg, 2 mg, 2.5 mg, 5 mg, 10 mg

Trade Name(s):

D: Ultandren (Ciba); wfm I: Halotestin (Upjohn) Halotestin (Upjohn); wfm

F: Halotestin (Pharmacla & J: Halolest~n (Kodama) Ora-Testryl (Squibb); wfm

GB: Ullandren (Ciba); wfm wfm

Flupentixol

(Flupenthixol)

ATC: NOSAFOl Use: neuroleptic, antipsychotic

RN: 2709-56-0 MF: C2,H,,F3N20S MW: 434.53 EINECS: 220-304-9

LD,: 150 mglkg (M, i.p.)

CN: 4-[3-[2-(trifluoromethyl)-9H-thioxanthen-9-yliene]propyl]-I-piperazineethanol

dihydrochloride

RN: 241 3-38-9 MF: C,3H,sF3N,0S 2HCI MW: 507.45 ETNECS: 219-321-4

LD,,: 94 mgkg (M, i.v.); 423 mglkg (M, p.0.);

37 mglkg (R, i ~ ) ; 791 mglkg (R, p.0.)

decanoate

RN: 30909-51-4 MF: C,,H,,F,N20S C,oH,,O MW: 588.78

1 -(2-benzyloxyethyl)

piperazine

904 F Fluperolone acetate

ollylmognesiurn

bromide

Reference(s):

a GB 925 538 (Smith Kline & French; appl 3.3.1961 ; USA-prior 7.3.1960, 5.5.1960)

US 3 282 930 (Smith Kline & French; 1.1 1.1966; prior 7.3.1960, 5.5.1960)

b US 3 116 291 (Kefalas; 3 1.12.1963; DK-prior 4.12.1958)

Kaiser, C et a].: J Med Chem (JMCMAR) 15,665 (1972)

flupentixol decanoate:

DAS 2 029 084 (Kefalas; appl 12.6.1970; USA-prior 20.6.1969)

US 3 681 346 (Kefalas; 1.8.1972; prior 20.6.1969)

starting material:

GB 925 539 (Smith Kline & French; appl 3.3.1961; USA-prior 7.3.1960,5.5.1960)

vial 200 mg (20 mglml) (as decanoate)

Trade Name(s):

D: Fluanxol (Bayer Vital) Fluanxol (Lundbeck); wfm J: Metamin (Takeda; 1973) F: Fluanxol (Lundbeck; 1976) I: Deanxit (Lusofarmaco)-

GB: Depixol (Lundbeck; 1972); comb

Use: glucocorticoid, anti-inflammatory RN: 21 19-75-7 MF: C,,H,,FO, MW: 434.50 EINECS: 218-327-4

CN: [I 1 P,l7a,l7(S)]- 17-[2-(acety1oxy)-1 -oxopropyl]-9-fluoro-11,17-dihydroxyandrosta-1,4-dien-3-one

Fluphenazine F 905

Reference(s):

Agnello, E.J et al.: J Org Chem (JOCEAH) 28, 1531 (1963)

Agnello, E.J et al.: Experientia (EXPEAM) 16, 357 (1960)

(also alternative syntheses)

1 H3C-S02CI, DMF, pyridine

CH3 O 2 H,C-CO-NH-Br

4 HZF2 THF

1 methanesulfanyl chloride

2 N-bromoocetarnide

4 hydrogen fluoride

I: Alacortil (Pfizer); wfm USA: Methral (Pfizer); wfm

(m)

Fluphenazine

Fluperolone acetate

ATC: N05AB02 Use: neuroleptic, antipsychotic RN: 69-23-8 MF: Cz2H2,F3N30S MW: 437.53 EINECS: 200-702-9

LD,,: 51 mgkg (M, i.v.); 220 m g k g (M, p.0.)

CN: 4-[3-[2-(trifluoromethyl)-lOH-phenothiazin-l0-yl]propyl]-l-piperazincethanol

dihydrochloride

RN: 146-56-5 MF: CZ2H2,F3N3OS 2HC1 MW 510.45 EINECS: 205-674-1

LD5,: 56 mgkg (M, i.v.); 220 mglkg (M, p.0.)

decanoate

RN: 5002-47-1 MF: C22H,6F3N30S CloH,80 MW: 591.78

1-(3-hydroxypropy1)- methyl

4-(3-hydrouypropyl)- piperazine- 1 -corbox- aldehyde

NOOH

-+ 11

amide 4-(3-chlar0propyl)- Z-trifluoromethyl-

piperazine-I -carbox- phenothiozine

906 F Flupirtine

.CF- 2 oq HCI

'

- H 1 2-bromoethyl acetote

10-[3-(1 -piperazinyl)propyl]-

2-trifluoromethyl-

phenothiazine (II)

US 3 058 979 (Smith Kline & French; 16.10.1962; prior 13.5.1957)

DE 1 095 836 (Squihb; appl 8.12.1956; USA-prior 23.12.1955, 12.7.1956)

alkanecarboxylic acid esters:

DE 1 165 602 (Olin Mathieson; appl 25.4.1962; USA-prior 26.4.1961)

US 3 194 733 ( O h Mathieson; 13.7.1965; prior 26.4.1961,28.1.1963)

US 3 394 131 (Squibb; 23.7.1968; prior 26.4.1961,28.1.1963)

Kurland, A.A et al.: Curr Ther Res (CTCEA9) 6 , 137 (1964)

(as decanoate); drops 4 mglrnl; f c drg 3 mg, 6 mg; f c tabl 0.5 mg, 1 mg, 4 mg;

sol 2.5 mglml; tabl 1 mg, 2.5 mg, 4 mg, 5 mg, 10 mg (as dihydrochloride)

Trade Name(s):

D: Dapotum (Bristol-Mycrs

Squibb; Sanofi Winthrop)

Lyogen (Promonta

Lundbeck)

Omca (Bristol-Myers

Squibb)

F: Modecate (Sanofi

Winthrop)

Moditen (Sanofi Winthrop)

Motival (Sanofi Winthrop)-

comb

GB: Modecate (Sanofi

Winthrop)

Moditen (Sanofi Winthrop) Motipress (Sanofi Winthrop)-comb

Motival (Sanofi Winthrop)- comb

I: Anatensol (Bristol-Myers Squibb)

Dominans (Recordati)

comb

Moditen (Bristol-Myers Squibb)

J: Anatensol (Showa) Fludecasine (Yoshitomi)

Sevinol (Schering- Shionogi)

IJSA: Pennitil (Schenng); wfm

Pennitil (Schering-Plough); wfm

Prolixin (Squibb); wfm Prolixin (Bnstol-Myers Squibb); wfm generics

Use: analgesic RN: 56995-20-1 MF: C,sH,7FN,02 M W 304.33 EINECS: 260-503-8

LD,,: 617 mglkg (M, p.0.);

1660 mgikg (R, p.0.)

CN: [2-amino-6-[[(4-fluorophenyl)methyl]amino]-3-pyridinyl]carbamic acid ethyl ester

monohydrochloride

RN: 33400-45-2 MF: C,,H,,FN,O, HC1 MW: 340.79 EINECS: 251-496-2

LD,,,: 432 mg/kg (M, s.c.)

maleate (1:l)

RN: 75507-68-5 MF: C,,HI,FN40, C4H4O4 MW: 420.40 EINECS: 278-225-0

Fluprednidene acetate F 907

2,6-dichloro- 2,6-dichloro- 2.0mina.6.chloro- benzylomine

pyridine 3-nitropyridine 3-nitropyridine

2 ethyl chloroformate

Referencers):

DE I 670 522 (Degussa; appl 12.5.1966)

DE 1795 858 (Degussa; appl 19.7.1968)

US3 481 943 (Degussa; 2.12.1969; D-prior 12.5.1966)

US 3 513 171 (Degussa; 19.5.1970; D-prior 12.5.1966)

Bebenburg, W v et al.: Chern.-Ztg (CMKZAT) 103, 387 (1979)

Bebenburg, W v et al.: Chern.-Ztg (CMKZAT) 105, 217 (1981)

US 5 959 115 (ASATA Medica; 28.9.1999; appl 23.4.1 998; D-prior 23.4.1997)

(1)

Formularion(s): cps 5 0 mg, 100 mg; suppos 75 mg, 150 mg (as maleate)

Flupirtine

Trade Name(s):

D: Katadolon (ASTA Medica Trancopal (Sanofi I: Katadolon (ASTA Medica)

Fluprednidene acetate ATC: D07AB07; D07CB02; D07XB03

Use: topical glucocorticoid

RN: 1255-35-2 MF: C,,H,,FO, MW: 432.49 EINECS: 215-013-9

CN: (1 1P)-21-(acety1oxy)-9-fl uoro-11,17-dihydroxy-l6-methylenepregna-1,4-diene-3,20-dione

0 CH,

methane

1 6-dehydropregnenolone

acetate

1 H20, NaOH

1 hydrogen peroxide 38-acetoxy-16-methyl-20-

908 F Fluprednidene acetate

1 I, COO

2,

0

1 iodine

(111)

rnicrobiologicol dehydrogenotion [Flovobacterium dehydrogenons]

2 H;C-SO2-CI rnicrobiologicol hydroxylotion

[Fusoriurn equiseti Soccordo]

2 methonesulfonyl chloride

0

1 0 - B r , HCIO, H 2 0

3 H,F2

1 N-brornosuccinimide

3 hydrogen fluoride

rnicrobiologicol dehydrogenation -

Fluprednidene ocetotc

Refercnce(s):

GB 1 230 671 (Merck Patent GmbH; appl 10.7.1969)

Irmscher, K et al.: Arzneim.-Forsch (ARZNAD) 18,7 (1968)

(also other syntheses reviewed)

Wettstein, A.: Helv Chim Acta (HCACAV) 27, 1803 (1944)

alternative syntheses:

GB 946 860 (Merck & Co.; appl 17.3.1960; USA-prior 24.3.1959)

US 3 068 226 (Merck & Co.; 11 l2.1962; appl 22.12.1961; prior 24.3.1959)

US 3 163 760 (Merck & Co.; 9.7.1964; appl 24.3.1959)

US 3 309 272 (Merck & Co.; 14.3.1967; appl 24.4.1961; prior 24.3.1959)

Fluprednisolone acetate F 909

Trade Name(s):

D: Candio-Hermal (Herma1)- Decoderm (Hermal) Sali-Decoderm (Herma1)-

Fluprednisolone acetate Use: glucocorticoid

RN: 570-36-5 MF: C,,H,,FO, MW: 420.48 EINECS: 209-330- 1

CN: (6a,11 P)-21-(acety1oxy)-6-fluoro- 1 1,17-dihydroxypregna- l,4-diene-3,20-dione

fluprednisolone

RN: 53-34-9 MF: C2,H2,FOS MW: 378.44 EINECS: 200-170-8

acid

cis-methyl 3,3-

ethylenediaxy-1 1 - a m -

5.1 7(20)-pregnadiene-

21-carboxylate

1 LIAIH,

2 O O , pyridine

H~CWTH~

b

1 lithium alanote

2 acetic anhydride

b

1 N-methylmorpholine hydrogen peroxide osmium(Wll) oxide

1 CHCIS, HCI

2 microbiological dehydrogenation

[Septomyxa affinis (ATTC 6737)]

or Se02

Fluprednisolone acetote

Reference(s):

U S 2 841 600 (Upjohn; 1958; prior 1957, 1955)

DE 1 079 042 (Syntex; appl 1958; MEX-prior 1957)

910 F Flurazepam

starting material:

US 2 707 184 (Upjohn; 1955, prior 1953, 1952)

alternative synthesis:

US 4 041 055 (Upjohn; 9.8.1977; prior 17.1 1.1975)

Trude Name(s):

D: Isopredon (Hoechst); wfm I: Etadrol (Carlo Erha); wfm

F: Decoderme (Merck- Etadrol (Farmitalia); wfm

CICvenot); wfm USA: Alphadrol (Upjohn); wfm

Use: hypnotic, sedative RN: 1761 7-23-1 MF: C,,H,,ClFN,O MW: 387.89 EINECS: 241-591-7

LD,,,: 59.1 mgfkg (M, i.v.); 500 m g k g (M, p.0.);

38.7 mglkg (R, i.v.); 980 mgkg (R, p.0.)

CN: 7-chloro- 1 -[2-(diethylamino)ethyl]-5-(2-fluorophenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-one dihydrochloride

RN: 1 172-18-5 MF: C,,H,,C1FN30 2HC1 MW: 460.8 1 EINECS: 214-630-0

LD,,,: 59.1 rng/kg(M, i.v.); 596mg/kg(M, p.0.);

38.7 mglkg (R, i.v.); 879 mglkg (R, p.0.)

hydrochloride

RN: 36105-20-1 MF: C,,H,,CIFN,O~ HCl MW: 424.35

/

cl%F 2-amino-5-chlaro

P-fluorobenzo-

phenone

(cf, flunitrozeporn

synthesis)

bromaocetyl chlaride

n

0