US3668208A - Hexahydro imidazoquinolines - Google Patents

Abstract

A series of novel substituted hexahydro imidazoquinoline compounds have been prepared from the corresponding 2aminomethyl-1,2,3,4-tetrahydroisoquinolines. These compounds are useful in the field of chemotherapy as anti-schistosomal agents. Preferred members include 2-(lower alkyl)-7-methyl-8-nitro1,2,3,3a,4,5-hexahydroimidazo-(1,5-a)-quinolines, 2-(lower alkyl)-7-hydroxymethyl-8-nitro-1,2,3,3a,4,5-hexahydroimidazo(1,5-a) -quinolines and 2-(lower alkyl)-7-methyl-8-chloro1,2,3,3a,4,5-hexahydroimidazo-(1,5-a)-quinolines, as well as various 1- and 9-substituted derivatives thereof.

Description

United States Patent Baxter 14 1 June 6, 1972 [541 HEXAI-IYDRO IMIDAZOQUINOLINES 3,557,120 1/1971 Archer ..260/288 [72] Inventor: Charles A. R. Baxter sandwich, England 3,565,902 2/1971 Wright ..260/268 [73] Assignee: Pfirer Inc., New York, NY. FOREIGN PATENTS 0R APPLICAT'ONS 22 Filed; 13, 1970 1,166,538 10/1969 Great Britain ..260/288 [21 1 Appl' Primary Examiner-Donald G. Daus Attorney-Connolly and Hutz [30] Foreign Application Priority Data Feb. 19, 1969 Great Britain ..8,882/69 [57] ABSIRACT A series of novel substituted hexahydro imidazoquinoline [52] U.S.Cl. ..260/283 S, 260/268 C, 260/283 CN, compounds have been prepared from the corresponding 2.

260/286 R, 260/288 R, 7 R, 42 /25 aminomethyl-l,2,3,4-tetrahydroisoquinolines. These com- [5 Int. Clpounds are useful in the of chemotherapy 35 anti- [58] Field of Search ..260/288, 287, 283 S schiswsoma] agents P f d ber include 2-(lower alkyl )-7-methyl-8-nitrol ,2,3,3a,4,5-hexahydroimidazo-[ l ,5- [56] References Clted a]-quinolines, 2-(lower alkyl)-7-hydroxymethyl-8-nitrol,2,3,3a,4,5-hexahydroimidazo-[ 1,5-a]-quinolines and 2- UNlTED STATES PATENTS (lower alkyl)-7-methyl-8-chloro-1,2,3 ,3a,4,5-hex- 3,253,986 5/1966 Franklin ..260/288 ahydroimidazo [1,5 a;-quin]ines, as we as various and 9- 3,329,620 1968 Archer et substituted derivatives thereof. 3,454,579 7/1969 Wright 3,393,195 7/1968 Thesing ..260/288 10 Claims, No Drawings HEXAHYDRO MDAZOQUINOLINES BACKGROUND OF THE INVENTION This invention relates to certain new and useful hexahydro imidazoquinoline compounds of principal interest to those in the field of chemotherapy. More particularly, it is concerned with various novel substituted hexahydro imidazoquinolines and their non-toxic acid addition salts,-which are of especial value in view of their anti-schistosomal properties.

Inthe past, various attempts have been made by numerous investigators in this particular field of therapy to obtain new and still better forms of agents and/or methods for the treatment of schistosomiasis. In many instances, these efforts have further involved the synthesis and testing of various new organic compounds, particularly in the category of nitrogen heterocycles. For instance, in British Pat. No. 837,306, there is disclosed a series of dicarboxylic acid monopiperazides with a 3-halogen-4-methylphenyl moiety located at the 1-position of the piperazine ring that are reported as being active against schistosomiasis. However, little is known about the effect of other di-nitrogen ring heterocycles in this area and the existing therapy, unfortunately, still suffers from a number of known drawbacks, such as, e.g., relatively low potency (requiring more than a single dose of therapy), problems of toxicity, the lack of a demonstrated prophylactic effect, etc.

SUMMARY OF THE INVENTION In accordance with the present invention, it has now been surprisingly found that certain novel substituted hexahydro imidazoquinoline compounds are extremely useful when employed in the field of drug therapy as anti-schistosomal agents. The novel compounds of this invention are all selected from the group consisting of substituted l,2,3,3a,4,5-hexahydroimidazo-[ l,5-a]-quinline bases of the formula:

and the N-oxide derivatives and pharmaceutically acceptable acid addition salts thereof, wherein R, is a member selected from the group consisting of alkyl having from one to six carbon atoms, hydroxyalkyl having from two to six carbon atoms, alkoxyalkyl having from two to six carbon atoms in the oxyalkyl moiety and from one to six carbon atoms in the alkyl moiety, alkanoyloxyalkyl having from two to six carbon atoms in the oxyalkyl moiety and from two to six carbon atoms in the alkanoyl moiety, cycloalkyl having from three to six carbon atoms and phenylalkyl having up to three carbon atoms in the alkyl moiety; R is a member selected from the group consisting of methyl, formyl, hydroxymethyl, alkoxymethyl having from one to six carbon atoms in the alkyl moiety and alkanoyloxymethyl having from two to six carbon atoms in the alkanoyl moiety; R is a member selected from the group consisting of nitro, cyano, fluorine, chlorine and bromine; R and R are each a member selected from the group consisting of hydrogen and alkyl having from one to six carbon atoms, and R is a member selected from the group consisting of hydrogen, alkyl having from one to six carbon atoms, phenylalkyl having up to three carbon atoms in the alkyl moiety, phenyl, nitrophenyl, naphthyl, furyl, thienyl' and pyridyl. These compounds all possess anti-schistosomal activity and are therefore, useful in the treatment of schistosomiasis and/or for the control of schistosome infections.

Of especial interest in this connection are the preferred atoms (and most preferably, a branched-chain alkyl having 3-4 carbon atoms, e.g., isopropyl), R is methyl, hydroxymethyl, or ethoxymethyl, R is nitro or chloro, R, is hydrogen, R, is hydrogen or methyl, and R is hydrogen, methyl, ethyl, phenyl, nitrophenyl or thienyl. Typical member compounds of the preferred class include such 2-(lower alkyl)-7-methyl (or hydroxymethyl)-8-nitro (or chloro)- 1,2,3,3a,4,5-hexahydroimidazo-[ l,5-a]-quinolines as 2- isopropyl-7-methyl-8-nitrol ,2,3 ,3a,4,5-hexahydroimidazo-[ l ,S-al-quinoline, 1 ,7-dimethyl-2-isopropyl-8-nitrol ,2,3,3a,4,5-hexahydroimidazo-[ l,5-a]-quinoline, 2- isopropyl7-hydroxymethyl-8-nitrol ,2,3 ,3a,4,5-hexahydroimidazo-[ l ,S-aI-quinoline, l-ethyl-2-isopropyl-7- methyl-S-nitrol ,2,3,3a,4,5hexahydroimidazo-[ l ,5-a]-quinoline, l-phenyl-2-isopropyl-7-methyl-8-nitro-l ,2 ,3 ,3 a,4,5 hexahydroimidazo-[ l,5-a]-quinoline, 2-isopropyl-7,9- dimethyl-8-chlorol ,2,3,3a,4,5-hexahydroimidazo-[ 1 ,5a]- quinoline, 1,2,7-trimethyl-8-nitrol ,2,3,3a,4,5-hcxahydroimidazo-[ l ,5-a]-quinoline, l-( 2-thienyl)-2-isopropyl- 7-methyl-8-nitrol ,2,3,3a,4,5-hexahydroimidazo-[ l ,5-a]- quinoline, l-(2-nitrophenyl)-2-isopropyl-7-methyl- 8-nitrol,2,3,3a,4,5-hexahydroimidazo-[l,5-a]-quinoline and lmethyl-2-isopropyl-7-ethoxymethyl-8-nitrol ,2 ,3 ,3a,4,5-hexahydroimidazo-[ l,5-a]quinoline, respectively. These particular compounds are all highly potent as regards antischistosomal activity.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the process employed for preparing the novel compounds of this invention, an appropriately substituted 2-aminomethyl-1,2,3,4-tetrahydroquinoline (see British Pat. No. 1,166,538) is treated with an aldehyde of the formula li -CHO, where R; is defined as aforesaid. This particular reaction is normally carried out in the presence of a suitable solvent for the aldehyde, e.g., water or ethanol, or it may be carried out in the absence of a solvent by merely suspending the tetrahydroquinoline compound in the liquid aldehyde. In general, the reaction is conducted at a temperature that is in the range of from about 0 C. to about C. for a period of about 15 minutes to about four hours.

The N-oxide derivatives of the compounds of this invention, i.e., N-oxide derivatives of the aforementioned novel substituted hexahydro imidazoquinolines, may be prepared by simply using well-known synthetic methods to efiect such a conversion from the parent compound, e.g., oxidation via 30 percent hydrogen peroxide or benzoyl peroxide, etc. The esters of those compounds containing free hydroxyl groups are also prepared by conventional means.

Inasmuch as the substituted hexahydro imidazoquinoline compounds of this invention all possess asymmetric carbon atoms at positions 1 and 3a of the imidazoquinoline fused ring system, they may exist in separated dand l-optically active forms, as well as in racemic dl-mixtures necessarily produced by the present synthetic methods as hereinbefore described. The invention contemplates the d, land racemic forms within its scope.

The acids which are used-to prepare the pharmaceuticallyacceptable acid addition salts of the aforementioned hexahydro imidazoquinoline base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate, methanesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1- methylene-bis-2-hydroxy-3-naphthoate) salts.

The compounds of the invention can be administered alone, but will generally be administered in conjunction with a pharmaceutical carrier. The carrier is normally selected with regard to the intended route of administration, as well as standard pharmaceutical practice. For example, these compounds may be administered orally in the form of tablets containing excipients such as starch or milk sugar (lactose), or in cap sules either alone or on admixture with excipients, or else in the fonn of elixirs or suspensions containing flavoring or coloring agents, etc. For purposes of parenteral administration, they are best used in the form of a sterile aqueous solution of a water-soluble salt (e.g., the methanesulfonate salt), which solution may also contain sufficient saline or glucose to render the final composition isotonic.

The activity of the compounds of the present invention, as schistosomicides, has been determined by a technique which depends on the movement of adult sehistosomes from their normal sites in the mesenteric veins to the veins within the liver, as effected by chemotherapeutically-active compounds. This technique has been described in detail in the Journal of Tropical Medicine & Hygiene, Vol 71, pp. 139-145 (June, 1968). In the present case, white mice of 3-4 weeks age were infected percutaneously with 120 cercariae of Schistosoma manroni (East African strain). Eight weeks after infection, the compound to be assessed was administered orally or intraperitoneally at a basic dosage of 25 mg./kg. daily for a period of 4 days, or at 50 mg./kg. in a single dose. Efficacy was then assessed 24 hours after the last dose of multiple dosage, or 72 hours after a single dose. Mice were perfused post mortem to recover the worms separately from the mesenteric veins, as well as from the hepatic portal vein and from the veins within the liver. The proportional movement of worms from the portal and mesenteric veins to the veins within the liver formed the basis for the assessment.

EXAMPLE 1 A suspension of 2-isopropy1aminomethyl-6-methyl-7-nitrol,2,3,4-tetra-hydroquinoline (1.5 g.) in formalin (10 ml.) was mechanically shaken for a period of two hours, after which time a dark-red solid precipitated. The reaction mixture was then treated with water containing 5N sodium hydroxide solution (20 ml.) and extracted with diethyl ether (2 X 75 ml.). The ethereal solution was dried over anhydrous magnesium sulfate and evaporated in vacuo to yield a viscous blood-red oil, which crystallized on standing. The latter material was subsequently dissolved in hot petroleum ether (b.p. 6080 C.), filtered and allowed to cool to room temperature (-25" C.) to yield 2-isopropyl-7-methyl-8-nitro-1,2,3,3a,4,5-hexahydroimidazo-[ l,5-a]-quinoline (1.25 g.) in the form of red clusters, m.p. 83-84 C.

Anal.

Calcd. for C, H ,N O C, 65.46; H, 7.64; N, 15.27. Found: C, 65.30; H, 7.56; N, 14.96.

EXAMPLE 11 A solution of acetaldehyde (2.5 ml.) in absolute ethanol ml.) was added to a solution of 2-isopropylaminomethyl-6- methyl-7-nitro-1,2,3,4-tetrahydroquino1ine 1.0 g.) in absolute ethanol (30 ml.). The slightly exothermic reaction mixture was then allowed to stand at room temperature (25 C.) for 2 hours, after which time the solution was concentrated in vacuo. The resulting orange oil was dissolved in hot petroleum ether (b.p. 6080C.) and thereafter allowed to cool to afford 1,7-dimethyl-2isopropyl-8-nitrol ,2,3,3a,4,5-hexahydroimidazo-[1,5-a]-quinoline (0.75 g.) as an orange fluffy solid, m.p. l03-l04 C.

Anal.

Calcd. for c,.,H,,N,0,; C, 66.43; H, 7.96; N, 14.53. Found: C, 66.23; H, 7.81; N, 14.29.

EXAMPLE I11 Formalin 20 ml.) was added to a solution of 6-hydroxymethyl-2-isopropyl-aminomethy-7-nitro-1,2,3,4- tetrahydroquinoline (2.0 g.) in ethanol (125 m1.) and the resulting reaction mixture was set aside at room temperature =25 C.) for a period of four hours. The solvents were then removed from the solution in vacuo, and the crude product obtained in this manner was subsequently treated with dilute aqueous sodium hydroxide (5N) and then extracted with chloroform (2 X 75 ml.). The chloroform solution was dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 2-isopropyl-7-hydroxymethyl-8nitro-1,2,3,3a,4,5- hexahydroimidazo-[1,5a]-quinoline, which recrystallized from methanol as a golden yellow fluffy solid (1.85 g.), m.p. l59160 C. Anal.

Calcd. for C H N O C, 61,86; H, 7.22; N, 14.43.

Found: C, 62.00; H, 7.01; N, 14.10.

EXAMPLE 1V Propionaldehyde (5 ml.) was added to a solution of 2- isopropylaminomethyl-6-methyl-7-nitrol ,2,3 ,4- tetrahydroquinoline 1.6 g.) in ethanol (50 ml.). After about 15 minutes, an orange solid precipitated and the reaction mixture was then allowed to stand at room temperature (=25 C.) for a further 2 hours. The mixture was then filtered, and the orange fluffy solid washed with ethanol and dried in vacuo to yield 1.4 g. of l-ethyl-2-isopropyl-7-methyl-8-nitro- 1 ,2,3,3a,4,5-hexahydroimidazo-[ l,5-a]-quinoline, m.p. l22-124C.

Anal.

Calcd. for C, H ,-,N O C, 67.33; H, 8.25; N, 13.85. Found: C, 67.26; H, 8.12; N, 13.75.

EXAMPLE V A large excess of benzaldehyde (7.1 g.) was added to a wellstirred solution of 2-iospropylaminomethyl-6-methyl-7-nitro- 1,2,3,4-tetrahydroquionoline (1.5 g.) in absolute ethanol (20 ml.) which was warmed to about 50 C. via a water-bath. After stirring for a period of 4 hours, a further quantity of benzaldehyde (10 ml.) was added to the mixture and the resulting reaction solution was maintained at this point (i.e., 50 C.) for a further 3 hours. The alcohol was then removed by means of evaporation under reduced pressure, and the crude product so obtained was subsequently dissolved in benzene and chromatographed on a neutral alumina column, using benzene as the eluent. The first 25 ml. of eluent was shown by thin-layer paper chromatographic analysis to contain benzaldehyde and a compound which was not the original starting material. The benzaldehyde was removed (and recovered) by distillation in vacuo (b.p. 65C./ 18 mm. Hg.) and the residue dissolved in hot petroleum ether (b.p. 60-80 C.). On cooling to room temperature, the solution soon deposited l-phenyl-2- isopropyl-7-methyl-8-nitro-1,2,3,3a,4,5-hexahydroimidazo- [1,5-a]-quinoline (850 mg.) as orange crystals, m.p. l30l3l C.

Anal.

Calcd. for C ,H N O C, 71.77; H, 7.17; N, 11.96. Found: C, 71.71; H, 7.06; N, 12.19.

EXAMPLE VI A mixture of formalin 10 ml.) and 7-chloro-6,8-dimethyl-2 -isopropylaminomethyl-1,2,3,4-tetrahydroquinoline 1.05 g.) in ethanol (30 ml.) was shaken for a period of one hour. The reaction mixture was then poured into water and the resulting white solid extracted into diethyl ether. The ethereal solution was dried over anhydrous magnesium sulfate and subsequently evaporated in vacuo to yield a colorless oil, which was then dissolved in ethyl acetate and treated with a solution of one equivalent of maleic acid in hot ethyl acetate. Upon the addition of dry diethyl ether to the combined ethyl acetate solution, there were ultimately obtained 1.2 g. of 2-isopropyl- 7,9-dimethyl-8-ch1oro-1,2,3,3a,4,5-hexahydroimidazo-[ l ,5- a]-quinoline hydrogen maleate as a white powder, m.p. 133 C.

Anal.

Calcd. for C,,,l-1 ClN -C H O C, 60.80; H, 6.89; N, 7.09. Found: C, 60.83; H, 6.74; N, 6.53.

EXAMPLE VIII Thiophene-Z-aldehyde and 2-isopropylaminomethyl-6- methyl-7-nitro-l,2,3,4-tetrahydroquinoline were reacted in ethanol in the manner described in Example 11 for acetaldehyde, except that the reaction-time period was extended to 17 hours. The red oil obtained on evaporation of the alcohol was crystallized from petroleum ether (b.p. 60-80 C.) and then twice recrystallized from n-hexane to yield l-(2-thienyl)- 2-isopropyl-7-methyl-8-nitro- 1 ,2,3,3a,4,5-hexahydroimidazo- [1,5-a]-quinoline as a yellow fluffy solid, mp. 134-l 35 C. Anal.

Calcd. for c,,H,,N,o,s: C, 63.86; H, 6.44; N, 11.76.

Found: C, 63.94; H, 6.59; N, 11.74.

EXAMPLE IX o-Nitrobenzaldehyde was reacted with 2- isopropylaminomethyl-6-methyl-7-nitro 1 ,2,3,4- tetrahydroquinoline in the same manner as described in Example V for benzaldehyde, except that the reaction mixture was refluxed on a steam bath in order to ensure completeness. After chromatographing in the usual manner to eliminate impurities, 1-( 2-nitropheny1)-2-isopropyl-7-methyl-8-nitro- 1 ,2,3,3a,4,5-hexahydroimidazo-[ 1,5-a]-quinoline was obtained, m.p. 95-97 C. Anal.

Calcd. for C M- M0 C, 63.63; H, 6.06; N, 14.14

Found: C, 63.37; H, 6.19; N, 14.32.

EXAMPLE X A solution of 6-ethoxymethy1-2-isopropylaminomethyl-7- nitro-l,2,3,4-tetrahydroquinoline (2.5 g.) in ethanol (90 ml.) was treated with an alcoholic solution of acetaldehyde (7.5 ml.) in ethanol (30 mL). A mildly exothermic reaction then ensued and after 1 hour, thin-layer paper chromatographic analysis indicated that the reaction was essentially complete. The reaction solution was then evaporated to dryness while under reduced pressure to give 1-methyl-2-isopropyl-7-ethoxymethyl-8-nitro-1,2,3,3a,4,'5-hexahydroimidazo-[ l,5-a]-quinoline as an orange solid, which was subsequently recrystallized from ethanol to yield 1.6 g. of product, m.p. l03-105C. Anal.

Calcd. for C I-I N O C, 64.85; H, 8.1 l; N, 12.62.

Found: C, 64.45; H, 8.39; N, 12.62

EXAMPLE XI The following substituted hexahydro imidazoquinoline compounds are prepared by employing the condensation procedure described in the previous examples, starting from the corresponding Z-aminomethyl-l,2,3,4 tetrahydroquinoline base and the appropriate aldehyde (R -CH0) reagent of choice in each instance:

R1 R2 R3 RI R5 0 N02 H C2H5 CHa CI H n-CuH a H CI H CH3 H N 02 H H H N 02 H H H N02 CH3 CH3 n-CaHia N 02 H H H N02 H H CH N02 11-04110 H CflHf, N02 H H III'NO2C6H4 N02 H H p-NOzCuHr N02 H CH3 3-thienyl. N0 H CH Z-thienyl No: II H I1-CuH13 0 N02 11 H CH3 CHQCHQOH CH3 Bl C2H5 H CaH5CH2 n-CuHnOH CHaOH CN n-CoHm H S-iuryl. CHzCHrO CQHIS (I1) CH3 F Il-CaHw ll-CaHn Z-Iuryl. II-CuHizC CH3 CHO Cl H n-CuHm H n-Czs nC0OCH2CHz CH3 Br H H CzHs CH COCCQHHUI)..- CHzOH N02 CH3 H CH5 CYOlO-CaHr CH: CN CH3 CH3 H CYQIO-CqHu CHO F H CH3 u-Naphthyl. CQHH2 CH: C] H H fl-Naphthyl CuH (CH2)a CHzOH Bl CzH H CH3 CH3 CH3 N02 H H ll-CqHl: CzH5 CH3 CN 11 II 3431118113 1. ISO-Ca 7 CHQO CO CH F ISO-C3H7 H 2-th1enyl. Tart-0 H CHa Cl ll-CaH'; n-CaH- CQI'I5(CH2)3 (CHa)zCHOH CHO Dr H ISO-CaH7 0-N02CH| CH2CHzOCH3 CH3 NO: ll II ISO-C3H7 CYClO-C4H1... CHQOCzIIr. CH3 II 1l-C H Cycle-0 115.. 3 1" (J11: 011 3-pyrldyl. CHQOCOCiIIH Cl H CH3 2-pyr1dyl. CH Br H II l-pyridyl. H13 CH3 N02 H H C5H5 s CH3 N02 H H 3-thienyl. n-CuHu CH3 H H 2-thieny1.

EXAMPLE xn A mixture of 2.0 g. of 2-isopropyl-7-methyl-8-nitro- 1,2,3,3a,4,5-hexahydroimidazo-[l,5-a]-quinoline and a three molar excess of 30 percent hydrogen peroxide in 15 ml. of acetone is stirred at room temperature ==2S C.) for a period of 3 days. An additional quantity of 30 percent hydrogen peroxide (a five molar excess) is then added and the stirring thereafter continued for a further seven hours. At this point, the reaction is substantially complete and the excess hydrogen peroxide is decomposed by the addition of platinum oxide to the spent mixture. Upon filtering and removal of the solvent by concentration in vacuo, there is obtained a viscous oil as the liquid residue. Trituration of the latter material with diethyl ether then gives a powdery solid, which is subsequently collected by means of filtration and recrystallized from acetone to afford pure 2-isopropyl-7-methyl-8-nitrol,2,3,3a,4,5-hexahydroimidazo-[ l,5-a]-quinoline N-oxide as a crystalline solid.

In like manner, the other N-oxide compounds of this invention are each similarly formed by merely employing the appropriate substituted l,2,3,3a,4,5-hexahydroimidazo-[ l ,5-a]- quinoline base as starting material in the above reaction procedure, in place of the particular quinoline base compound used previously.

What is claimed is:

1. A hexahydro imidazoquinoline compound selected from the group consisting of substituted l,2,3,3a,4,5hexahydroimidazo-[ l,5-a]-quinoline bases of the formula:

and the N-oxide derivatives and pharmaceutically acceptable acid addition salts thereof, wherein R, is alkyl having from one to six carbon atoms; R, is a member selected from the group consisting of methyl and hydroxymethyl; R, is a member selected from the group consisting of nitro and chlorine; R, is hydrogen; R, is a member selected from the group consisting of hydrogen and methyl; and R is a member selected from the group consisting of hydrogen, alkyl having from one to six carbon atoms, phenyl, nitrophenyl and thienyl.

2. A compound as claimed in claim 1 wherein R, is alkyl having from one to six carbon atoms, R, is methyl, R, is nitro, and R,, R, and R, are each hydrogen.

3. A compound as claimed in claim 1 wherein R, is alkyl having from one to six carbon atoms, R, and R, are each methyl, R is chlorine, and R and R are each hydrogen.

4. A compound as claimed in claim 1 wherein R, is alkyl having from one to six carbon atoms, R, is hydroxymethyl, R, is nitro, and R,, R, and R, are each hydrogen.

5. A compound as claimed in claim 1 wherein R, and R, are each alkyl having from one to six carbon atoms, R, is methyl, R is nitro, and R and R, are each hydrogen.

6. A compound as claimed in claim 1 wherein R, is alkyl having from one to six carbon atoms, R, is methyl, R is nitro, R, and R are each hydrogen, and R,, is phenyl.

8. A compound as claimed in claim 1 wherein R, is alkyl having from one to six carbon atoms, R, is methyl, R is nitro, R, and R, are each hydrogen and R is thienyl.

9. The compound as claimed in claim 3 wherein R, is isopropyl and R is methyl.

10. The compound as in (ilailll 4 wherein R, is isopropyl.

Claims (9)

1. 2. A compound as claimed in claim 1 wherein R1 is alkyl having from one to six carbon atoms, R2 is methyl, R3 is nitro, and R4, R5 and R6 are each hydrogen.
2. 3. A compound as Claimed in claim 1 wherein R1 is alkyl having from one to six carbon atoms, R2 and R5 are each methyl, R3 is chlorine, and R4 and R6 are each hydrogen.
3. 4. A compound as claimed in claim 1 wherein R1 is alkyl having from one to six carbon atoms, R2 is hydroxymethyl, R3 is nitro, and R4, R5 and R6 are each hydrogen.
4. 5. A compound as claimed in claim 1 wherein R1 and R6 are each alkyl having from one to six carbon atoms, R2 is methyl, R3 is nitro, and R4 and R5 are each hydrogen.
5. 6. A compound as claimed in claim 1 wherein R1 is alkyl having from one to six carbon atoms, R2 is methyl, R3 is nitro, R4 and R5 are each hydrogen, and R6 is phenyl.
6. 7. A compound as claimed in claim 1 wherein R1 is alkyl having from one to six carbon atoms, R2 is methyl, R3 is nitro, R4 and R5 are each hydrogen, and R6 is nitrophenyl.
7. 8. A compound as claimed in claim 1 wherein R1 is alkyl having from one to six carbon atoms, R2 is methyl, R3 is nitro, R4 and R5 are each hydrogen and R6 is thienyl.
8. 9. The compound as claimed in claim 3 wherein R1 is isopropyl and R5 is methyl.
9. 10. The compound as in claim 4 wherein R1 is isopropyl.