CH632243A5 - Process for preparing N2-substituted L-arginine amides - Google Patents

Abstract

N<2>-substituted L-arginine amides of the formula I, in which the symbols have the meaning given in the claim, and their salts with acids, are highly specific thrombin inhibitors. They are suitable for the treatment or prophylaxis of thrombphilic diatheses. The compounds of the formula I are prepared by acidolysing or hydrogenolysing an amide of the formula IX and, where appropriate, converting the resulting compound into a salt using an acid. <IMAGE>

Description

632243

O

PATENT CLAIM

Process for the preparation of N2-substituted L-argininamides of the general formula I.

HN

\ H

, C - N - (CH2) 3 - CHCOR / I

H, N HN-S02

(I)

R '

in which R is a group of the general formula

-R2

means

10 and their salts with acids, characterized in that an NG-substituted N2-substituted L-argininamide of the general formula IX

HN

-n

/ \

r,

in which R2 and R3 are hydrogen atoms, Cj. ^ - alkyl radicals, C7_i5-aralkyl radicals, C [.i0-alkyl radicals which are substituted by a Ci_10-alkoxy radical, a C2.io-alkoxycarbonyl radical or a carboxyl group, or a group of the general formula

—N ~ ^ Z,

means in which Z is a divalent radical from (a) at least two methylene groups or (b) monosubstituted methylene groups of the general formula

R *

HN

I.

y

% /

c- n - (ch2) 3 - chcor

Y '

hn-s02

I.

R '

(IX)

h represents, in which R4 represents a C 1-4 alkyl or C 1-4 alkoxy radical, and Z optionally also at least (c) an oxy group, (d) thio group, (e) alkyl-substituted imino group of the general formula

Î '

—N—

in which Rs represents a C 1-4 alkyl radical, or (f) an acyl-substituted imino group of the general formula o = c-r6

-N-

contains, in which R6 is a C |. | 0-alkyl radical, the groups (a) to (f) mentioned being in any arrangement and the

Group —N Z contains up to 21 ring members, and R 'is a group of the general formula

OR "

OR '»

means in which R "and R '" each represent C10-10 alkyl radicals or R "and R'" together represent a C ^ Q alkylene radical, or R 'is a group of the general formula

€ 0 £ 0

-00

in which R '"represents a C | _] 0-alkoxy radical, a group of the general formula

20 in which R and R 'have the meaning given and Y and Y' represent hydrogen atoms or nitro groups, but at least one of the radicals Y and Y 'is a nitro group which is subjected to acidolysis or hydrolysis and, if appropriate, the compound obtained with an acid in a salt transferred.

30 There have been numerous attempts to develop drugs to treat thrombosis. From US-PS No. 3622615 N2- (p-tolylsulfonyl) -L-arginine esters are known which are suitable for the treatment of thrombophilic diathesis. Finally, DT-OS No. 24438851 proposes N2-dansyl-L-arginine-35 esters and amides which are thrombin inhibitors and are suitable for the therapy or prophylaxis of thromboses.

The invention has for its object to provide new N2-substituted L-argininamides of the general formula I below, which are highly specific thrombin inhibitors and are suitable for the treatment or prophylaxis of thrombophilic diathesis. This object is achieved by the invention.

The invention thus relates to the object characterized in the claim.

In the compounds of general formula I

45 HN

\ H

; c-n- (ch2) 3-chcor / [(I)

h2n hn-so2

R '

R means either

(a) a radical of the general formula - N

R2

/ \

or r,

(b) a radical of the general formula - N Z.

R2 and R3 denote hydrogen atoms, unbranched or verso branched C ^ Q-alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl or heptyl group, C7.15- Aralkyl radicals, such as the benzyl, phenethyl or 3-phenylpropyl group, C | .10-alkyl radicals which are substituted by a C 1-4 alkoxy radical, a C2.10 alkoxycarbonyl radical or a carboxyl group, such as the 2-methoxyethyl -, 3-methoxypropyl, 2-ethoxyethyl, ethoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl, carboxymethyl or 2-carboxyethyl group.

632 243

Z represents a divalent radical from (a) at least two methylene groups or (b) monosubstituted methylene groups of the general formula

Î '

-C-

I.

H

in which R4 denotes a C | _ | 0-alkyl or C [_I0-alkoxy radical, and Z optionally also (c) at least one oxy group (—O—), (d) thio group (- S—), (e) alkyl-substituted Imino group of the general formula

? "

-N-

in which R5 represents a C 1-4 alkyl radical, or (f) an acyl-substituted imino group of the general formula o = c-r6

- N—

contains, in which R6 is a Ci_10-alkyl radical, said groups (a) to (f) being in any arrangement and the

Group - N Z contains up to 21 ring members.

Specific examples of the radical R are the 1-polymethyleneiminyl group or its derivatives, such as the 1-aziridinyl, 1-azetidinyl, 3-methoxy-l-azetidinyl, 3-ethoxy-l-azetidinyl, 1-pyrrolidinyl -, Piperidino, 4-methylpiperidino, 4-ethylpiperidino, 4-propylpiperidino, 4-isopropylpiperidino, 2-methylpiperidino, 3-methylpiperidino, 4-methoxypiperidino, 1-hexamethyleneiminyl and 1 Octamethyleneiminyl group, oxazole or thiazole groups, such as the 3-oxazolidinyl and 3-thiazolidinyl group, isoxazole or isothiazole groups, such as the 2-isoxazolidinyl and 2-isothiazolidinyl group, an oxazine group such as the morpholino, 2.6 -Dimethylmor-pholino or tetrahydro-l, 3-oxazin-3-yl group, a thiazine group, such as the tetrahydro-l, 4-thiazin-4-yl group, a methyl-1-piperazinyl or 4-acetyl-l -piperazinyl group.

The preferred radicals R are as follows:

R,

(1) If R is a group of the general formula —N

/ \

Tetrahydro-l, 4-thiazin-4-yl, 4-methyl-l-piperazinyl and 4-acetyl-1-piperazinyl group.

R 'can mean the following radicals:

(a) A substituted naphthyl radical of the general formula

■ OR "

i "in which R" and R '"individually denote a CM0, preferably a CU5 alkyl radical, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl group, or R" and R '"together represent a C] .10-, preferably a C | _5-alkylene radical, such as the methylene, ethylene or trimethylene group. The lì alkoxy - (- OR" and - OR "') - or the alkylenedioxy -

(—OR "—R '" 0 -) - group and the sulfonyl group can be in any one of the 1- to 8-positions of the naphthalene nucleus. In general, the sulfonyl group is in the 1- or 2-position and the alkylene-dioxy group in the 6,7-position.

(b) A chromanyl group

"CQ -00

(c) a 1,4-benzodioxanyl group

30 (d) a 2H-3,4-dihydro-1,5-benzodioxepinyl group

(e) Derivatives of (d) with a substituent in the 3-position of the 35 formula

in which R '"represents a C.sub.1-, preferably a C1.5-alkoxy radical

(f) a dibenzofuranyl group

0 '

means Q.g-alkylamino, C2.6-o) -alkoxyalkylamino, C3_8-to-alkoxycarbonylalkylamino, C7.10-aralkylamino or C2_10-di-alkylamino residues.

(2) If R is a group of the general formula - N Z

means C3_io-N, N-polymethyleneiminyl residues, which are optionally substituted by a Qj-alkyl or C1.5-alkoxy residue, tetrahydro-1, n-oxazine, n-yl residues, where n is 2, 3 or 4 has, tetrahydro-1, n-thiazin-n-yl radicals, where n is 2,3 or 4, or 1-piperazinyl radicals, which are replaced by a C 1-6 alkyl or C] .5-acyl radical are substituted.

Particularly preferred radicals R are the following:

45 (g) a xanthenyl group

50 (h) a dibenzo-p-dioxinyl group

or

R2

(1) If R is a group of the general formula —N

/ \

The following groups are specific examples of the radicals R ':

t

0CHo

W,

OCH,

OCH,

means the butylamino, 2-methoxycarbonylethylamino, 2-ethoxycarbonylethylamino, benzylamino and N-methyl-N-butylamino group.

(2) If R is a group of the general formula - N Z

means the piperidino, hexamethyleneiminyl, 4-methylpiperidino, 4-ethylpiperidino, 4-methoxypiperidino, morpholino,

0X! "'

° C2H5

CO '€ O-0>

632243

4th

(1) Amides (R = - ^

R-3

N2- (6,7-dimethoxy-2-naphthalenesulfonyl) -N- (2-methoxyethyl) -L-argininamide,

N2- (6,7-dimethoxy-2-naphthalenesulfonyl) -N-benzyl-L-arginine amide and

N2- (2-xanthene sulfonyl) -N-methyl-N-butyl-L-argininamide.

(2) amides (R = - N Z)

4-methyl-l- [N2- (6,7-dimethoxy-2-naphthalenesulfonyl) -L-arginyl] piperidine,

4-ethyl-1 - [N2- (6,7-dimethoxy-2-naphthalenesulfonyl) -L-arginyl] piperidine,

l- [N2- (6,7-dimethoxy-2-naphthalenesulfonyl) -L-arginyl] hexamethyleneimine,

4- [N2- (6,7-dimethoxy-2-naphthalenesulfonyl) -L-arginyl] morpholine,

4-methoxy-l- [N2- (6,7-dimethoxy-2-naphthalenesulfonyl) -L-arginylj-piperidine,

4-methyl-l- [N2- (4,6-dimethoxy-2-naphthalenesulfonyl) -L-arginylpiperidine,

4-ethyl-l- [N2- (4,6-dimethoxy-2-naphthalenesulfonyl) -L-f arginyl] piperidine,

4-ethyl-l- [N2- (2H-3,4-dihydro-l, 5-benzodioxepin-7-sulfonyl) -L-arginyl] piperidine, 5 4-methyl-l- [N2- (2H-3, 4-dihydro-1,5-benzodioxepin-7-sulfonyl) -t L-arginyl] piperidine,

4-ethyl-1 - [N2- (3-methoxy- (2H-3,4-dihydro-1,5-benzodioxepin) -7-sulfonyl) -L-arginyl] piperidine,

4-ethyl-l- [N2- (2-xanthensulfonyl) -L-arginyl] piperidine, io 4-ethyl-l- [N2- (2-dibenzofuran sulfonyl) -L-arginyl] piperidine, 4-ethyl-1 - [ N2- (4-dibenzofuran sulfonyl) -L-arginyl] piperidine, 4-ethyl-l- [N2- (dibenzo-p-dioxin-2-sulfonyl) -L-arginyl] piperidine and l- [N2- (4- Dibenzofuran sulfonyl) -L-arginyl] hexamethyleneimine. 45 The following compounds are particularly preferred due to their high antithrombin activity:

N2- (6,7-dimethoxy-2-naphthalenesulfonyl) -N- (2-methoxyethyl) -L-argininamide,

4-methyl-l- [N2- (6,7-dimethoxy-2-naphthalenesulfonyl) -L-20 arginyl] piperidine,

4-ethyl-l- [N2- (6,7-dimethoxy-2-naphthalenesulfonyl) -L-arginyl] piperidine,

4-methoxy-l- [N2- (6,7-dimethoxy-2-naphthalenesulfonyl) -L-arginylpiperidine, 25 4-methyl-1- [N2- (4,6-dimethoxy-2-naphthalenesulfonyl) -L-arginyl ] piperidine,

4-ethyl-l- [N2- (4,6-dimethoxy-2-naphthalenesulfonyl) -L-arginyljpiperidine,

4-ethyl-1 - [N2- (2-xanthensulfonyl) -L-arginyl] piperidine, 30 4-ethyl-1 - [N2- (4-dibenzofuran sulfonyl) -L-arginyl] piperidine and 4-ethyl-l- [ N2- (dibenzo-p-dioxin-2-sulfonyl) -L-arginyl] piperidine. Various processes can be used to prepare the compounds of the general formula I, which depend on the starting compounds and / or intermediates.

The cleavage of the NG substituents from an NG-substituted N2-substituted L-argininamide can be explained by the following reaction scheme:

hn

«

./ "I

v rh (iii) ^ c - n - (ch2) 3 - chcooh (vi)

hn y 'hn

I L

y y hn hn

^ c - n - (ch2) 3 - chcor (vii) ► ^ c - n - (ch2) 3 - chcor (viii)

hn y 'hn hn y' nh2

I I I

y y "y hn rs02x (iv) - ^ -n - (ch2) 3 - chcor (ix)

HN y 'hn-s02

1 R '

y r hn

\ H

^ c-n- (ch2) 3-chcor (i)

h2n hn-so2

r '

5

632 243

R represents a group of the general formula - N

^ n r3

or -N Z,

where R2, R3, Z, R 'and X have the above meaning, Y "represents an amino protecting group, such as the benzyloxycarbonyl or tert-butoxycarbonyl group, and Y and Y' represent hydrogen atoms or nitro groups. At least one of the substituents Y and Y ' is a nitro group.

The nitro group (NG substituent) is split off by acidolysis or hydrogenolysis. Acidolysis is generally carried out with an excess of an acid, such as hydrogen fluoride, hydrogen chloride or hydrogen bromide or trifluoroacetic acid, and optionally in a solvent, for example an ether, such as tetrahydrofuran or dioxane, an alcohol, such as methanol or ethanol, or acetic acid, at temperatures of - 10 to 100 ° C, preferably at room temperature, and for a period of 10 minutes to 24 hours. The products are isolated by evaporating the solvent and the excess acid or by digesting with a solvent and then filtering off the product which has crystallized out and drying. Since the acid is used in excess for acidolysis, the products are generally obtained as salts of the N2-substituted L-argininamides of the general formula I, which can be converted into the free amides by neutralization.

The hydrogenolysis is generally carried out in an inert solvent, such as methanol, ethanol, tetrahydrofuran or dioxane, and in the presence of a hydrogenation catalyst, such as Raney nickel, palladium or platinum, in a hydrogen atmosphere at temperatures from 0 ° C. to the boiling point of the solvent used during a Period of 2 to 120 hours. The hydrogenation can be carried out at normal pressure. When the hydrogenation has ended, the catalyst is filtered off and the solution is evaporated. The N2-substituted L-arginine amides obtained can be purified by the methods described above.

The NG-substituted N2-substituted L-argininamides of the general formula IX used in accordance with the process can be obtained by condensation of an NG-substituted N2-substituted L-arginine of the general formula VI (in general the N2 substituent is an amino protective group such as the benzyloxycarbonyl or tert-butoxycarbonyl group) with the corresponding amine of the general formula III by the azide, mixed anhydride, activated ester or carbodiimide method, selective elimination of the N2 substituent from the compound of the general formula VII by catalytic hydrogenation or Acidolysis and subsequent condensation of the compound of general formula VIII obtained with a sulfonyl halide of general formula IV, preferably a chloride, in the presence of a base and in a solvent. These reaction conditions are the same as those described above for the condensation of an L-arginine amide with a sulfonyl halide and the cleavage of the NG substituent from an NG-substituted N2-substituted L-arginine amide.

The compounds of general formula I form salts with a wide variety of inorganic and organic acids. The products of the reactions described above can be isolated in the form of the free base or as a salt with an acid. To prepare pharmacologically acceptable salts, the free bases can be mixed with an inorganic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid, or with an organic acid, such as acetic acid, citric acid, maleic acid, succinic acid, lactic acid, tartaric acid, gluconic acid. acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. Treatment of the salts with a base provides the free amides or esters.

The compounds of general formula I and their salts with acids are valuable drugs that specifically inhibit thrombin. The compounds can therefore be used for the determination of thrombin in the blood and for the treatment or prevention of thrombophilic diathesis.

The thrombin inhibition of the compounds of the invention is compared with the effectiveness of the thrombin inhibitor N2- (p-toluenesulfonyl) -L-arginine methyl ester known from US Pat. No. 3,622,615 by determining the fibrinogen coagulation time.

The measurement was carried out as follows: A fibrinogen solution is prepared by dissolving 150 mg bovine fibrinogen (Cohn fraction I) in 40 ml of a borate-sodium chloride buffer (pH 7.4). To prepare a blank sample, 0.8 ml of this fibrinogen solution is mixed with 0.1 ml of a borate-sodium chloride buffer (pH 7.4). A further 0.8 ml of the original fibrinogen solution is mixed with 0.1 ml of a sample solution in the same buffer. Finally, each of these two solutions is mixed in an ice bath with 0.1 ml of a thrombin solution (5 units per ml). After the addition, the reaction mixtures are immediately removed from the ice bath and placed in a bath thermostatted at 25 ° C. The coagulation time is the time that elapses between the introduction into the bath heated to 25 ° C and the time of the first appearance of fibrin threads. In cases where no sample was added, the coagulation time is 50 to 55 s.

The results are summarized in Table I below. The expression “concentration required to double the coagulation time” means the concentration of the active ingredient required to double the normal coagulation time from 50 to 55 s to 100 to 110 s. The concentration required to double the coagulation time when using N2- (p-tolylsulfonyl) -L-arginine methyl ester is 1100 µmol.

The inhibitors of the general formula I given in Table I are characterized by the radicals R and R '. The acid used for salt formation is also given. When a solution of the compounds of the general formula I is administered intravenously to animals, the thrombin inhibition remains in the bloodstream for 1 to 3 hours. The half-life of the compounds in the bloodstream is about 30 minutes. The physiological conditions of the experimental animals (rats, rabbits, dogs and chimpanzees) are well maintained. The experimental decrease in fibrinogen in animals caused by thrombin infusion is successfully controlled by the simultaneous infusion of the compounds of the invention.

The acute toxicity (LD50) is determined 24 hours after oral administration of the compounds of the general formula I to male mice with a body weight of 20 g. It is about 1000 to 10,000 mg / kg body weight.

The compounds of the invention can be administered parenterally in the form of conventional pharmaceutical preparations, i.e. administered intramuscularly, intravenously or subcutaneously, or orally. In addition to the active ingredient, the medicinal preparations contain customary carriers and / or diluents and / or auxiliaries.

The examples illustrate the invention.

Example 1:

1.0 g (0.0018 mol) of 4-ethyl-l- [NG-nitro-N2- (6,7-dimethoxy-2-naphthalenesulfonyl) -L-arginyl] piperidine in 5.7 g (0.0053 mol ) Anisole is mixed with 3 ml of hydrogen fluoride while cooling in a dry ice acetone bath. The mixture is then stirred in an ice bath for 30 minutes. The anisole and excess hydrogen fluoride are then distilled off under reduced pressure and with cooling. An oil remains, which is slurried with 100 ml of anhydrous diethyl ether. The ether layer is decanted and the powder obtained is dissolved in methanol and precipitated again with diethyl ether. 4-Ethyl-l- [N2- (6,7-dimethoxy-2-naphthalenesulfonyl) -L-arginyl] piperidine hydrofluoride is obtained in a yield of 75% of theory. Th. Received.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

632 243

6

Elemental analysis for C2sH3705NsS ■ HF:

Calculated: C 55.64 H 7.10 N 12.98 Found: C 55.50 H 7.12 N 12.87

Example 2:

In a suspension of 1.0 g (0.00186 mol) of 4- [NG-nitro-N2- (6,7-dimethoxy-2-naphthalenesulfonyl) -L-arginyl] morpholine and 0.1 g of palladium black in 30 ml of ethanol and 10 ml of acetic acid, hydrogen is introduced for 60 h at room temperature. When the hydrogenation has ended, the catalyst is filtered off and the solvent is distilled off under reduced pressure. The oily residue is taken up in methanol and precipitated with diethyl ether. The 4- [N2- (6,7-dimethoxy-2-naphthalenesulfonyl) -L-arginyl] morpholine acetate is obtained as a powder in 82 percent yield. Elemental analysis for C22H3i06N5S • CH3COOH:

Calculated: C 52.07 H 6.37 N 12.65 Found: C 51.99 H 6.28 N 12.41

Example 3:

A solution of 1.2 g (0.0020 mol) of 4-ethyl-1- [NG-nitro-N2- (6-chromosulfonyl) -L-arginyl] piperidine in 0.64 g (0.0060 mol) of anisole with cooling in a dry ice-acetone bath with 3 ml of hydrogen fluoride. The mixture is then stirred in an ice bath for 30 minutes. Excess hydrogen fluoride is then distilled off under reduced pressure and with cooling. The oily residue is slurried in 100 ml of anhydrous diethyl ether. The ether solution is decanted and the powder obtained is dissolved in methanol and diethyl ether is added to the solution. The precipitated 4-ethyl-l- [N2- (6-chromanesulfonyl) -L-arginyl] piperidine hydrofluoride is powdered in a yield of 63% of theory. Th. Received.

s

Elemental analysis for C22H3604N5S ■ HF:

Calculated: C 54.41 H 7.47 N 14.42 Found: C 54.70 H 7.45 N 14.31

| (| Example 4:

In a suspension of 1.2 g (0.0020 mol) of 4-ethyl-l- [NG-nitro-N2- (1,4-benzodioxane-6-sulfonyl) -L-arginyl] piperidine and 0.1 g of palladium black in 30 ml of ethanol and 10 ml of acetic acid, hydrogen is passed in at room temperature for 30 h. After the hydration

15 tion, the catalyst is filtered off and the solvent is distilled off under reduced pressure. The viscous oily residue is taken up in methanol and precipitated with diethyl ether. It is the 4-ethyl-1 - [N2- (1,4-benzodioxane-6-sulfonyl) -L-arginyl] piperidine acetate as a powder in a yield of 85% of theory. Th. Received.

20th

Elemental analysis for C21H33OsNsS • CH3COOH:

Calculated: C 52.35 H 7.07 N 13.27 Found: C 52.65 H 7.01 N 13.12

25 In addition to the compounds prepared in the preceding examples, Table I lists further compounds of the general formula I which were prepared in the manner described above.

Table I

No.

hn

\ H

- n - (ch2) 3 - chcor h2n hn-so2

r '

acid

Concentration to double the coagulation time ((Amol)

Manufacturing acc. example

Properties or F., (c)

Elemental analysis above: calculated below: found i.r. (KBr) (cm ')

r r '

c

H

n

5

"0" ° 2h5

v ^ - ^% j-0ch3 ^ yJ ^ n <^ och3

HF

0.15

1

powder

55.64 55.50

7.10 7.12

12.98 12.87

6

y> y ^ 0ce 3

CH3COOH

0.55

2nd

powder

55.21 55.04

6.95 6.78

12.38 12.26

7

-0-och3

v? Y ^ ° CH3

CH3COOH

0.60

2nd

powder

53.69 53.48

6.72 6.68

12.04 12.00

8th

-n V-ch ^

\ / 3

t ^ rt00 *

0ch3

2CH3COOH

4.0

2nd

powder

51.75 51.49

6.76 6.39

13.41 13.21

3400 3200 1640

9

-40- ^

0ch3

k> J * s ^ 0ch3

2HF

4.0

1

powder

50.54 50.48

6.64 6.21

15.37 15.28

10th

-o "02h5

tX>

HF

15

3rd

powder

54.41 54.70

7.47 7.45

14.42, 14.31

3300 (wide) 1640

Table I (continued) oj

No.

hn

\ H

j * c-n- (ch2) 3 -chcor h2n hn-so2

r '

acid

Concentration to double the coagulation time ([amol)

Manufacturing acc. example

Properties or F., (° C)

Elemental analysis above: calculated below: found

I.R. (KBr) (cm)

R

R '

C.

H

N

11

"0" c2h3

t30

ch3cooh

25th

4th

powder

52.35 52.65

7.07 7.01

13.27 13.12

3320 1640

12

"O-0" 3

XX>

ch3cooh

8th

4th

powder

52.35 52.60

7.07 6.95

13.27 13.40

3100 (wide) 1640

13

/ ch3 -nif j

° 4h9

TX)

ch3cooh

100

4th

powder

51.25 51.53 '

7.23 7.46

13.58 13.29

3350 1640 1280

14

tX> ™>

-

6

4th

powder

53.99 53.75

7.29 7.61

13.69 13.50

3400 1630

15

-o-0 ^

eoo ch3cooh

0.3

4th

powder

58.62 58.32

6.85 6.58

12.21 11.99

3340 1630 1265

16

-o °, «5

txo

'/ 2H2O

0.3

4th

powder

59.03 58.84

6.54 6.48

13.77 13.63

3350 1630 1275

Table I (continued)

No.

HN

\ H

^ c-n- (ch2) 3-chcor h2n hn-scj2

r '

acid

Concentration to double the coagulation time ([amol)

Manufacturing acc. example

Properties or F.,

co

Elemental analysis above: calculated below: found i.r. (KBr) (cm)

r r '

c

H

N

17th

"0" ° 2h5

(XO

ch3cooh

0.2

4th

powder

57.94 57.64

6.66 6.65

12.51 12.24

3350 1630 1160

18th

-0-c2h5

oco ch3cooh

0.15

4th

powder

56.33 56.08

6.48 6.45

12.17 11.96

3300 1630 1290

19th

-0

«Xo ch3cooh

0.5

4th

powder

57.23 57.01

6.47 6.41

12.84 12.61

3350 1635 1270

20th

ch

"<J

04h9

oco ch3cooh

5

4th

powder

57.02 56.74

6.81 6.93

12.79 12.65

3310 1640 1260