Pharmaceutical Substances Syntheses, Patents, Applications - Part 42 potx

4-tluorobenz- ethyl aldehyde isobutyrylacetate ethyl 3-amino- 4-methyl-2- pentenoate 1.. CN: 5-oxo-~-prolyl-~-glutaminyl-~-a-asparty-O-sulfo-~-tyrosyl-~-threonylglycyl-~-tryptophyl-~

4-tluorobenz- ethyl

aldehyde isobutyrylacetate

ethyl 3-amino-

4-methyl-2-

pentenoate

1 DDO, CH2C12

2 Red-Al, THF

5.6-dicyano-p-

benzoquinone

2 sadium bis(2-

methoxyethoxy)-

dihydridoaluminate

2.6-diisopropyl-

4-(4-fluoropheny1)-

5-methoxymethyl-

3-pyridine-

carboxaldehyde (111)

ethyl 2-isobutyryl- 3-(4-fluoropheny1)- acrylate (I)

C H 3 ~ C H 3

F

diethyl 1,4-dihydro-2,S-

diisopropyl-4-(4-fluoropheny1)-

pyridine-3.5-dicarboxylate (11)

F

ethyl 2,6-diisopropyl-4-

(4-fluorophenyl)-5-hydroxy-

methylpyridine-3-carboxylate

H ~ C '

diethyl 2 - (cyclohexylamino)- vinylphosphonate

1 H3C-I, NOH, THF

2 L i A l k THF

1 methyl iodide

2 lithium aluminum hydride

3 pyridinium chlorochromate

NOH THF 25 OC

0 0 THF, -65 OC

H3C u~/CH3 2 triethylborane

methyl

412 C Cerivastatin sodium

1 THF, 50 "C

2 chromotogrophic separation of

OH

F

methyl erythro-(E)-7-[2,6-diisopropyl- ( + ) - ( ~ ) - ~ h e n ~ l -

4-(4-fluorophenyl)-5-methoxymethyl- glycinol

3-pyridyll-3,5-dihydroxy-hept-6-enoote (V)

OH

F

Cerivostotin sodium

u

Reference(s):

a DE 4 040 026 (Bayer; appl 14.12.1990)

EP 325 130 (Bayer AG; appl 9.1.1989; D-prior 20.1.1988)

EP 491 226 (Bayer AG; appl 3.12.1991; D-prior 14.12.1990)

AU 9 189 615 (Bayer AG; appl 11.12.1991; D-prior 14.12.1990)

(R)-(+)-a-phenethylamine can be used instead ofS-(+)-phenylglycinol

b Drugs Future (DRFUD4) 19,537-541 (1994)

Formulation(s): tabl 0.1 mg, 0.2 mg, 0.3 mg

Trade Name(s):

D: Lipobay (Bayer) GB: Lipobay (Bayer) USA: Baycol (Bayer)

Ceruletide C 413

Ceruletide

(Caerulein)

ATC: V04CC04; V04CK Use: diagnostic (for pancreatic function), stimulant of gastric secretory RN: 17650-98-5 MF: C5RH73N1302LS2 MW: 1352.42

LD,,: 1012 mgkg (M, i.v.)

CN: 5-oxo-~-prolyl-~-glutaminyl-~-a-asparty-O-sulfo-~-tyrosyl-~-threonylglycyl-~-tryptophyl-~-methionyl-

L-a-aspartyl-L-pheny lalanin amide

Boc-Tyr Boc-Tyr-NH-NH-Z Tyr-NH-NH-Z HCI (I)

0

Boc: 40&?H,

CH3

H

N COOH

- i f O \ B z l

0

1 HCI

,

2 Boc-Gln

1 HCI

Boc,

2 Z-Pyr

Pyr-Gln-Asp-Tyr-N,

414 C Ceruletide

1 HCI

3 HCI

CI

HCI

COOH CH3

Ac-Thr-Gly-Trp-Met-Asp-Phe-NH HCI (VI)

H

Pyr-Gln-kp -Tyr(s03H)-Thr(Ac)-~ly-Trp-Met-Asp-Phe-NH (W)

Ceruletide

DE 1 643 504 (Soc Farmaceutici Italia; appl 6.4.1972; I-prior 9.8.1966)

US 3 472 832 (Soc Farmaceutici Italia; I-prior 9.8.1966)

Bernardi, L et al.: Experientia (EXPEAM) 23, 700 (1967)

structure and isolation from Hyla caeruleu:

Anastasi, A et al.: Experientia (EXPEAM) 23, 699 (1967)

Cetalkonium chloride C 4 15

Formulation(s): amp 5 ~ g l m l , 40 pgl2 ml; vial 20 kg, 30 kg, 40 kg

Trade Name(s):

D: Takus (Pharmacia & J: Ceosunin (Kyowa Hakko)

Upjohn)

Cetalkonium chloride ATC: SOlAA

Use: antiseptic, bactericide RN: 122-18-9 MF: C2,H4,C1N MW: 396.10 EINECS: 204-526-3

CN: N-hexadecyl-N,N-dimethylbenzenemethanaminium chloride

cetyl chloride dimethyl-

omine

N-cetyl-N,N- dimethylomine (I)

Reference(s):

FR 77 1 746 (I G Farben; 1934)

Formulation(s): sol 13 g/100 g, 130 mg

Trade Narne(s):

benzyl chloride

D: Baktonium (Bode) F: Pansoral (Pierre Fabre GB: Bonjela (Reckitt &

Mundisal (Mundipharma)- SantC)-comb Co1man)-comb

Cetalkonium chloride

Cethexonium bromide ATC: DOSAX; R02AA20

Use: antiseptic RN: 1794-74-7 MF: C2,H,,BrN0 MW: 448.57

CN: N-hexadecyl-2-hydroxy-N,N-dimethylcyclohexanaminium bromide

chloride

RN: 58703-78-9 MF: CxHSoCINO MW: 404.12

2-amino- cetyl

4 1 6 C Cetiedil

(yH2)15-CH3 1 anion exchanger

,- (OH- form)

Keference(s):

Winternitz, F et al.: Bull Soc Chim Biol (BSCIA3) 33, 369 (1951)

Formulation(s): collutorium 0.025 g1100 ml, 0.1 mgI0.4 ml, 0.3 gI100 ml; eye.drops 0.025 % (bromide);

ointment 1 d l 0 0 g; powder 1.5 gllOO g; sol 50 rng/100 ml

Cethexoniurn bromide

Trade Name(s):

F: Biocidan (Menarini)

hexanol

Use: vasodilator (peripheral) RN: 141 76- 10-4 MF: C,,,H3,N0,S MW: 349.54 EINECS: 238-028-2

LD,,,: 1726 mg/kg (M, p.0.)

CN: a-cyclohexyl-3-thiopheneacetic acid 2-(hexahydro-IH-atepin-1-y1)ethyl ester

citrate (1:l)

RN: 16286-69-4 MF: C2,,H3,N02S C6HR0, MW: 541.66 EINECS: 240-381-2

( C 2 ~ 5 ) 2 0 -70 O C

cyclohexyl- 3-thienyl-

glyoxylic ocid lithium

(from 3-bromo- thiophene and butyllithiurn)

glycolic acid acetic acid (1)

hexohydro- 1H-

Cetirizine C 417

Referencefs):

FR 1 460 571 (InnothCra; appl 10.6.1965)

FR-M 5 504 (Innothefa; appl 10.6.1965)

Robba, M.; Guen, Y Le: Chim Ther (CHTPBA) 1967 (No 2), 120

synthesis of starting materials:

Robba, M.; Guen, Y Le: Chim Ther (CHTPBA) 1966 (No 4), 238

FR-appl 2 260 575 (Innothefa; appl 11.2.1974)

FR-appl 2 260 576 (ImothQa; appl 11.2.1974)

synthesisfrom 3-thienylacetonitrile:

US 4 108 865 (Labaz; 22.8.1978; prior 29.8.1974, 1.3.1976)

Formulation(s): cps 100 mg (as citrate)

Trade Name(s):

F: Stratene (Gerda) Vasocet (Cipharm) I: Stratene (Sigma-Tau); wfm

Use: non-sedative antihistaminic RN: 83881-51-0 MF: C21H25C1N203 MW: 388.90

CN: (~)-[2-[4-[(4-chlorophenyl)phenylmethyl]-I-piperazinyl]ethoxy]acetic acid

dihydrochloride

RN: 83881-52-1 MF: C21H25CIN203 2HCI MW: 461.82

LD,: 365 mg/kg (R, p.0.);

>320 mgkg (dog, p.0.)

0 + L C H 3

& CI + (;I _, No2COJ (;I _, HCI [;I

H cfoC, dnc,

4-chlorobenzhydryl N-corbethaxy- ethyl 4-(4-chlorabenzhydryI)- 1 -(4-chl~radi~henyl-

chlo"de piperorinc piperazine- 1 -carbarylate methyl)piperozine (I)

Cl-~JoA+3 9 Na2C03

methyl 2-(2-chloroethoxy)-

acetate sodium carbonate

chlarodiphenylmcthyl)-

1 -piperazinyl]ethoxy]ocetate

Referencefs):

EP 58 146 (UCB; appl 5.2.1982; GB-prior 6.2.1981, 8.4.1981)

alternative synthesis (also enantiomers):

GB 2 225 321 (UCB; appl 23.11.1988)

EP 801 064 (UCB; appl 9.4.1997; BE-prior 10.4.1996)

WO 9 737 982 ( U C B ; - ~ ~ ~ I 28.3.1997; ~ ~ - ~ r i o r 4.10.1996)

WO 9 802 425 (Apotex; appl 1 1.7.1997; CA-prior 11.7.1996)

4 1 8 C Cetrimonium bromide

synthesis of 1-(4-chlorodipheny1methyl)piperazine:

US 2 8 19 269 (Abbott; 1958)

HU 17 343 (Richter Gedeon; appl 26.5.1977)

US 2 709 169 (UCB; 1952)

4

Formulatlon(s) drops 10 mg, sol 0 1 %, tab1 10 mg (as dihydrochloride) 1

4

Trade Name(s)

D Zyrtec (UCB, Rodleben, GB Zlrtek (UCB) USA Zyrtec (Pfizer, as

Vedim) I Formlstln (Formenti, 1990) h ydrochlonde)

F Vlrllx (SynthClabo) Vlrllx (Chemil)

Zyrtec (UCB) Z~rtec (UCB; 1990)

Cetrimonium bromide

(Cetrimide)

ATC: R02AA17 Use: antiseptic RN: 57-09-0 MF: C,,H,,BrN MW: 364.46 EINECS: 200-311-3

LD,,,: 32mgkg(M,i.v.);

44 m g k g (R, i.v.); 410 m g k g (R, p.0.)

CN: N, N, N-trimethyl- 1 -hexadecanaminium bromide

hydroxide

RN: 505-86-2 MF: C,,H,,NO MW: 301.56 EINECS: 208-022-4

Shelton, R.S et al.: J Am Chem Soc (JACSAT) 68,753 (1946)

Formulation(s): sol 117 mg1100 g; tabl 4 mg

Trade Name(s):

D: Lemocin (Novartis Buccawalter (SmithKline GB:

Consumer Health) Beecham)-comb

Xylastesin (Espe) CCtavlon (Zeneca)

numerous combination DCrinox (ThCrabel Lucien)- I:

F: Aseptit (Riom) Rectoquotane (Evans J:

Medical)-comb

Ceanel Conc (Quinodem)- comb

Cetavlex (Zeneca) Cetavlon (Zeneca) Xylonor (0gna)-comb

Cetavlon (Sumitorno Chem.)

Cetrorelix

(SB-75; D-20761)

ATC: HOlCC02 Use: LHRH-antagonist RN: 120287-85-6 MF: C,,H,,ClN,,O,, MW: 143 1 O6

CN: N-Acetyl-3-(2-naphthalenyl)-~-alanyl-4-choro-~-phenyaanyl-3-(3-pyridinyl)-~-alanyl-~-seryl-~- tyrosyl-~-(aminocarbonyl)-~-ornithyl-~-leucyl-~-arginy~-~-prolyl-~-alaninamide

Cetrorelix C 419

acetate

RN: 145672-81-7 MF: C70Hy2ClN,7014 xC2H402 MW: unspecified

diacetate

RN: 130143-01-0 MF: C70Hy2ClN,70,4~2C2H402 MW: 1551.17

trifluoroacetate

RN: 130289-71-3 MF: C70Hy2ClN17014 C2HF,0, MW: 1545.09

pamoate

RN: 132741 -85-6 MF: C70Hy2ClN170,4 C2,H,,0, MW: 1819.44

@ solid-phom synthesis:

0-(p-C1)Phe 0-Pol Ssr T Y ~ 0-Cit Leu Pro 0-Ala

Cit:

Pal:

Nal:

(p-CI)Phe:

Boc:

BZL:

2-Br-2:

Ac:

Tos:

7p

BZL

BZL

citrulline ( N ~ - ~ a r b a m o ~ l o r n i t h i n e )

3-pyridylalanine

2-naphthylalanine

4-chlarophenylolonine

tert-butoxycarbonyl

benzyl

2-bromabenzyloxycarbonyl

acetyl

tosyl

NH-A

,2-Br-Z ,2-Br-Z 2-Br-Z

NH-R

,2-Br-Z

NH-R

,2-Br-2

, NH-R

NH-R NH2

polystyrene- divinylbenzene

CH3 (MBHA-resin)

After cleovoge from the resin the crude peptide is dissolved

420 C Cetrorelix

Cetrorelix

@ clossicol, liquid-phose synthesis:

Cetrorelix

u

obbreviotions see method a

Reference(s):

a Bajusz, S et al.: Int J Pept Protein Res (IJPPC3) 32,425 (1988)

EP 299 402 (ASTA Medica; appl 11.7.1988; USA-prior 17.7.1987)

a,b Kleemann, A et al.: Proc Akabori Conf.: Ger.-Jpn Symp Pept Chem., 4th, 1991,96-101

b Kunz, F.R et al.: Proc Akabori Conf.: Ger.-Jpn Symp Pept Chem., Sth, 1994, 15-16

long-acting injection suspension with pamoate salt:

US 773 032 (ASTA Medica; 10.6.1996; ~ - ~ r i o r 9.12.1993)

sterile acetate formulation:

EP 61 1 572 (ASTA Medica; D-prior 19.2.1993)

use in fertility control:

EP 788 799 (ASTA Medica; USA-prior 7.2.1996)

use for BPH o r prostate cancer:

WO 9 810 781 (ASTA Medica; USA-prior 12.9.1996)

Formulation(s): vial 0.25 mg, 3 mg (as acetate)