Pharmaceutical Substances Syntheses, Patents, Applications - Part 130 docx

Merck AG; appl... rocemote resolution with -- 1 -phenylethylomine 1 Methyldopo selective crystallization of the hydrogen sulfites 1.. rocemote resolution with --10-comphonulfonic

Methoxyflurane M 1291

Use: inhalation anesthetic

LD,,: 150 mglkg (M, i.v.);

3600 m g k g (R, p.0.)

CN: 2.2-dichloro-1, l -difluoro-1-methoxyethane

F KOH CI F H3C-OH KOH

1.1-difluoro- 1 , l -dichloro-

2,Z.Z-trichloro- 2,2-difluoro-

I Methoxyflurane

Reference(s):

GB 928 786 (Dow; appl 9.2.1960; USA-prior 3.4.1959, 20.7.1959)

Formulation(s): sol 125 mg1125 ml

Trade Narne(s):

Methscopolamine bromide

(Hyoscine methobromide)

Use: parasympatholytic, antispasmodic

LD,,: 26.806 m g k g (M, i.v.); 619 mg/kg (M, p.0.);

42.5 mglkg (R, i.v.); 3400 mg/kg (R, p.0.)

CN: [7(S)-(la,2~,4~,5a,7P)1-7-(3-hydroxy-l-oxo-2-phenylpropoxy)-9,9-dimethyl-3-oxa-9-

azoniatricyclo[3.3.1 02.4]nonane bromide

nitrate

methylsulfate

RN: 18067-13-5 MF: C1,H2,N04 , CH3S04 MW: 429.49 EINECS: 241-975-4

scopolamine bromide Methscopolamine bromide

(4 v.1

1292 M Methyclothiazide

H

rnethscopolarnine nitrate

Reference(s):

DE 145 996 (E Merck AG; appl 1902)

US 2 753 288 (Upjohn; 1956; prior 1952)

Formulation(s): cps 2.5 mg; syrup 1.25 mg/5 ml; tabl 1.25 mg

Trade Name(s):

Use: diuretic

LD,,,: 400 m g k g (M, i.v.); 210 glkg (M, p.0.);

>4 glkg (R, p.0.)

CN: 6-chloro-3-(chloromethyl)-3,4-dihydro-2-methyl-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,l-dioxide

5-chloro-2.4-di- urea 7-sulfomoyl-6-chloro-3-

benzothiodiazine 1 , l -dioxide

chloro-

H

aldehyde

Methyclothiazide

Reference (s):

Close, W.J et al.: J Am Chem Soc (JACSAT) 82, 1132 (1960)

Formulation(s): tabl 2.5 mg, 5 mg

Trade Name(s):

Methyldopa M 1293

Use: antihypertensive

CN: 3-hydroxy-a-methyl-L-tyrosine

+ ( N H 4 ) 2 C 0 3 +

H3C-0 / N K N H

pheny1)ocetone (I) cyanide corbonote rnethoxybenzy1)hydantoin (U)

1 N-acetylotion

2 rocemote resolution with

(-)- 1 -phenylethylomine

1 Methyldopo

selective crystallization

of the hydrogen sulfites

1 rocemote resolution with (-)-10-comphonulfonic

(4-hydroxy-3-meth-

oxypheny1)acetone (IV)

DL-a-amino-a- vonillylpropionitrile

1294 M Methyldopa

@ Starting products:

hornoveratronitrile

isoeugenol

US 2 868 818 (Mcrck & Co.; 13.1.1959; prior 15.12.1953)

GB 936 074 (Merck & Co.; appl 18.10.1960; USA-prior 8.4.1960,24.8.1960)

DE 1 171 931 (Merck & Co.; prior 6.10.1960)

Tristram E.W et al.: J Org Chem (JOCEAH) 29,2053 (1964)

Stein, G.A et al.: J Am Chem Soc (JACSAT) 77,700 (1955)

Chem Eng from 8.1 1.1965; p 247

US 3 158 648 (Merck & Co.; 24.1 1.1964; prior 11.7.1961,9.4.1962)

Reinhold, D.F et al.: J Org Chem (JOCEAH) 33, 1209 (1968)

FR 1 492 765 (Merck & Co.; appl 10.10.1963; USA-prior 11.10.1962, 19.9.1963)

similar method via L-a-acetylamina-a-vanillylpropionitrile:

GB 1 142 595 (Merck & Co.; appl 23.5.1967, 12.2.1969)

alternative syntheses:

US 3 366 679 (Merck & Co.; 30.1.1968; prior 11.10.1962, 19.9.1963)

DOS 2 302 937 (Tanabe; appl 22.1.1973; J-prior 22.1.1972)

US 3 517 057 (Merck & Co.; 23.6.1970; appl 21.9.1967)

DE 1 235 946 (Boehringer Mannh.; appl 8.8.1964)

DE 1 235 947 (Bayer; appl 16.1.1963)

DE 1 258 416 (Knoll; appl 9.10.1964)

DE 1 269 622 (Knoll; appl 22.12.1966) -

DOS 2 406 898 (BASF; appl 14.2.1974)

AT 250 936 (Egyesiilt; appl 3.11.1964; HU-prior 18.11.1963)

FR 1 502 972 (Merck & Co.; appl 21.10.1966; USA-prior 22.10.1965)

FR 1 531 877 (Sankyo; appl 18.7.1967; J-prior 11.8.1966, 21.2.1967)

GB 1 321 802 (D.D.S.A.; appl 5.2.1971)

Da Steinetal, G.A.: J Am ~ h e k Soc (JACSAT) 77, 700 (1955)

Db GB 2 059 955 (Merck & Co.; appl 9.9.1980; USA-prior 13.9.1979, 28.9.1979)

medical use:

US 3 344 023 (Merck & Co.; 12.4.1983; prior 8.4.1960,24.8.1960, 1.2.1963; reexamination requcst 21.12.1981)

Formulation(s): drg 250 mg, 500 mg; f c tabl 125 mg, 250 mg, 500 mg; tabl 250 mg, 500 mg

Trade Name(s):

Methyldopate M 1295

[Jse: antihypertensive RN: 2544-09-4 MF: C,,H,,NO, MW: 239.27 EINECS: 219-821 -2

CN: 3-hydroxy-a-methyl-L-tyrosine ethyl ester

hydrochIoride

rnethyldopa

(9 v.)

I Methyldopate

Reference(s):

US 2 868 818 (Merck & Co.; 13.1.1959; prior 15.12.1953)

medical use (for injection):

US 3 230 143 (Merck & Co.; 18.1.1966; appl 22.6.1961, 28.12.1962, 14.5.1965)

FR-M 2 153 (Merck & Co.; appl 20.9.1962; USA-prior 22.6.1961)

Formulatiot~(s): amp 250 mglml, 500 mglml; f c tabl 125 mg, 250 mg, 500 mg

Trade Natne(s):

Aldomet Ester HC 1 Inj (Merck Sharp & Dohme)

Methylergometrine

(Methy lergonovine)

Use: uterotonic, oxytocic

LD,,,: 85 m g k g (M, i.v.); 187 mglkg (M, p.0.);

23 m g k g (R, i.v.); 93 m g k g (R, p.0.)

CN: [8~(S)]-9,10-didehydro-N-[l-(hydroxymethyl)propyl]-6-methylergoline-8-carboxamide

maleate (1:l)

RN: 57432-61-8 MF: C2,H2,N302 C4H404 MW: 455.51 EINECS: 260-734-4

LD,,,: 85 m g k g (M, i.v.); 187 mgkg (M, p.0.);

23 m g k g (R, i.v.); 93 mglkg (R, p.0.)

tartrate (2:l)

1296 M Methylestrenolone

HO N3

D-lysergozide (+)-2-omino-

1 -buton01 (I)

KOH (isomerizotion)

Methylergometrine

Reference(s):

US 2 265 207 (Sandoz; 1941; CH-prior 1939)

Fonnulation(s): amp 0.2 mglml; drg 0.125 mg; drops 0.25 mglml; sol 0.24 mg1100 ml; tabl 0.125 mg (as

maleate)

Trade Name(s):

Met hylestrenolone

(Normethandrone; Normethandrolone)

Use: progestogen

CN: (l7P)- 17-hydroxy-l7-methylestr-4-en-3-one

CrO, CH,COOH chromium(L4)

nandrolone

Methylmethionine sulfonium chloride M 1297

I Methylestrenolone I

1 H3C-MgBr

bromide

w

lithium

0

ammonia

3-0.1 7a-dimethyl-

estrodiol

1 Li NH3

2 Cm3 CH3COOH , r contd os under

1 lithium, ammonia

2 chromium(VI) oxide

estrone 3-methyl

ether

a,b Djerassi, C et al.: J Am Chem Soc (JACSAT) 76,4092 (1954)

c US 2 744 122 (Syntex; 1956; MEX-prior 1951)

US 2 774 777 (S yntex; 1956; prior 1952)

Djerassi, C et al.: J Am Chem Soc (JACSAT) 76,4092 (1954)

alternative synthesis:

US 2 849 461 (P de Ruggieri; 1958; appl 1957)

Trade Name(s):

LD,,: 259 m g k g (M, i.v.); >6 g/kg (M, p.0.);

432 mglkg (R, i.v.); >6 glkg (R, p.0.)

CN: (S)-(3-amino-3-carboxypropyl)dimethylsulfonium chloride

bromide

iodide

1298 M Methylpentynol

H C NH2

' \~'-"%ooH

CH3

Referencefs):

DE 1 239 697 (Degussa; appl 20.2.1963)

therapy of renal diseases:

US 4 122 189 (Kaken; 24.10.1978; J-prior 3 1.3.1976)

GB 1 538 000 (Kaken; appl 30.3.1977; J-prior 31.3.1976)

DOS 2 714 391 (Kaken; appl 3 1.3.1977; J-prior 31.3.1976),

hyperlipidernic effect:

Seri, K et al.: Arzneim.-Forsch (ARZNAD) 28, 171 1 (1978)

Formulation(s): drg 12.5 mg; sol 0.4 gI100 g

Trade Narne(s):

LD,,,: 525 mglkg (M, p.0.)

CN: 3-methyl- 1 -pentyn-3-01

NO5CM 15 sedative

Reference(s):

DRP 285 770 (Bayer; 1913)

DRP 289 800 (Bayer; 1913)

DRP 291 1 85 (Bayer; 1914)

No or NoNHZ liq NH,

H C E C H + OwCH3

H3C

Forrnulafion(s): cps 250 mg

OH CH3

H C F C ~ / CH3 Methylpentynol

Trade Narne(s):

Oblivon (British Schering); wfrn

USA: Dormison (Schering); wfrn

Methylphenidate M 1299

Use: psychotonic RN: 1 1 3 - 6 1 MF: CI4HlyNO2 MW: 233.31 EINECS: 204-028-6

LD,,: 41 m g k g (M, i.v.); 150 mg/kg (M, p.0.);

48 m g k g (R, i.v.); 367 mg/kg (R, p.0.)

CN: a-phenyl-2-piperidineacetic acid methyl ester

hydrochloride

LD,,: 40 m g k g (M, i.v.); 60 mg/kg(M, p.0.);

50 m g k g (R, i.v.); 350 mg/kg (R, p.0.)

benzyl 2-chloro- phenyl-

cyanide pyridine (2-pyridyl)-

acetonitrile

methyl phenyl- (2-pyridiy1)- ocetote (1)

HP P t

1 -+

Reference(s):

US 2 507 631 (Ciba; 1950; CH-prior 1944)

& 0, CH3

Methylphenidate

separation of diastereomers:

US 2 957 880 (Ciba; 1960; CH-prior 1953)

Panizzon, L.: Helv Chim Acta (HCACAV) 27, 1748 (1948)

Formulation(s): amp 20 mg; tabl 5 mg, 10 mg, 20 mg (as hydrochloride)

Trade Name(s):

Methylphenobarbital

(Mephobarbital; Methylphenobarbitone)

Use: anticonvulsant, sedative

LD,,: 300 mglkg (M, p.0.)

CN: 5-ethyl-1 -methyl-5-phenyl-2,4,6(1 H,3H,5H)-pyrimidinetrione

1300 M Methylprednisolone

NoOC,H,

diethyl axalate

-

CH3

diethyl 3-0x0-

diethyl ethyl-

phenylmolonote (11)

diethyl phenyl- rnolonote

rnethylureo

DRP 537 366 (I G Farben; 1929)

DRP 590 175 (I G Farben; 1932)

Formulation(s): tabl 30 mg, 60 mg, 200 mg

Trade Narne(s):

NoOC2H5

ethyl bromide

Methylphenobarbital

USA: Mebaral (Sanofi)

Use: glucocorticoid

LD,,: >4 glkg (R, p.0.)

CN: (6a,11 @-I 1,17,21-trihydroxy-6-methylpregna-1,4-diene-3,20-dione

acetate

LD,,,: >10 g/kg (R, P.o.)

succinate

succinate sodium salt

LD,,,: 750 mg/kg (M, i.v.); >5 g/kg (M, p.0.);

640 mglkg (R, i.v.); >5 glkg (R, p.0.)