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Publication numberUS3013020 A
Publication typeGrant
Publication dateDec 12, 1961
Filing dateJan 24, 1958
Priority dateJan 24, 1958
Publication numberUS 3013020 A, US 3013020A, US-A-3013020, US3013020 A, US3013020A
InventorsOtis E Fancher
Original AssigneeMiles Lab
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
N,n'-bis-phenyl-alkylene-diamines
US 3013020 A
Abstract  available in
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Description  (OCR text may contain errors)

" atent Ofifice 3,013,020 Patented Dec. 12, 1961 This invention relates to a novel class of compounds represented by the general formula Ilt R wherein R is a cyclic or open chain lower alkyl radical, Z is an alkylene radical, X is a lower alkylene radical and Y is a radical from the group consisting of aryl and substituted aryl. It also includes pharmaceutically acceptable acid addition salts which may be formed from said compounds, in accordance with well known procedures, by using appropriate organic and inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, hydrobromic, acetic, lactic, succinic, malic, aconitic, aminoacetic and tartaric acids.

The application is a continuation-in-part of my copending application for patent Serial No. 482,880 which was filed on January 19, 1955, now abandoned.

An important object of the invention was to provide a compound or group of compounds which would indicate sulficient amebicidal activity as to be useful in chemotherapy of amebiasis and other protozoal diseases. It was also desired that such compound or compounds should when used for this purpose, be accompanied by a minimum of limiting side effects.

In'various tests conducted, certain compounds of the above class were found to be particularly etfective in killing the organism Endamoeba histolylica, strain 'F-22. In some instances these compounds were also found to demonstrate activity against Trypanosoma cruzi, the causative agent of Charges disease or South American trypanosomiasis. Generally speaking, the tests also indicate that these compounds were of low toxicity.

In one of these tests, the compounds were tested to determine the lowest concentration thereof which appears to kill the ameba present in a selected medium as evidenced by. negative subculture. The medium used in this test was the so-called WEL medium which is a modified Boeck-Drbohlav diphasic medium such as used by the Laboratory of Tropical Diseases of the National Institutes of Health and which employs a whole egg and Lockes Solution slant with a Lockes Solution overlay. In the test procedure approximately 30 mg. of sterile rice powder was added to each test tube before use. The test organism, Enda-moeba histolytica, strain F-22,

hour stock was maintained in association with a single species of bacteria, organism t.

To obtain reproducible results for testing purposes, media preparation procedures were quantitated as far as possible. The amount of medium in both phases was accurately measured and the angle of the slant standardized to present equal areas of solid medium surface for use by the growing ameba and for adsorption of the test material. Stock solutions of the test material were prepared in distilled water to contain ten times the concentration to be tested. Addition of a stock solution to a tube of medium constituted the additional dilution necessary to obtain the test concentration. Control tubes received a similar amount of distilled water. Inoculum for testing cultures, diluted with Lockes Solution to contain between 20,000 and 40,000 ameba per ml.

Observations were made after 48 hours incubation at 37 C. Each tube which did not show ameba or bacteria by microscopic examination, or which showed little or questionable growth or either organism was subcultured to a fresh tube of riced WEL medium and subcultures were incubated an additional 48 hours. Changes in pH were observed with a Beckmann pH meter, Model G. The tube containing the lowest concentration of test material which did not demonstrate viable ameba was considered the endpoint inthe test.

Certain of the symmetrical bis-amines of the aforesaid novel class of compounds to which this invention relates Were found in the above described test to indicate a particularly low level of concentration needed to kill the ameba. Thus many of the compounds would kill the ameba when added in concentrations as low as 100 ng. per ml. of test solution while others would have a killing effect on the ameba at even lower concentrations, as for example 50 ,ug/ml. These compounds were found to fall within the general formula:

R R Y-( CH2) XNH0 H(C H2) Pt) H-NH-(C H2) ,;Y wherein x is an integer of 1 to 3, n is an integer of 2 to 10, when R is an alkyl radical containing 2 to 6 carbon atoms and Y is phenyl, hydroxyphenyl, alkoxyphenyl, dialkoxyphenyl, trialkoxyphenyl or methylenedioxyphenyl.

One of the surprising results of these tests was the apparent significance R has in these compounds on their amebicidal activity level. For example, the above tests were also applied to several symmetrical bis-amines which do not have an alkyl at the R position and the amebidical activity levels of these compounds were determined to be as follows:

Arnebicldal Example Compound Activity,

' /rnL, WEL

I N,N-bis(p-methoxy benzyDethylene diamine inactive at CH3OGOHZ NII (CHZ)QNH CHZ O GHQ 11 1,6-bis(p-methoxy-phenyl propylamino)hexane 500.

CH3O(CH2)3NH(CH;)sNH-(C'H2)a 0 CH3 III 1,6 bis(3,4 methoxy phenyl-propylamino)hexane 1,000.

CHa0-(CH2)aNH( CH2) t-NH( 0 H2) a O CH3 1 CHaO 0 CH3 IV 1,7-bis(piperony1arnin0)heptane 1,000-500.

procedures was provided from pooled 72 Amebicidal Example Compound Activity,

/rn1.,WEL

OC CH2NH(CHz)1-NHCH -o Hg(L-J) --(LH2 V l,B-bis(piperonylamino)-2-methyl-2-n-propylpropane 500.

CHa

As will be seen, these compounds tested essentially inactive or required the addition of such large amounts thereof to the test solutions of ameba as to indicate they have little potential value as amebicides. The tests indicated that only those symmetrical bis-amines which have an alkyl branching on the carbons of the central moiety to which the amino groups Y-(CH NH- are attached show amebicidal activity. The inactivity of Example V also points up that it is not sufficient that the interconnecting moiety between the amino groups be branched but rather that the branching be on the carbon atoms to which the amino groups are attached. Only in the case of symmetrical bis-amines where their amino groups Y--(CH NH- were connected at other than to the terminal carbons of the interconnecting saturated hydrocarbon or alkylene chain was any significant amebicidal activity noted. The improvement was particularly pronounced in compounds of this class where R is an open chain alkyl such as ethyl, propyl, butyl and amyl or is a cyclic-alkyl such as cyclohexyl. Although the reason is not apparent, the symmetrical bisamines appear to be ineifective amebicides where R is hydrogen, and compounds of the general formula wherein R is aryl, substituted aryl or aralkyl do not demonstrate significant amebicidal activity in tests thus far conducted.

The compounds of the present invention may be prepared by reacting the his primary amine with an appropriate aldehyde, the product of which is then hydrogenated, using a platinum or Raney nickel catalyst according to the following equations:

Y(CH2)X-NH-iIH-(CHt)rH-NH-(CHQrY Catalyst Alternatively, the starting his primary amine might also be reacted with an appropriate organic carboxylic acid and reduced with lithium aluminum hydride according to the following:

her, J. Chem. Soc. (1949) as outlined by the following series of equations:

In the group of compounds represented by the present invention, each compound and the intermediate dicarboxylic acids and diamines contain two identical asymmetrical carbon atoms as indicated by the asterisks in the generic formula which follows and is therefore capable of existing both as a racemate and as a meso form.

When R=n--C H and n=5 a crystalline and a noncrystalline dicarboxylic acid were obtained. These gave diamines having identical boiling points. The diarnine from the crystalline acid gave a Schifi base with piperonal which melted at 105-107". The mixed acids gave a low melting Schifi' base which could be separated by crystallization to give the high melting Schiff base plus an isomer which melted at 74-755". The latter product was also isolatable in small amounts from the mother liquors from recrystallization of the Schiff base derived in two steps from the crystalline acid. This indicates incomplete separation of the isomeric acids.

The following examples are given for specific illustra- Li AlHi The his primary amines used as the starting materials to form the compounds of the class may be obtained according to the procedure of Hall, Mahboob and Turtion of the invention but it should be understood that these are selected for illustration of the invention and are not to be considered as limitative.

I. Starting with the primary bis-amine, 5,1l-diaminopentadecane prepared from the crystalline dicarboxylic acid the intermediate N,N'-dipiperonylidene-5,ll-diaminopentadecane was initially prepared by mixing 260 grams or 1.07 moles of the amine with 338 g. or 2.25 moles of piperonal in three liters of absolute alcohol and 500 ml. or" dry benzene. The mixture was heated to reflux and one liter of distillate Was removed through a 30" column. The crystalline solid which separated on cooling of the residue, was filtered and dried. It weighed 490 g. and melted at l107. ing 55 g. and melting at 105107 was obtained for conisomer of N,Ndipiperonyl-5,1l-diaminopentadecane 2 HCl which melted at 175176 mixed M.P. with the high melting isomer, 163-165 Percent N found was 4.77 as 10 compared with the theoretical of 4.80% calculated for from the higher melting Schitf base was measured at 50-100 rig/ml. WEL and that from the lower melting Schilf base was 100 rig/ml.

EXAMPLE 2 A second crop Weigh- Preparation of N,N'dipiperonyl-5,IO-diaminotetradecane dihydrochloride C4Ha 04H H2o0 centration of the mother liquor. Percent N found, 5.46; calc. for C H H O 5.52%. The total yield was 545 g., which is practically quantitative. In some cases recrystallization from alcohol has been necessary in order to get material of proper melting point.

II. 200 g. of the high-melting Schiff base, MP. 105- 107", were made up to one liter with absolute alcohol. 15 grams of Raney nickel catalyst were added and the mixture was reduced at an initial hydrogen pressure of 1000 p.s.i., first at room temperature and with a final heating to 80. Reduction was complete in two to three 39 found 13.01; calcd for C H Cl N O 12.45%.

Its amebicidal activity level Was measured and found to be 100 ,ug/ml. WEL.

EXAMPLE 3 Preparation of N,N-di(p -methoxybenzyl)-5,I0-diamino- 2,13-dimethyltetradecane verted melted at 53-54.

This material was obtained by reduction of 5,10-diamino-2,13-dimethyl tetradecane and p-methoxybenzaldehyde according to the procedure of Example 1. The dihydrochloride to which the reduced product was con- Percent N found was 4.79; calculated for C32H54Cl N2O2,

the residue was then taken up in 500 ml. of anhydrous ether and added to 500 ml. of isopropanol saturated with excess anhydrous HCl. The crystalline solid, which sep- 55 arated, weighed 218 g., and melted at 178-180. Recrystallization from absolute alcohol gave 202 g. of

H2C(|) the acid addition salt which melted at 1S3184. Percent N found, 4.82; calc. for C H Cl N O 4.80%.

IV. By exhaustive recrystallization of material isolated from the mother liquors from the preparation of a large batch of the high melting Schiff base, the low melting Schiff base having a melting point of 7475.5 was also isolated. Percent N found, 5.48; calc. for C H N O 5.52%. 21.5 grams of this low melting Schifif base was similarly reduced, as in the case of the higher melting Schiff base, in absolute alcohol using a Raney nickel catalyst. The reduced product was also converted to its dihydrochloride and recrystallized from a mixture of absolute alcohol and ethyl acetate to yield the low melting 7.5

| OCH2 Its amebicidal activity level was measured as described above and determined to be 50 ,ag/ml. WEL.

EXAMPLE 4 Preparation of N,N'-dipiperonyl-5,10-diamin0-2,13-dim ethyltetradecane dihydrochloriae 65 to the procedure of Example 1. The dihydrochloride to which the reduced product was converted melted at 86- 88. Percent N found was 4.82; calculated for Its amebicidal activity level was measured as described above and determined to be ,ug./ml. WEL.

7 8 EXAMPLE Its amebicidal activity level was measured as described Preparation of N,N'-dibenzyl-I,6-dicycl0hexyl-1,6-diamiabove and determined to be 100 ugjmlno-hexane dihydrochloride EXAMPLE 8 L m gfl 5 Preparation of N,N-dz'veratryl-1,6-diamino-1,6-dicyclohexylhexane dihydrachloride CHsO 0 CH3 I (3611a QcHn l This material was obtained from 1,6-diami11o-L6-dicy- This material was obtained by reduction of 1,6-diclohexylhexane and veratraldehyde according to the proamino-1,6-dicyclohexylhexane and benzaldehyde accord- Cedure 0f EXample After Crystallization, the y ing to the procedure f Example The dihydmchloride 15 chloride melted at 237-245. Percent N found was 4.32; which was subsequently obtained melted at 259-264". Calculated for ae ss z z e, 423%- Percent N found was calculated for CsZHEOClZNZ, Its amebicidal activity level was measured as described 526% above and determined to be 100 ,ug/ml. WEL.

Its amebicidal activity level was measured as described EXAMPLE 9 above and determined to be 100 ,ug./ml. WEL. Preparation of N,N'-di(3,4,5-trimethoxybenzyl)-1,6-diamino-1,6-dicycl0hexylhexane dihydrochloride 01 130 OCH:

(36 1: (EGHII CH-C C11 NH-0H-(OH9 tCHNHOHzO OHa-2HC1 IFHaO CHa EXAMPLE 6 This material was obtained from l,6-diamino-1,6-dicy- Preparation of N,N-dz'(p-hydroxybenzyl)-1,6-dia i clohexylhexane and 3,4,S-trimethoxybenzaldehyde ac- 1,6-dicycl0hexylhexane dihydrobromide cording to the procedure of Example 1. After crystal- Ca u 05 11 To 100 ml. of 48% hydrobromic acid and 50 ml. of 5 lization, the dihydrochloride melted at 236239. Perglacial acetic acid was added 12 g. of N,N-dibenzyl-l,6- cent N found was Calculfltfld for 38 62 2 2 s, dicycloheXyl-1,6-diaminohexane dihydrochloride from 333%- Example 5 and the mixture was refluxed for 4 hours Its arnebicidal activity level was measured as described The acetic acid was removed by distillation. On cooling above and datermmed to be 100 the residue a thick brown syrup separated. The aqueous EXAMPLE 1O layer was poured off and the syrup was partially dried Preparation of N,N'-dipiper0nyl-5,11-diamin0-2,14-di by heating in a water bath under vacuum, dissolved in hot methylpentadecane dihya'rochloride Q5 1i i (fHll (JGoH2NHoH oH2)5oH NH-orr2-o-2Ho1 uzo o (F-(3H This material Was obtained from 5,1l-diamino-2,l4-dimethylpentadecane and piperonal according to the procedure of Example 1. After crystallization, the dihydrochloride melted at 74-76". Percent N found Was 4.71;

isopropyl alcohol and dried over magnesium sulfate. The dried solution was concentrated to 100 ml. and diluted with 100 ml. of hot ethyl acetate. A crystalline prodcalcul A aLed for C3 H52Ci2N O4, not separated- Percent N found was calculated for Its amebicidal activity level was measured as described sz so zNzpz W above and determined to be 100 ,ugJml. WEL.

Its amebicidal activity level was measured as described 55 EXAMPLE 11 above and detfirmmed to be 100 Preparation of N,N'-a'iveratryl-5,11-diamin0-2,14-dimethylpentadecane dihya'rochloride i-CfsHn i %a n HaC Q' OH2NH0H oH2)sCHNHCIL0 0153-21101 H300 ()CH;

EXAMPLE 7 This material was obtained from 5,ll-diarnino-2,l4- preparation f N, d b l 1,6-di i dirnethylpentadecane and veratraldehyde according to the 1,6-dicycl0hexylhexane dihydrochl'oride procedure of Example 1. After crystallization from the IJn ii l s u This material was obtained from solvent, the dihydrochloride melted at 67-69. Percent clohexylhexane 'p-methoxybenzaldehyde according to the 1 procedure of Example 1. The dihydrochloride melted N found i f for C35H6UC12N2O4, to Percent N found was calculated for Its amebrcidal activity level was measured as described C H C1 N O 4,72%, above and determined to be -5O ag/ml. WEL.

9 EXAMPLE 12 Preparation f N,N-di(3-phenylpropyl) -5,]1diamin0- 2,14-dimethylpentadecane dihydrochloride i-C Hu i-C5Hu This was obtained from 5,12-diaminohexadecane and p-methoxybenzaldehyde according to the procedure of Example 1. The dihydrochloride to which the reduced This material was obtained from 5,ll-diamino-2,14-dimethylpentadecane and cinnamaldehyde according to the procedure of Example 1. calculated for CH Cl2N Its amebicidal activity level was measured as described above and determined to be 50 ,ug/ml. WEL.

Hz EXAMPLE 13 Preparation of N ,N '-di 3 p-metlwxyphenyl propyl] -5, l1-diaminc-2,14-dimethylpentadecane dihydrochloride i-CsHn IC5Hn This material was obtained from 5,l1-diamino-2,14-dimethylpentadecane and p-methoxycinnamaldehyde according to the procedure of Example 1. The dihydrochloride melted at 233-236. Percent N found was 4.34; calculated for C H Cl N O 4.38%.

Its amebicidal activity level was measured as described above and determined to be 50 ,ug/ml. WEL.

IIsCO EXAMPLE 14 Preparation of N,N'-dibenzyl-5,IZ-diamino-hexadecane dihydrochloride C-lHQ 94119 This material was obtained from 5,12-diamin0hexadecane and benzaldehyde according to the procedure of Example 1. The dihydrochloride to which the reduced product was converted melted at 186-188". Percent N found was 5.55; calculated for C H Cl N 5.50%.

Its amebicidal activity level Was measured as described above and determined to be 50 ug/ml. WEL.

HaCO- H300 EXAMPLE 15 Preparation of N,N-di(p-hydroxybenzyl) 5,12-diamin0- hexadecane dihydrobromide C4119 C-IHQ Percent N found was 4.87; 10

40 Example 1.

product was converted melted at -164. Percent N found was 4.96; calculated for C H Cl N O 4.96%.

Its amebicidal activity level was measured as described above and determined to be 50 ng/ml. WE

EXAMPLE 17 Preparation of N,N'dipz'per0nyl 5,12-diamin0hexadecane dihydrochloride C4H9 04H;

This material was obtained from 5,12-diaminohexadecane and piperonal according to the procedure of Example l. The dihydrochloride melted at 186-189". Percent N found was 4.72; calculated for C H Cl N O 4.68%.

Its amebicidal activity level was measured as described above and determined to be 100 ,ag/ml. WEL.

EXAMPLE 18 Preparation of N,N-diveratryl 5,12 diaminohexadecane dihydrochloride 04119 CHI CHa This material was obtained from 5,12-diamin0hexadecane and veratraldehyde according to the procedure of The dihydrochloride melted at 163166.

Percent N found was 4.47; calculated for C H Cl N O 4.45%.

Its amebicidal activity level was measured as described above and determined to be 100 g/ml. WEL.

EXAMPLE 19 50 Preparation of N,N'-di(3,4,5-trimethoxybenzyl) 5,12-diaminohexadecane dihydrochloride O CH: C4119 C411 I C )CHa This material was obtained from 5,12-diamin0hexadecane and 3,4,5-trimethoxybenza1dehyde according to the procedure of Example 1. The dihydrochloride melted This was prepared by treatment of the compound of Example 16 with 48% HBr as described in connection with Example 6 above. The dihydrobromide melted at 182. Percent N found was 4.42; calculated for C30H50Br N O2, 4.44%.

Its amebicidal activity level was measured as described above and determined to be 100 g/ml. WEL.

EXAMPLE 16 Preparation of N,N'-di(p-methoxybenzyl) 5,12, diaminohexadecane dihydrochloride 3,013,020 11 12 This material was obtained from 3,14-diaminohexadecane and benzaldehyde according to the procedure of EXAMPLE 24 Preparation of N,N-di(3,4,5-trimethoxybenzyl)-3,14-

Example 1. Percent N found was 5.66; calculated for C H Cl N 5.51%. diaminohexadecane dihydrochloride This material was obtained from 3,14-diaminohexadecane and 3,4,S-trimethoxybenzaldehyde according to the procedure of Example 1. Percent N found was 4.09;

r calculated for C H Cl N -O 4.07%.

Its amebicidal activity level was measured as described above and determined to be 50 ,wgjml. WEL.

Its amebicidal activity level was measured as described above and determined to be 50 ug./ ml. WEL.

EXAMPLE 21 Preparation of N,N'-di-p-hydr0xybenzyl 3,14-diamin0- hexadecane dihydrobromide This was prepared by demethylation of the corresponding dimcthyl ether with 48% HBr, as described in Example 6 above. Percent N found was 4.35; calculated for CgqHmBIgNgOz, 4.44%.

EXAMPLE 25 Preparation of N,N'(p-meth0xybenzyl)-5,16-diaminoeicosane dihydrochloride Its amebicidal activity level was measured as described above and determined to be gjml. WEL.

EXAMPLE 22 Preparation of N,N-dipiper0nyl 3,14-diamin0hexadecane dihydrochloride This material was obtained from 3,14-diaminohexadecane and piperonal according to the procedure of Ex- EXAMPLE 26 ample 1. Percent N foundwas 4.91; calculated for Preparation of N,N-dipiperonyl-5,16-diaminoeicosane C3QH50C12N202, 4.70%. dihydrochloride (lh o (MI-I9 (1)00Hz-NEOH(CH2)mCH-NHCHQT&HCI

Its amebicidal activity level was measured as described above and determined to be 50 ag./ ml. WEL.

This material was obtained from 5,16-diaminoeicosane and piperonal according to the procedure of Example 1. Percent N found was 4.34; calculated for C I-I C1 N O EXAMPLE 23 4 29% Prep rati of N,N-diveratryl-3,14-diaminohexadecane Its amebicidal activity level was measured as described dihydrochloride above and determined to be 50 g./ ml. WEL.

C2 5 C2135 HZC 0- CH2-NHCH(CHa)1o-CH-NHCH, 00113-21101 H300 OCH; This material was obtained from 3,14-diarninohexa- Emu IPLE 27 decane and veratraldehyde according to the procedure of 5 Preparation of N,N'-diverazryl-5,16-diaminoeicosane dihydrochloride l H300 OCH;

This material was obtained from 5,16-diaminoeisocane and veratraldehyde according to the procedure of Example 1. Percent N found was 404; calculated for Example 1. Percent N found was 4.50; calculated for C34H53C12N204,

Its amebicidal activity level was measured as described above and determined to be 50 g./ ml. WEL.

Its amebicidal activity level was measured as described 2. A symmetrical bis-amine having the formula:

fsHn (lls n (|)O(CH2),NHOH(CHzh-CH-NH-(CHz)XQ(F H2C--(|) O--CH3 above and determmed to be 50 wherein n is an integer of 2 to 10 and x is an integer of EXAMPLE 28 1 t 3.

3. N,N'-dipiperonyl-5 ,1 l-dian'iinopentadecane.

I Prepamnon of dip 1p eronyl dmmmopema l0 4. N,N-dipiperonyl-5,l'0-d1am1notetradecane.

decane dihydrochloride IlCH DC5H1i This material was obtained from 6,10-diaminopenta- 5. A symmetrical bis-amine having the formula:

H2C 0-0H, decane and piperonal according to the procedure of Exwherein x is an integer of 1 to 3 and n is an integer of ample 1. Percent N found 4.79; calculated for (3 1-11 2 to 10.

Cl N O 4.80%. 6. N, N-dipiperonyl-3,14-diaminohexadecane.

Its amebicidal activity level was measured as described 7. N,N'-dipiper0nyl-6,IO-diaminopentadcane. above and determined to be 10 g/ml. WEL.

Having described my invention, I claim:

1. A compound selected from the group consisting of References Cited in the file of this patent UNITED STATES PATENTS blsflamlnes of the formula szajbo Feb. 3, f I 2,653,977 Craig et al. Sept. 29, 1953 Y-(CHz)FNHCH(CH2)nCHNH(CH2)X-Y 2,739,981 Szabo Mar. 27, 1956 wherein R is a monovalent hydrocarbon radical selected 2,746,959 Bruce y 212, 1956 from the group consisting of alkyl of 2 to 5 carbon atoms FOREIGN PATENTS and cyclohexyl, Y is a moiety from the group consisting of phenyl, monohydroxyphenyl, monomethoxyphenyl, di- 611,476 Great Bntam 1 methoxyphenyl, trimethoxyphenyl and methylenedioxyphenyl, x is an integer of 1 to 3 and n is an integer of 2 to 10, and pharmaceutically acceptable acid addition 40 salts thereof.

OTHER REFERENCES Wagner-Zook: Synthetic Organic Chemistry, Wiley, New York, page 728, 1953.

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Classifications
U.S. Classification549/435, 564/139, 564/367, 564/370, 560/190, 564/468, 564/276, 560/127, 564/511
International ClassificationC07D317/00, C07D317/44
Cooperative ClassificationC07D317/44
European ClassificationC07D317/44