NL8220421A - Carcinostatic compsns. for lung cancer treatment - comprise condensation prods. of amino-isopropyl phenyl ketone with e.g. substd. amine(s) or hydrazine(s) or aminoacid derivs. - Google Patents

Abstract

Cpds. of formula Ph-C(=NR)-C(Me)2-NH2 (I) are new (where R is NHCSNH2, NHCOOC(Me)3, NHCH2COOEt, CH(Me)CH2CH2CH(Et)2 or CH(R')CONH2; R' is H, Me, i-Pr, CH2Ph, 3-indolyl, CH2CH2SMe or CH2OH). (I) are antitumour agents, e.g. active against Lewis carcinoma at doses of 138-229 mg/kg, adenocarcinoma 755 at 30 mg/kg, sarcoma 37 at 30-83 mg/kg and Ehrlich carcinoma at 45-138 mg/kg (i.p., mouse). (I) is prepd. by reacting cpd. of formula (II) with cpd. of formula RNH2 in stoichiometric amts. The reaction is carried out in methanol at 17-20 deg.C. Cpd. (II) may be prepd. by alkaline decomposition of a quaternised salt of isopropyl phenyl ketone N,N-dimethylhydrazone.

Description

-1-23814 / Vk / mvl 8220421

Brief designation: Condensation products of α-aminoisopropylphenyl ketone at the carbonyl C = O bond with substituted amines of functionally substituted hydrazines or with derivatives of naturally occurring amino acids, which have anti-tumor activity.

Technical area.

The present invention relates to new chemical compounds and in particular to condensation products of α-amino-10-isopropylphenyl ketone at the carbonyl C = O bond with substituted amines or functionally substituted hydrazines or with derivatives of naturally occurring amino acids that have anti-tumor activity.

State of the art.

Known in the art are the closest structural analogues of new compounds of the invention such as, for example, anyl-α-ammonium isobutyrophenone perchlorate (see J. Nelson et al., Org.

Chem., 1967, Vol. 33, p. 827) and α-aminodimethylaminoisoproyl ketone ethoxyhydrazone (H. Link Helv. Chim. Acta, 1978, Vol. 61, p. 2419).

However, these structural analogues, which are prepared according to known methods, have no biological activity.

Description of the invention.

One of the objects of the invention is to obtain such new compounds which have a selective anti-tumor activity against a number of tumors that are insensitive to known antiblastic chemotherapeutic preparations.

Thus, according to the invention, new compounds are obtained, namely condensation products of α-aminoisopropylphenyl ketone at the carbonyl C = O bond with substituted amines or functionally substituted hydrazines or with derivatives of naturally occurring amino acids of general formula

\ = ξ / M

35 I

R.

8220421 -2- 23814 / Vk / mvl where R = NH-C-NH2, NH-COOCiCH ^, NH-C ^ -COOC ^, S CH3 CH (CH3) (CH2) 2CH (C2H5) 2, CH2CONH2, CH ( CH3) CONH2 CH (ά) CONHg, ch3 CH (CH2C6H5) CONH2, CH (3-indolyl) CONH2, CH (CH2CH2SCH3) CONH2> CH (CHgOH) CONHg.

2-Amino-2-methyl-1-phenyl-1-propanone thiosemicarbazone has general "formula:

f ^ _C-c (CH5) 2 ^ 2 10 \ / II

hl-NH-C-Nh2

S

2-Amino-2-methyl-1-phenyl-1-propanecarb-tert-butoxyhydrazone has the following formula: 15 ^ Λ-ς-ο (ίΗ3) 2ΝΗ2

Nv = / H-NHCOOcfCH ^ g 2-Amino-2-methyl-1-phenyl-1-propanoneethoxyacetylhydrazone has the following formula: 20 H-NH-CH 2 COOC-iHs 2- [n- (2-amino-2- methyl-1-phenyl-1-propylidene f) -amino-1,1-di-25-ethylpentane has the following formula: <QCC (CH3) 2 rH2 h-ch (ch3) ch2ch2ch (c2h5) 2 2-amino shift bases -2-methyl-1-phenyl-1-propanone with amino acid derivatives have the following general formula 0, -cc (ch3) 2nh2 CjH3 where R is CHgCONHg, CH (CH3) CONH2, CH (CH) CONH2,

Jh 8 2 2 0 4 7.1 3 t -3- 23814 / Vk / mvl CH (CH2C6H5) CONH2, CH (3-indolyl) C0NH2, CH (CH2CH2SCH3) C0NH2, CH (CH2OH) CONH2 · According to the present invention, the new compounds condensation products of α-aminoisopropylphenyl ketone at the carbonyl C = O bond with substituted amines or functionally substituted hydrazines or with derivatives of the naturally occurring amino acids of general formula;

<0 - C - C (CH1) a NH2 N-R

10 where R is NH-C-NH0, NH-COOC (CH-) NH-CHo-C00C „iL, || 2 33 2 25

S

CH (CHJ (CH0) 0CH (CJU0, CH.COML, CH (CHJC0NHo, CH (CH) C0NHo, 3 2 2 2 5 2 '2 2 3 2 2 ch3 ch3 15 CH (CH0C, HC) C0NHo, CH (3 -indolyl) CONIL, CH (CHoCHoSCHo) CONH 4, dO 0 dddd S d CH (CH 2 OH) CONH 2.

The compounds prepared have been tested for physicochemical properties.

Each individual compound is characterized by its own molecular and structural formula, melting or boiling point, solubility and spectral data.

Thus, 2-amino-2-methyl-1-phenyl-1-propanonthio-semicarbazone having the following structural formula becomes: 25 'Q-c-cKhNH.

M - NH - C. - NH2 characterized by a melting point of 168-169 ° C, being sparingly soluble in water, well soluble in alcohol and acetone.

The IR spectrum has an absorption band corresponding to vibrations of the C = N bond at 1640 cm, tension vibrations of the amino groups within the range of 3180-3360 cm, as well as the band of tension vibrations of the C = 3 bond at 1090 cm, characteristic of thioureids. In the NMR H spectrum, a singlet of gem-CH3-35 groups is registered at 1.16 ppm, widened singlets of NH2 groups at 3.47 and 8.27 ppm as well as a signal of NH protons (4.49 ppm ) and the phenyl ring protons at 7, 23 and 7.54 ppm.

2-Amino-2-methyl-1-phenyl-1-propanecarb-tert-butylhydrazone 8220421 -4-23814 / Vk / mvl with the following structural formula: QJe (CH4), NH2 H-NHC00C (cH5) 3 5 is characterized by the melting point of 104-105 ° C; this substance is sparingly soluble in water, well soluble in alcohol, chloroform, acetone.

The vibration spectrum is characterized by vibration bands -1 -1 10 of the C = N bond at 1630 cm, carbonyl group at 1738 cm, as well as _1 by the absorption of amino groups within the range 3190-3360 cm 1

In the NMR H spectrum there is a singlet of gem-CH 2 groups at 1.27 ppm, a singlet of protons of the tert-butyl group at 1.43 ppm, a broadened singlet of the groups Nt 1 and NH at 1 .74 ppm as well as 15 multiplets of phenyl ring protons at 7.12 and 7.47 ppm.

2-Amino-2-methyl-1-phenyl-1-propanoneethoxyacetylhydrazone of formula: 0-cc (ch3), nh2 20 N-NH-CH2C00C2h4- is characterized by a boiling point of 125-127 ° C under a pressure of 3 mm Hg; this substance is easily soluble in water, alcohol and acetone. In the IR spectrum there is an absorption band of the C = N bond at -1 1635 cm, a band of voltage vibrations of the C = 0 bond at 1740 cm \ as well as characteristic absorptions of amino groups within -1 1 the range 3170-3380 cm. In the NMR H spectrum there is a singlet of the gem CH groups at 1.16 ppm, characteristic multiplets of ethyl protons, an AB type signal from CH group protons at 3.79 and 3 , 89 ppm, widened singlets of protons from amino groups at 2.4 and 5.03 ppm, as well as multiplets of phenyl protons at 7.43 and 7.65 ppm. The melting point of 2-amino-2-methyl-1-phenyl-1-propanone-ethoxyacetylhydrazone hydrochloride is 54-55 ° C; it is hygroscopic, well soluble in alcohol.

2- [n- (2-amino-2-methyl-1-phenyl-1-propylidene)] amino-1,1-diethylpentane of the following formula: 8220421 -5- 23814 / Vk / mvl C-C (CH3 aMH2 N - CH (CH3) CHH2 H2 CH (C2 H5) 2 is characterized by a boiling point of 135-136 ° C under a pressure of 3 mm Hg; the substance is soluble in water, alcohol and acetone. In the IR spectrum, an absorption band of the C = N bond is -1 at 1640 cm and characteristic bands of symmetrical and asymmetrical -1 1 10 voltage vibrations of amino groups at 3290 and 3340 cm. In the NMR H spectrum, a singlet of protons of the gem-CH 2 groups at 1.23 ppm is registered, a broadened singlet of protons of the amino groups at 1.85 ppm, as well as characteristic multiplets of alkyl protons within the region from 0.98-2.8 ppm and multiplets of protons from the phenyl ring at 6.98 and 7.31 ppm. The melting point of the hydrochloride of the above compound is 96-97 ° C. It is easily soluble in water and ethanol.

A Schiff base of 2-amino-2-methyl-1-phenyl-1-propanone with amides of amino acids, represented by, for example, L-serine amide of the following formula: 0-yy-c (CH ») ïN.Hz n-ch (ch2oh) conh2 25 is characterized by the melting point of 98-99 ° C. It is hardly soluble in water, well soluble in alcohol and acetone.

In the IR spectrum there is an absorption band of the C = N bond at 1670 cm, voltage vibrations of the C = 0 bond of the amide group -1 -1 at 1690 cm, 1640 cm as well as bands of the voltage vibrations of

I

The amino groups and hydroxy group within the range of 3190-3350 cm 1

The NMR H spectrum indicates the presence of a singlet of the gem-CH 2 protons at 1.23 ppm, a broadened singlet of protons of the amino group and the hydroxy group at 1.83 ppm, characteristic multiplets of alkyl protons within the range of 3.11-3.38 ppm, as well as a broad signal of the amide protons at 6.98 ppm and multiplets of phenyl ring protons at 7.11 and 7.43 ppm. Other Schiff bases of 2-amino-2-methyl-1-phenyl-1-propanone with amides of amino acids have similar physicochemical properties.

8220421 -6- 23814 / Vk / mvl

A general process for the preparation of α-aminosiopropylphenyl ketone condensation products at the carbonyl C = O bond is performed via interaction of 2,2-dimethyl-3-phenylaziridine with a corresponding agent containing a free amino group. The reaction is carried out in methanol at a temperature of 17-20 ° C. All of the above reactants are used in the stoichiometric ratio. The reaction takes place according to the following general scheme:

HjNR -, 0 \ r nr where R is NH-C-NH2> NH-COOCtCH ^, NH-CH ^ COOC ^, CH (CH ^^) C0NH2, c * 5 CH3 CH (CH3) (CH2) 2CH, CH2C0NH2 CH (CH3) CONH2 CH (CH) CONH2, CH (3-indolyl) CONH2, 5 c'h <k2H5 3 CH (CH2CH2SCH3) CONH2, CH (C18 OH) CONH2.

The starting compound 2,2-dimethyl-3-phenylaziridine is prepared by an alkaline decomposition of a quaternized salt of Ν, Ν-dimethylhydrazonisopropyl ketone as a result of a modified Neber rearrangement (RP Parcell, Chem. And Industry, 1963, No. 33, p. 1396).

Recovery of the final product is not difficult: it is carried out according to a conventional technique such as recrystallization or distillation.

The new compounds of the present invention as noted above have been tested for antibacterial activity.

Thus, the antiblastic activity of the condensation products of α-aminoisopropylphenyl ketone at the carbonyl bond C = 0 is investigated with respect to Lewis lung carcinoma, adenocarcinoma 755, sarcoma 37, Ehrlich tumor using BDF1 mice of both sexes and albino mongrel- mice as the test animals. The preparations were administered intraperitoneally, daily, for 5 days. The criterion for effective action was the increase in longevity in mice and the percentage inhibition of tumor growth.

Experiments have shown that due to the action of the condensation products of α-aminoisopropylphenyl ketone at the carbonyl bond C = 0, the life span of mice with Lewis lung carcinoma was extended by 82-2021-7- 23814 / Vk / mvl and the tumor growth was increased. inhibited by 30-52%. Under the influence of the condensation products of α-aminoisopropylphenyl ketone at the carbonyl C = 0 bond, the life span of mice with adenocarcinoma 755 is extended by 45-50%, that of mice with sarcoma 37 by 23-56%, mice with 5 Ehrlich tumor with 15 -26%.

For a further explanation of the present invention, the data regarding the antiblastic activity of the condensation products of α-aminoisopropylphenyl ketone at the carbonyl C = O bond are summarized and shown in Table A.

10 This shows that the tested compounds have pronounced anti-tumor activity on a number of inoculated tumors in mice, including Lewis lung carcinoma, which is close to human tumors in terms of cell proliferation kinetics and insensitive to other chemical anti-tumor preparations.

An experimental study of anti-tumor activity has been conducted using 2-amino-2-methyl-1-phenyl-1-propanone as an example on a model of human tumor heterotransplantants.

A model of subrenal heterotransplantant was first identified by A.E. Bogden for conducting short chemotherapeutic experiments in non-syngenic systems (A.E. Bogden, Breast Cancer, 1978, Band 2, biz. 283-336).

TABLE A

Anti-tumor activity of condensation products of α-aminoisopropylphenyl ketone at the carbonyl C = O bond on a number of seeded tumors in mice. 25 ------- tumor days of extension optimal inhibition tumor administration lifetime (%) dose growth (%) ______ (mg / kg) __ carcinoma ^ ^ -3 ^ 7 ^ 138'229 20 ^ 2 30 ~ r 3 »~ sarcoma 37 1,2,3,4,7 23-56 30-83 F * Vvp1 i ph · * tumor 1,2,3,4,7 15-26 45-138 35 -----

According to a new research program at the US National Cancer Institute, the model of subrenal heterotransplantants has been used in the second selection step of new anti-tumor compounds 8220421 -8- 23814 / Vk / mvl by seeded lines of human tumors CX-1, LX-1 and BX-1 (according to A. Goldin, M. Vendittij Cancer Treat-Rev., 1980, 7, biz. 167; A. Goldin et al. Eur. 1. Cancer, 1981, vol. 17, biz. 129).

The transplantation of tumor fragments (1.0 mg) under the renal capsule of mice was performed by microsurgery and the growth (or regression) of the transplants was determined relative to the crosshairs scale in the stereo microscope -eye piece in the ocular micrometer units (omu) 1 omu = 0.1 mm.

An increase in the diameter of the subrenal grafts from grafted lines of human tumors is 3-10 µm in a 6-day experiment on thymusless mice (AE Bogden Breast cancer, 1978, vol. 2, pp. 283-336; AE Bogden Cancer, 1981, 48, 10). Primary transplants of human tumors under a mouse renal capsule grow significantly less and, according to the available data, essentially a "survival" of tumor fragments has been observed with an insignificant increase in their diameter from 10 to 11.5 + 1.0 um ( AE Bogden et al., Cancer, 1981, 48, 10).

According to the present invention, the anti-tumor activity of the compositions to be tested was examined on primary subrenal transplants of human tumors (surgical material) without any pretreatment thereof by chemotherapy or radiation. Transplant growth and regression was determined by the fragile mass change with an accuracy of up to 0.1 mg.

On day 0, tumor fragments with a mass of 1.0 mg are transplanted under a kidney capsule of immunocompetent mouse BALB / C. On days 2, 4 and 6, intraperitoneal administration of the preparations in 0.9% NaCl solution was performed and examined.

On day 8, the mass of the tumor is measured and the increase (Δ M) or decrease (-Δ M) (regression) of the tumor mass is determined.

The number of mice in the comparative group and the test group was 7-8 and 3-4, respectively.

The data from the experiments so performed are summarized and shown in Tables B and C.

The anti-tumor effect of α-amino-2-methyl-1-phenyl-1-propanone 35 on lung cancer-1 and lung cancer-2.

8220421 -9- 23814 / Vk / mvl

TABLE B

lung cancer-1__

preparation dosage (mg / kg) M + M

0.58 + 0.17 CP 3 times with 100 -0.07 + 0.06 ** 5 MTX 3 times with 3 0.27 + 0.15 * ADR 3 times with 3 0.30 + 0.40 E- 229 3 times with 200 -0.03 + 0.25 **

Notes: * and ** mean P 0.05 and P 0.01 according to 10 Student criterion + M and -M mean growth and regression of tumor mass compared to original value CP - cyclophosphane MTX - methothrexate 15 ADR - adriamycin TABLE C lung cancer-2

preparation dosage (mg / kg) M + M

20 --- 0.19 + 0.37 CP 3 times with 100 -0.53 + 0.21 ** MTX 3 times with 3 -0.37 + 0.32 E-229 3 times with 200 -0.40 + 0.23 25 Notes: * and ** mean P 0.05 and P 0.01 according to

Student criterion + M and -M mean growth and regression of tumor mass compared to the original value CP - cyclophosphane 30 MTX - methothrexate.

Modern anti-tumor preparations show a low selectivity with regard to the attack of the tumor tissue compared to the normal one. This results in a wide range of anti-tumor activity of cancerostatic preparations and a high toxicity thereof to the critical normal tissues.

The compound E-229 (2-amino-2-methyl-1-phenyl-1-propanonthio-semicarbazone) is distinguishable from clinical anti-tumor preparations such as cyclophosphane, methothrexate and adriamycin by a narrower 8220421 -10-23814 / Vk / mvl region of the anti-trust activity. Preclinical studies of compound E-229 on a model of human tumor heterotransplanters with different histogenesis (breast, stomach, rectal, lung) have found their high activity in lung cancer. The anti-tumor activity of the compound E-229 is comparable to that of cyclophosphane and better than the activity of methothrexate and adriamycin. Thus, compound E-229 refers to the group of highly effective anti-tumor preparations with a narrow range of activity and may be useful in the therapy of human lung cancer.

For a better understanding of the present invention, some specific examples are given for illustrative purposes.

Example I

To 10 g (0.06 mole) 2,2-dimethyl-3-phenylaziridine in 80 ml methanol, 5.45 g (0.06 mole) thiosemicarbazide was added, stirred at 17-20 ° C for 15 hours. Methanol was distilled off, the residue recrystallized from a mixture of ethyl acetate and petroleum ether (1: 3). The yield of 2-amino-2-methyl-1-phenyl-1-propanonthio-semicarbazone was 10.7 g (76%). Melting point is 168-169 ° C.

The data from the elemental analysis for the compound of formula C ^ H ^ N ^ S are: C (%) H (%) N (%) S (%) found 55.87 6.68 23.68 13, 50 calculated 55.93 6.78 23.73 13.56.

Example II

The procedure was performed as described in Example I.

using 2,2-dimethyl-3-phenylaziridine and carb-tert-butylhydrazine as starting materials. As a result, 2-amino-2-methyl-1-phenyl-1-propanone carbon tert-butylhydrazone was obtained. The product was obtained with a yield of 76%. The melting point is 104-105 ° C.

The data from the elemental analysis for the compound of formula C.rH__No0 „are: 15 23 3 2 C (%) H (%) N (%) found 64.74 8.15 15.11 35 calculated 64.98 8 30, 15.16.

Example III

The process was performed in a manner similar to that described in Example I using 2,2-dimethyl-1220421 -11-23814 / Vk / mvl 3-phenylaziridine and the ethyl ester of hydrazine acetic acid as starting materials; after distilling off methanol, the residue was recrystallized under reduced pressure to obtain 2-amino-2-methyl-1-phenyl-1-propanoneethoxyacetylhydrazone in 78% yield. The boiling point 5 was 125-127 ° C at 3 mm of mercury.

The data from the elemental analysis for the compound of formula are: C (%) H (%) N (%) found 63.76 7.85 15.91 calculated 63.88 7.98 15.97.

Example IV

The procedure was performed in a manner similar to that in Example 1 using 2,2-dimethyl-3-phenylaziridine and 2-amino-1,1-diethylpentane as starting materials; after distilling off methanol, the residue was distilled under reduced pressure to obtain 2- [N- (2-amino-2-methyl-1-phenyl-1-propylidene)] amino-1,1-diethylpentane in a yield of 68 %. The boiling point was 135-136 ° C / 3 mm of mercury.

The data from the elemental analysis for the compound of formula C ^ H ^ Ng are: C (%) H (%) N (%) found 78.92 11.03 9.68 calculated 79.16 11.11 9 , 72.

Example V

The process was performed in a manner similar to that in Example 1 using 2,2-dimethyl-3-phenyl-aziridine and amides of glycine, L-alanine, L-valine, L-phenylalanine, tryptophan, L-methionine L-serine as starting materials to obtain Schiff bases of 2-amino-2-methyl-1-phenyl-1-propanone with amides of naturally occurring amino acids; the physicochemical parameters are summarized and shown in Table D.

® 2 2 0 ΐ i 1, t i -12- 23814 / Vk / mvl

TABLE D

Physicochemical parameters of Schiff bases of 2-amino-2-methyl-1-phenyl-1-propanone with amides of the amino acids 5 0-c-c (ch3) 2 * h2

H -CH -C0NH2 R

M D melting point found (%)

No. R, oK ---

10_____C__H__N

12 3 A 5 6 1 H 108-109 65.68 7.68 19.10 2 CH3 111-112 66.87 8.08 18.0 15 3 CH (CH3) 2 108-109 68.98 8.75 15 .96 4 CHOC, Hc 142-243 73.71 7.35 13.50 2 6 5 5 3-indolyl 135-136 72.35 6.81 15.91 6 (CH 2) - SCH. 110-111 61.37 7.79 14.28 20 2 2 3 7 CH20H 98-99 62.58 7.57 16.79 TABLE D (continued) ^ general _found (/ o) _ yield 25 fonTlule C Η N ( %) 1 7 8 9 10 11 1 C12H1? N30 65.75 7.76 19.18 47 2 C13H1gN30 66.95 8.15 18.02 58 30 3 C15H23N3 ° 68.96 8.81 16.09 63 A C19H23N3 ° 73'78 7> S, Z <13'59 57 5 C21H24N4 ° 72'A1 6) 89 16'09 54 6 C15H23N3 ° 61, A3 7.84 14.33 63 7 C13H19N3 ° 2 62'65 7'63 16'86 48 8220421 -13- 23814 / Vk / mvl. »

Commercial applicability.

Condensation products of α-aminoisopropylphenyl ketone at the carbonyl C = O bond with substituted amines, functionally substituted hydrazines or with derivatives of naturally occurring amino acids which have anti-tumor activity can be used as a drug in anti-cancer preparations with a narrow spectrum of action in the treatment of lung tumor in humans.

In summary, the invention relates to condensation products of α-aminoisopropylphenyl ketone at the carbonyl C = O bond 10 with substituted amines or functionally substituted hydrazines or with derivatives of naturally occurring amino acids that have anti-tumor activity. The new compounds according to the invention are condensation products of α-aminoisopropylphenyl ketone at the carbonyl C = O bond with substituted amines or functionally substituted hydrazines or with derivatives of naturally occurring amino acids of general formula <Q-c-c (ch3) 2nh2

N-R

20 where R is NH-C-NH-, NH-COOC (CH-) „, NH-CH_-C00C„ H.-, || d JJ dd Z> S ch3 CH (CH3) (CH2) 2CH (C2H5) 2, CH2C0NH2, CH (CH3) C0NH2, ch () C0NH2, in3 CH (CH2C6H5) CONH2, CH (3-indolyl) CONH2, CH (CH2CH2SCH3) CONH2> CH (CH2OH) CONH2.

82 2 0 4? i

Claims (6)

1. Condensation products of α-aminoisopropylphenyl ketone at the carbonyl C = O bond with substituted amines or functionally substituted hydrazines or with derivatives of naturally occurring amino acids of general formula: 0-cc (ch 3) 2nh 2 N-R 10 where R is NH-C-NH_, NH-COOC (CH -) -, NH-CH ^ -COOC ^ H ^, Ij d YY dd 0 COHp. S CH_ 12 5 | 3 CH (CH -) (CHL) „CH, CHoC0NHo, CH (CH_) C0NHo, CH (CH) C0NH_, ó d d ^ d d 6 d y d C2H5 CH3 CH (CH „C, H1.) CONH„, CH (3-indolyl) CONH “, CH (CH„ CH „SCH_) CONH“, CH (CH „0H) CONH“. 2 O 5 2 2 2 2 J 2 d d 2. 2-Amino-2-methyl-1-phenyl-1-propanone thiosemicarbazone according to claim 1 having the formula: 0-CC (CH 3) 2 NHi N-NH-C-NH 2 II s 3,2-Amino-1-methyl-1-phenyl-1-propanone carb-tert-butoxyhydrazone according to claim 1, having the formula: <Q> - cc (ch3) 2nh2 m-mhcooc (ch3) 3 30 4. 2-Amino-1-methyl-1-phenyl-1-propanone ethoxyhydrazone according to claim 1 with formula: 0> - irc (CH >> 2NH2 35 n-nh- ch2-cooc2h5 8220421 J 1 I * -15- 23814 / Vk / mvl 5 2- [N- (2-amino-2-methyl-1-phenyl-1-propylidene)] - amino-1,1-diethylpentane according to claim 1, having the formula: <QCC (CHj) 2NH2 5 N-CH-αΗ2-ΟΗ2-ΟΗ (θ2Η5) 2 CHj 6. Shiff bases of 2-amino-2-methyl-1-phenyl-1-propanone with amides of amino acids according to claim 1 of the formula: 10 0-cc (ch}) 2nh2 N-CH-CONHp I c R where R is H , CH 2, iso-C 2 H 3, CH 2 C 2 H 3, 3-indolyl, (ch 2) 2sch 3, ch 2oh. Eindhoven, March 1984 8 2 2 0 4? 1k