Pharmaceutical Substances Syntheses, Patents, Applications - Part 47 potx

de Conseils de Recherche et d'Appl.. de Conseils de Recherche et d'Appl... synthesis of 4-aminomethylcyclohexanecarboxylic acid: Levine, M.; Sedlecky, R.: J... 10 mglml as ciclopirox; va

Cicletanine C 461

Cicletanine

(Cycletanide)

ATC: C03BX03 Use: diuretic, antihypertensive RN: 89943-82-8 MF: C14H,2ClN02 MW: 261.71

LD,,: 4500 mgkg (M, p.0.);

5000 mgkg (R, p.0.)

CN: (~)-3-(4-chloropheny1)-1,3-dihydro-6-methylfuro[3,4-c]pyridin-7-ol

hydrochloride

RN: 82747-56-6 MF: C,4H,2ClN02~ HCl MW: 298.17

~ 3 ~ OH %+ HIC ~, CHI ~

propylidene- pyridoxine

BrMg

t

C I

4-chlorophenyl- mognesium bromide

Reference(s):

DOS 3 204 596 (Soc de Conseils de Recherche et d'Appl Sci.; appl 10.2.1982; GB-prior 10.2.1981)

US 4 383 998 (Soc de Conseils de Recherche et d'Appl Sci.; 17.5.1983; GB-prior 10.2.1981)

synthesis of 2,2,8-trimethyl-5-formyl-4H-pyrido[3,4-d]-1,3-dioxane:

Koryntyk, W.; Wiedemann, W.: J Org Chern (JOCEAH) 27,2531 (1962)

Koryntyk, W.; Kris, E.J.; Singh, R.P.: J Org Chem (JOCEAH) 29, 574 (1964)

Sattsangi, ED.; Argoudelis, C.J.: J Org Chem (JOCEAH) 33, 1337 (1968)

Formulation(s): cps 50 mg, 100 mg (hydrochloride)

Trade Name(s):

D: Justar (Intersan; 1989) F: Tenstaten (Ipsen-Beaufour;

1988)

Use: glucocorticoid RN: 86022-88-0 MF: C32HuClN07 MW: 590.16 EINECS: 289-141-9

CN: [l 1~,16~,21(trans)]-21-[[[4-[(acetylamino)methyl]cyclohexyl]carbonyl]oxy]-9-chloro-l 1,17-dihydroxy- 16-methylpregna- l,4-dime-3,20-dione

462 C Ciclonium bromide

troneromic ocid

(9- v.)

N(C2H& THF

triethylornine

beclometasone

(9 v.1

Ciciometasone

Reference(s):

FR 2 280 384 (Rorer; appl 1.8.1974)

synthesis of 4-aminomethylcyclohexanecarboxylic acid:

Levine, M.; Sedlecky, R.: J Org Chem (JOCEAH) 24, 115 (1959)

Trade Nurne(s):

Use: antispasmodic, anticholinergic RN: 29546-59-6 MF: C22H3,BrN0 MW: 408.42 EINECS: 249-687-0

LD,,: 400 mglkg (M, p.0.);

1030 m g k g (R, p.0.)

CN: 2-(1 -bicyclo[2.2.1 Ihept-5-en-2-yl- 1 -phenylethoxy)-N,N-diethyl-N-methylethanaminium bromide

ocetophenone bicyclo[2.2.1]-

hept-5-en-2-yl- rnognesium chloride

chloride

H3C-Br

bromide

Ciclonium bromide I

Reference(s):

DE 1 052 982 (ASTA; appl 29.6.1957)

Fnrmulatior~(s): amp 10 mgl2 ml

Ciclopirox C 463

Trade Name(s):

D: Dolo-Adamon (ASTA)- Tranquo-Adamon (ASTA

Use: antifungal RN: 29342-05-0 MF: C,,H,,NO, MW: 207.27 EINECS: 249-577-2

CN: 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridinone

cidopirox olamine

RN: 41621-49-2 MF: C,,H,,N02 C2H7N0 MW: 268.36 EINECS: 255-464-9

LD,: 71 mgkg (M, i.v.); 1740 mglkg (M, p.0.);

72 mgkg (R, i.v.); 2350 mglkg (R, p.0.)

I

CH3

pyridine

'3'3

Ciclopirox

NH20H HCI, CH,COONo

hydroxylamine

CH3 hydrochloride

methyl 5-cyclohexyl-

3-methyl-5-0x0-2-

pentenoote (mixture

with the 3-pentenoote:

from methyl 4-methyl-

2-butenoate)

methyl 5-cyclohexyl- 3-methyl-5-hydroxyimino- 2-pentenoate (I)

' 3 3

Ciclopirox olarnine I

a US 3 883 545 (Hoechst AG; 13.5.1975; appl 16.1 1.1971; prior 22.12.1972)

US 3 972 888 (Hoechst AG; 3.8.1976; D-prior 25.3.1972)

b ZA 696 039 (Hoechst AG; appl 12.8.1969; D-prior 31.8.1968)

DE 1 795 270 (Hoechst AG; appl 31.8.1968)

DOS 2 214 608 (Hoechst AG; appl 25.3.1972)

Formulation(s): cream 1 5%; powder 1 % (as olamine); sol 10 mglml (as ciclopirox); vaginal cream 1 % (as

olamine)

Trade Name(s):

D: Batrafen (Hoechst; 198 1) Brumixol (Bruschettini) Micoxolamina (Delalande

F: Mycoster (Pierre Fabre; Miclast (Pierre Fabre Phar.) J: Batrafen (Hoechst)

I: Batrafen (Hoechst) Micomicen (Synthelabo) Roussel; 1983)

Ciclosporin

(Cyclosporin A)

ATC: L04AA01 Use: immunosuppressive RN: 59865-13-3 MF: C,,Hll,N,,O,, MW: 1202.64

hydroxy-N,4-dimethyl-~-2-amino-6-octenoyl-~-a-aminobutyryl-N-methylglycyl-N-methyl-~-leucyl-~-

valyl-N-methyl-L-leucyl)

Ciclosporin

Cyclic peptide from 11 amino acids Preparation by fermentation of Tolypoclndium injatum Gams with addition

of DL-a-aminobutyric acid lo the fermentation medium Isolation by homogenization of mycelium, extraction

with 90 % methanol and column chromatographic purification

Reference(s):

US 4 117 118 (Sandoz; 26.9.1978; priol 29.11.1974, 15.8.1975,9.9.1976; CH-prior 9.4.1976)

DE 2 455 859 (Sandoz; appl 26.1 1.1974; CH-prior 6.12.1973,21.10.1974)

Riiegger, A et at.: Helv Chim Acta (HCACAV) 59, 1075 (1976)

Kobel, H.; Traber, R.: Eur J Appl Microbial Biotechnol (EJABDD) 14, 237 (1982)

structure:

Petcher, T.J et al.: Helv Chim Acta (HCACAV) 59, 1480 (1976)

total syntheses:

Wenger, R.M.: Angew Chem (ANCEAD) 97, 88 (1985)

EP 34 567 (Sandoz; appl 13.2.1981; CH-prior 14.2.1980)

oral formulation:

US 5 766 629 (Sangstat Med Corp.; 16.6.1998; prior 25.8.1995, 21.3.1996)

Formulation(s): cps 25 mg, 50 mg, 100 mg; inj sol 250 mgf5 ml; oral sol 100 mglml; sol 100 mg

Trade Name(s):

D: Sandimmun (Novartis; F: Sandimmun (Novartis) Sandimmun (Novartis:

Cicloxilic acid C 465

1: Sandimmun (Sandoz) USA: Neoral (Novartis)

3: Sandimmun (Novartis; Sandimmune (Novartis;

Use: choleretic, hepatic protectant RN: 57808-63-6 MF: C,,H,,O, MW: 220.27 EINECS: 260-966-6

LD,: 2095 mgkg (M, p.0.);

1570 m g k g (R, p.0.)

CN: cis-2-hydroxy-2-phcnylcyclohexanecarboxy1ic acid

KMn04, No2C03

8 + HCHO 5 SOH

perrnonganote

cyclohexene aldehyde methyl)-1 -phenyl-

cyclohexonol

Rejerence(s):

BE 848 143 (Guidotti Int.; appl 9.12.1976; I-prior 12.1 1.1975)

alternative synthesis and use as choleretic:

U S 3 700 775 (L Turbanti; 24.10.1972; I-prior 29.4.1966)

stereochemistry:

Turbanti, L et al.: Arzneim.-Forsch (ARZNAD) 28 (II), 1449 (1978)

Fomulation(s): amp 60 mg; drg 40 mg

Trade Name(s):

I: Plecton (Guidotti) Pleiabil (Guidotti)-comb

Cicrotoic acid

(Acide cicrotoique)

Use: choleretic

RN: 25229-42-9 MF: CloH1,02 MW: 168.24 EINECS: 246-739-4

LD,: 1925 mglkg (M, p.0.);

2900 mglkg (R, p.o.1

CN: 3-cyclohexyl-2-butenoic acid

4 6 6 C Cidofovir

ethyl 3-cyclohexyl- I Cicrotoic acid I

2-butenoote (1)

Reference(s):

FR-M 4 665 (A E C Soc deChim Organ et Biol.; appl 3.5.1965)

Young et al.: J Org Chem (JOCEAH) 28,928 (1963)

Forrnulation(s): cps 250 mg

Trade Narne(s):

F: Accroibile (Adrian-

Marinier); wfm

Cidofovir

(HPMPC; GS-504; GS-0504)

ATC: J05AB12 Use: antiviral RN: 1 13852-37-2 MF: C,H14N30,P MW: 279.19

CN: (S)-[[2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-l-(hydroxymethyl)ethoxy]methyl]phosphonic acid

dihydrate

RN: 149394-66-1 MF: C8H,4N306P 2H20 MW: 315.22

CsCO,, OMF, 100 O C

A _,

0 N

\OH

(2.3-dihydroxypropyi)-

1 (C2H50)3P-0

2 aq NaOH

1 triethyl phosphate

CI

2 oqueaus alkali metal hydroxide chloromethyl- 3 mineral acid Cidofavir

phosphonic

dichloride

EP 253 412 (Ceskoslovenska Akademie Ved., Czech., appl 20.1.1988; CS-prior 18.7.1986)

WO 9 624 355 (Astra; appl 15.8.1996; WO-prior 6.2.1995)

WO 9 713 528 (Dumex-Alpharma; appl 17.4.1997; prior 12.10.1995)

svnthesis of (2s)-4-amino- 1 -(2,3-dihydroxypropy1)- 1 H-pyrimidin-Zone:

Holy, A,: Collect Czech Chem Commun (CCCCAK) 58 (3), 649 (1993)

Holy, A,: Collect Czech Chem Commun (CCCCAK) 43, 2054 (1978)

Martin, J.C et al.: Nucleosides Nucleotides (NUNUD5) 8 (5-6), 923 (1989)

Cilastatin C 467

b

Trade Name(s):

D: VISTIDE (Pharmacia & USA: Vistlde (Gilead Science)

Up~ohn)

Use: dehydropeptidase inhibitor (for combination with imipenem) RN: 82009-34-5 MF: C16Hz6Nz05S MW: 358.46 EINECS: 279-875-8

LDso: 8 glkg (M, route unreported);

8 g k g (R, route unreported)

CN: [R-[R*,S*-(2)]]-7-[(2-amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyc1opropyl)carbonyl]amino]-2-

heptenoic acid

monosodium saIt

RN: 81129-83-1 MF: C16H,,N2Na0,S MW: 380.44 EINECS: 279-694-4

LD,,: 6786 mgkg (M, i.v.); >I 0 glkg (M, p.0.);

5027 mgkg (R, i.v.); > I 0 glkg (R, p.0.)

carboxylote

0 0-CH,

ethyl 7-bromo-2- oxoheptanoote

11 + HzN &W3 0 C H 3 d toluene Br>fi:~3

7-bromo-2-0x0- heptonoic acid (11)

NoOH

C O O H

L-cysteine

C O O H Cilastotin

468 C Cilazapril

Rcference(s):

EP 10 573 (Merk & Co.: appl 24.7.1979; USA-prior 24.7.1978)

EP 48 301 (Merck & Co.; appl 24.9.1980)

Formulation(s): amp 250 mg, 500 mg, 750 mg (as sodium salt)

Trade Name(s):

D: Zienam (MSD; 1985)- I: Imipem (Neopharmed) Tienam (MSD)-comb

F: Tienam (Merck Sharp & Tenacid (Sigma-Tau)- comb

Use: antihypertensive (ACE inhibitor) RN: 88768-40-5 MF: C22H,,N,0, MW: 417.51

CN: [1S-[la,9a(K*)]]-9-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-l0-oxo-6H-pyridazino[1,2

a][l,2]diazepine- 1-carboxylic acid

monohydrate

RN: 92077-78-6 MF: C22H,,N,0s H 2 0 MW: 435.52

0

L-glutornote anhydride

(1) tert-butyl 1 -(benzyl-

axycorbony1)-hexo- hydro-3-pyridazine- corboxylate

1 Hz Pd-C

2 recrystollizotion f r o m 0 0

0 \tBu PCIv

n - III

COOH

0 0

PhthN; 0 ' t ~ u

BH, THF

tart-butyl octohydro-

6,lO-dioxa-9(S)-phthol-

imido-6H-pyridazo[l.2-01-

[I ,Z]diozepine- 1 (S)-

carboxylote (111)

1 NoBH,

2 recrystollizotion

3 CF3COOH or HBr/CH,COOH

+

tart-butyl 9(S)-ornino-

actahydro-10-axo-6H-pyri-

dozo[l,2-o][l ,2]diazepine-

l(S)-corboxylote (N)

I Cilozopril

Reference(s):

US 4 512 924 (Hoffmann-La Roche; 23.4.1985; GB-prior 12.5.1982, 28.2.1983)

US 4 658 024 (Hoffmann-La Roche; 14.4.1987; GB-prior 12.5.1982)

Attwood, M.R et al.: FEBS Lett (FEBLAL) 165, 201 (1984)

let?-butyl l-(benzyloxycarbonyl)-hexahydro-3-pyridazinecarboxylate:

Hassall, C.H et al.: J Chem Soc., Perkin Trans 1 (JCPRB4), 1451 (1979)

Formulation(s): f c tabl 0.5 mg, 1 mg, 2.5 mg, 5 mg

Trade Narnefs):

D: Dynorm (MercWRoche) GB: Vascace (Roche)

F: Justor (Jacques Logeais) 1: Inibace (Roche)

Initiss (Carlo Erba)

Cilnidipine

(FRC-8653)

Use: antihypertensive, calcium antagonist

RN: 132203-70-4 MF: C27H28N207 MW: 492.53

LD,< >5 g/kg (M, ~'0.1;

4412 mgkg (R, p.0.);

>2 glkg (dog, p.0.)

CN: (E)-(?)-I ,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-methoxyethyl 3- phenyl-2-propen yl ester

unspecified stereochemistry

RN: 102106-21-8 MF: Cz7Hz,Nz07 MW: 492.53

(+)-enantiomer

RN: 132338-87-5 MF: C27H,RN,07 MW: 492.53

(-)-enantiomer

RN: 132295-21-7 MF: C,,H,,N,O, MW: 492.53

Reference(s):

EP 16 1 877 (Fujirebio; appl 2.5.1985; J-prior 4.5.1984, 20.6.1984)

Drugs Future (DRFUD4) 21(3), 249-253 (1996)

2-methoxyethyl cinnamyl 2-(3-

Formulation(s): tabl 5 mg, 10 mg

Cilnidipine

Trade Narnefs):

3-aminocrotonate nitrobenzy1idene)-

ocetoocetote

J: Atelec (AjinomotolNippon- Cinalong (Fujirebio)

HMR)

Ciscard (Nippon Boehringer Inp.)

Cilostazol

(OPC- 1301 3)

ATC: BOlAC Use: platelet aggregation inhibitor, cerebral vasodilating activity RN: 73963-72- 1 MF: C2,,HZ7N,O2 MW: 369.47

LD,,,: 25 glkg (M, p.0.);

>5 g/kg (R, p.0.);

>2 g/kg (dog, p.0.)

cyclohexyl- 5-chloropento-

H

HO

bicyclo- [5.4.0]undec-

1 -cyclohexyl-5-(4- 6-hydroxy-3,4- 5-ene Cilostozol

chlorobutyl)tetrozole (1) dihydrocarbo-

styril (cf corteolol