US3787491A

US3787491A - Substituted sulfonyl urea and its stereoisomers

Info

Publication number: US3787491A
Application number: US00184902A
Authority: US
Inventors: K Grassmayr; Oehringen K Hohenlohe; A Grussner; H Bretschneider
Original assignee: Individual
Current assignee: Individual
Priority date: 1971-09-29
Filing date: 1971-09-29
Publication date: 1974-01-22
Anticipated expiration: 1991-01-22

Abstract

A HYPOGLYCEMIC AGENT, 1-(P-TOLUENESULFONYL)3-(2-HYDROXY-3-BORNYL)-UREA, IS PREPARED, FOR EXAMPLE, FROM TOSYL ETHYL URETHANE AND 3-AMINO-BORNEOL OR 3-AMINO-ISOBORNEOL. ONE OF THE ISOMERS, I.E., 1-((1R)-2-ENDO-HYDROXY-3-ENDO-BORNYL) - 3 - (P-TOLYLSULFONYL)-UREA, IS PARTICULARLY USEFUL AS A HYPOGLYCEMIC AGENT.

Description

3,787,491 SUBSTITUTED SULFONYL UREA AND ITS STEREOISOMERS Hermann Bretschneider, 11 Nikodemweg; Klaus Grassmayr, 65 Sistrans, near Innsbruck; and Kraft Hohenlohe-Oehringen, 26 Kartnerstrasse, all of Innsbruck, Austria; and Andre Grussner, 53 Oberer Rheinweg, Basel, Switzerland No Drawing. Filed Sept. 29, 1971, Ser. No. 184,902 Int. Cl. C07c 127/00 US. Cl. 260-553 D 3 Claims ABSTRACT OF THE DISCLOSURE A hypoglycemic agent, 1-(p-toluenesulfonyl)-3-(2-hydroxy-3-bornyl)-urea, is prepared, for example, from tosyl ethyl urethane and 3-amino-borneol or 3-amino-isoborneol. One of the isomers, i.e., 1-[(1R)-2-endo-hydroxy-3-endo-bornyl] 3 (p-tolylsulfonyl)-urea, is particularly useful as a hypoglycemic agent.

CROSS-REFERENCE TO RELATED APPLICATIONS The parent of this application is U.S. patent application Ser. No. 675,796, filed Oct. 17, 1967, now abandoned.

References applied by the Patent Ofiice in U.S. patent application Ser. No. 675,796 are:

U.S. Pat. No. 3,352,884; U.S. Pat. No. 3,334,302; and U.S. Pat. No. 2,968,158.

Other U.S. patents which show the state of the art are:

U.S. Pat. No. 2,928,871; and U.S. Pat. No. 3,155,721.

BACKGROUND OF THE INVENTION It is known that select compounds belonging to the class of benzene sulfonylureas are capable of lowering the blood sugar value in warm-blooded animals A benzene-sulfonylurea which is presently in wide commercial use as a hypoglycemic agent, i.e., tolbutamide, is described in U.S. Pat. No. 2,968,158. The recommended daily dose for tolbutamide ranges from 250 mg. to as much as 3000 mg. daily. Obviously", the advantages in providing a hypoglycemic agent which can function at least as etficaciously as tolbutamide at a substantially lower daily dosage regimen are apparent.

The present invention provides a hydroxybornyl-toly1- sulfonyl-urea which lowers the blood sugar values in warm-blooded animals and yet achieves this highly gainful result at significantly lower dosage amounts than are required for maintenance by a tolbutamide regimen. The hydroxybornyl-tolylsulfonylurea derivative of the present invention is characterized by the lack of undesirable side effects such as nausea, emesis and lower abdominal problems, as well as having very low toxicity. Also, because the toxicity of the compounds of the present invention is lower than tolbutamide and the daily dosage regimen is also very low, the therapeutic index thereof is extremely favorable when compared with tolbutamide, particularly with respect to the preferred l-[(1R)-2-endo-hydroxy-3- endo-bornyl]-3-(p-tolylsulfonyl)-urea of the invention.

United States Patent 0566? 3,787,491 Patented Jan. 22, 1974 BRIEF DESCRIPTION OF THE INVENTION In one aspect the invention relates to a l-(p-toluenesulfonyl)-3-(2-hydroxy-3-bornyl)-urea of the formula CH3- CH3 NHCONHSOa-QCH; (I)

and, particularly, the 1[(1R)-2-endo-hydroxy-3-endobornyl]-3-(p-tolylsulfonyl)-urea enantiomer, and salts thereof with pharmaceutically acceptable bases.

In another aspect, the invention relates to processes for preparing a compound of Formula I.

In yet another aspect, the invention relates to a method of lowering blood sugar levels in warm-blooded animals by administering a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION The invention relates to a 1-(p-toluenesulfonyl)-3-(2- hydroxy-3-bornyl)-urea of the formula NHGONHSOaQ-CH:

I CH:- CH:

and salts thereof with pharmaceutically acceptable bases. Stated another way, the invention relates to a compound of the formula 0H (endo) K- CH:

H i-zrrooNHsor-cm (endo) formula era-Q-somvn-oo on or a sulfonylisocyanate of the formula CHz-Q-SOPNC 0 with the corresponding bicyclic amine of the formula of the formula om-Q-s 03H with the corresponding bicyclic isocyanate of the formula CH: O

CH1- -CH3 NCO (VI) and reducing the product bearing the ring-located keto group to the corresponding hydroxy compound. [Procedure (b).]

Still another process for preparing a compound of Forrnula I comprises treating the corresponding compound of the formula bonn-sm-Q-om with an alkali metal compound, such as sodium hydroxide, potassium hydroxide or the like. [Procedure (c).]

After the ring-located keto group in the reaction product obtained in accordance with procedures (a) or (b) is reduced, the isomers obtained thereby may be separated.

A compound characterized by the formula:

z-c O-NHS m-Q-pn,

wherein Z is lower alkoxy, aryloxy, lower alkylthio, arylthio, imidazolyl-(l) or 3,5-di-lower alkylpyrazolyl-(l), is preferably used as the reactive sulfonylcarbamic acid derivative in process variant (a).

As used herein, the term lower alkyl denotes a straight chain or branched chain alkyl group containing 1-7 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like. The term lower alkoxy" denotes lower alkyl ether groups in which the lower alkyl moiety is as defined above. The term aryl as used herein denotes a group such as phenyl or tolyl.

Examples of the invention are:

1- (p-toluenesulfonyl)-3-(2-endo-hydroxy-3-endobornyl)-urea;

1-(p-toluenesulfonyl)-3-(2-endo-hydroxy-3-endo- D-bornyl)-urea;

1- (p-toluenesulfonyl)-3-(2-endo-hydroxy-3 -endo- L-bornyl)-urea;

A compound of Formula I forms salts with pharmaceutically acceptable bases and such salts are also within the scope of this invention. Thus, a compound of Formula I forms salts with pharmaceutically acceptable bases which preferably include alkali metal bases such as sodium hydroxide, potassium hydroxide and the like, or alkaline earth metal bases such as calcium hydroxide. Strong organic bases such as tetraethyl ammonium hydroxide can also be used.

In one embodiment of the process variant (a), there is used a compound of Formula Ila, wherein Z is imidazolyl-( 1). Conveniently, the corresponding sulfonamide (preferably as an alkali metal salt) is reacted with carbonyldiimidazole in a suitable anhydrous organic solvent which is inert to carbonyl compounds and does not contain hydroxy groups, and the sulfonylcarbamic acid imidazolide which is formed is then allowed to react in situ with a compound of Formula IV. Organic solvents, for example, dimethylformamide, hydrocarbons, such as benzene and halogenated hydrocarbons, such as chloroform, are suitable for this reaction.

A ring-located keto-group which may be present in the reaction product obtained can subsequently be reduced to the hydroxyl group. This can be brought about in a known manner, for example, by treatment with a complex metal hydride, such as sodium borohydride, or by catalytic hydrogenation. The geometric'isomers which are obtained in the reduction can then, if desired, be separated according to known methods, for example, by crystallization or by chromatography.

According to another process of the invention, a compound of the Formula VI, is reacted with a salt of the amide of a sulfonic acid of Formula V. A salt of a strong base, for example, an alkali metal salt, such as the sodium salt, is conveniently employed. Examples of such amides are sodium p-toluenesulfonamide, potassium p-toluenesulfonamide and the like. Organic solvents of the type mentioned above which are inert to the reactants can be suitably utilized.

1-(p-toluenesulfonyl)-3-(2 hydroxy 3 bornyl)urea can exist in various configurations, for example, as a racemate or in the optically active form, depending upon the stereochemistry of the starting materials of Formula 1V or VI used in the preparative techniques described above. Especially preferred is a compound of Formula I above which is derived configuratively from DL- or D- borneol.

The starting materials for the processes of the invention can, insofar as they are not known, be manufactured according to methods which are generally known in the literature. Thus, the starting compounds of Formula IV can, for example, be obtained by converting the corresponding ketone into the isonitroso ketone, for instance, by treatment with amyl nitrile and reducing the reaction product to the amino ketone, for example, by means of zinc in caustic soda. The amino ketone thus obtained can, if desired, be ketalized or reduced to the amino a1- cohol. The reduction of an amino ketone to the amino alcohol can, for example, be effected with sodium borohydride or by catalytic hydrogenation. The isocyanates of the Formula IV can be obtained from the corresponding amino ketones or ketals by reaction with phosgene.

A compound of Formula VII is prepared by reacting a compound characterized by the formula Except for the starting materials whose preparation has been herein described, all other starting materials necessary for the processes of the invention are compounds which are known in the prior art.

The compounds of Formula I, it being understood that Formula I includes stereoisomers, are distinguished by their blood sugar depressant activity on oral administration; thus, they are useful as hypoglycemic agents or as anti-diabetic agents. Their useful hypoglycemic properties are manifested upon administration to warm-blooded animals. For example, when 1-(2-endo-hydroxy-3-endo- D-bornyl)-3-(p-toluenesu1fonyl)-urea, also referred to as 1-[(lR)-2-endo-hydroxy-S-endo-bornyl] 3 (p tolylsulfonyl)-urea, which has demonstrated an LD of 5000 mg./ kg. p.o. in rats is administered to dogs in doses in the range of 0.35 to 3.0 mg./kg. it causes a marked lowering of blood sugar levels over a 24-hour period as compared to controls. While the foregoing LD is indeed very impressive, further studies designed to establish the absolute LD of the compound, if possible, have demonstrated that it has an LD of more than 16,000 mg./kg. p.o. Furthermore, the compound has effects qualitatively similar in many respects to those of 1-buty1-3-sulfanilylurea tolbutamide, well known for its therapeutic uses and properties. Thus, the 1-[(1R)-2-endo-hydroxy-3-endobornyl]3-(p-tolylsulfonyl)-urea of the invention can be used in the same general manner as known hypoglycemic agents.

A compound of Formula I can be used as a medicament in the form of tablets, capsules or dragees. Suitable dosage units contain from about 10 to 250 mg., preferably from about 10 to 50 mg. Suitable dosage regimens in warmblooded animals are from about 0.15 mg./kg. per day to about 7.0 mg./kg. per day, preferably 0.2 rng./kg. per day to about 1.2 ing/kg. per day, but for any particular subject, the specific dosage regimen should be adjusted according to individual need and professional judgment of the person administering or supervising the administration of a compound of Formula I.

The orally administerable pharmaceutical preparations can contain in admixture with a compound organic or inorganic carrier materials, such as, for example, lactose, starch, talc, magnesium stearate, and the like. They can also contain other active ingredients, including other hypoglycemic agents.

The invention includes within its pun-view, the stereoisomers, encompassed by Formula I, i.e., isomers differing in the position of the hydroxy group and the tosylureido moiety (endo or exo with respect to the camphane sceleton) and isomers differing with respect to the configuration of the asymmetric carbon atoms [1(R) or 1(8)]. The separation of the mixture of geometric (endo/exo) isomers can be carried out by known procedures, preferably by fractional crystallization.

The following non-limiting examples further illustrate the invention. All parts are by weight and all temperatures are in degrees centigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of 1-(p-toluenesulfonyl)-3-(2-endohydroxy-B-endo-D-bornyl) -urea 13.6 g. of 3-endoamino-D-borneol and 19.6 g. of tosyl ethyl urethane are ground and mixed together. The mixture is heated with 4 ml. of pyridine for 5 hours on a boiling water-bath with occasional agitation. After cooling, the resulting yellow resin is dissolved in 250 ml. of 1 N sodium hydroxide at room temperature. This solution is shaken out three times with 50 ml. of ether and the aqueous-alkaline phase is acidified with half-cone. HCl, whereby an oil settles out. The mixture is allowed to stand at for about an hour until the mother liquor is only slightly turbid. The supernatant liquid is decanted and the solidified residue is washed with about 10 ml. of water. After recrystallization from alcohol/water, 11.5

H OH (endo) CH3- CH3 NHCONHSOz-Q-CH; (endo) 1-[(lR)-2-endo-hydnoxy-3endo-bornyl] 3 (p tolylsulfonyl)-urea has been administered to healthy volunteers and to patients with maturity-onset diabetes. In healthy humans oral doses as low as 5 mg. have caused a significant decrease in blood glucose and 10 mg. of this compound had the same effect as 1000 mg. of tolbutamide. On the other side, persons without diabetes tolerated single oral doses of up to 200 mg. without any other effect than lowering the blood glucose.

In particular with maturity-onset diabetes the abovementioned compound is a highly effective antidiabetic agent. In this type of patients therapeutic trials have been performed in more than 3000 individuals. Oral doses of 25 mg. are at least as effective as 1000 mg. of tolbutamide. The individual need varies between 12.5 and 75 mg. per day. In respect to general tolerance it can be stated that higher doses were given to patients with severer degrees of diabetes and it is worth mentioning that in one special investigation daily doses of 225 mg., 300 mg. and even 650 mg. given for several weeks were well tolerated. No gastrointestinal side effects (no nausea, vomiting, abdominal pain) were observed.

EXAMPLE 2 Preparation of l-(p-toluenesulfonyl)-3-(2-endohydroxy-3-endo-D-bornyl)-urea 10 g. of 1-(p-toluenesulfonyl)-3-(3-endo-D-camphoryl)-urea are dissolved in ml. of dilute caustic soda (1.4 g. of sodiumhydroxide in 120 ml. of water), treated with 3 g. of sodium borohydride (about 71 percent) and stirred at 20 for 15 hours. The strongly alkaline solution is carefully acidified with dilute acetic acid, whereby, following an initial evolution of hydrogen, the desired product precipitates. The product is isolated, washed with ice-water and recrystallized from alcohol/water. After drying to constant weight, there is obtained 6.5 g. of l- (p-toluenesulfonyl)-3-(2 endo hydroxy 3 endo-D- bornyl)-urea.

After two recrystallizations from acetone/petroleum ether, the product has a specific rotation of ]D (in ethanol; c.=5) and a decomposition point of 193.

EXAMPLE 3 Preparation of 1- (toluenesulfonyl)-3-(2 endo-hydroxy- 3-endo-D-bornyl)-urea l g. of N (p toluenesulfonyl-carbamoyl)-endo-D- bornano[3',2:4,5]-oxazo1idin-2 one is suspended in 10 ml. of 1 N sodium hydroxide solution and heated at reflux for 3 hours. The cooled solution is diluted with 20 ml. of water, whereby the separated oil is dissolved. The solution is then strongly acidified with 2 N hydrochloric acid. The precipitate which forms is removed by filtration, washed with water and recrystallized from alcohol/water to yield 1 (p-toluenesulfonyl)-3-(2-endo-hydroxy-3- endo-D-bornyl)-urea, which is identical to the product obtained in Example 1.

7 EXAMPLE 4 Preparation of 1-(p-toluenesulfonyl)-3-(2-endo-hydroxy- 3-endo-D,L-bornyl -urea In an analogous manner to Example 2, through the reduction of 1-(p-toluenesulfonyl)-3-endo-D,L-camphoryl-urea, there is obtained l-(p-toluenesulfonyD-S-(2-endohydroxy-3-endo-D,L-bornyl)-urea having a decomposition point of 189 (after recrystallization from acetone-petroleum ether).

EXAMPLE 5 Preparation of 1-(p-toluenesulfonyl)-3-(3-endo-hydroxy- 3-endo-L-bornyl)-urea In an analogous manner to Example 2, through the reduction of 1-(p-toulenesulfonyl)-3-(3endo-L-camphoryl)-urea, there is obtained 1-(p-toluenesulfonyl)-3(3- endo-hydroxy-3-endo-L-bornyl)-urea having a decomposition point of 193: [or] =62.5 (ethanol, c.=4).

EXAMPLE 6 Preparation of 1-(p-toluenesulfonyl)-3-(2-exo-hydroxy-3- endo-D-bornyl -urea l g. of endoamino-D-isoborneol, 1.3 g. of tosyl ethyl urethane and 12 drops of absolute pyridine are heated on a boiling water-bath with occasional agitation for 7 hours. The reaction mixture is thereafter dissolved in 30 ml. of 0.5 N sodium hydroxide. The resulting solution is extracted with two 20 ml. portions of ether and the aqueous phase is acidified with half-cone. hydrochloric acid. The product which separates out is taken up in ether. The residue obtained following evaporation of the ethereal solution yields, when recrystallized from acetone/ petroleum ether, 0.75 g. of l-(p-toluenesulfonyl)-3-(2-exo-hydroxy-3-endo- D-borny1)-urea, having a melting point of 158; and [a] =+34.4 (c.=3 in methanol).

EXAMPLE 7 Preparation of l-toluenesulfonyl)-3-(3-endo-D- camphoryl)-urea 26 ml. of p-tosyl isocyanate are added dropwise with stirring to a solution of 20.3 g. of 3-endoamino-D-camphor hydrochloride in 150 ml. of absolute dimethylformamide. The reaction mixture warms to about 40. After cooling to 20, 28 ml. of absolute triethylamine are added dropwise over a half hour period, whereby the reaction mixture once again warms to about 40. It is cooled and stirred at 20 for an additional 15 hours. The dimethylformamide and the excess of triethylamine are removed under vacuum. The remaining semi-solid residue is treated with 500 ml. of 0.5 N sodium hydroxide and shaken until dissolved. This solution is shaken out with two 100 ml. portions of ether, filtered and acidified with dilute hydrochloric acid. The precipitate that forms is removed by filtration, washed with ice-water, pressed out and recrystallized from methanol/Water (about 300 ml. of methanol and 50 ml. of water). After vacuum drying at 100 to a constant weight, there is obtained 24.4 g. of l-(p-toluenesulfony1)-3-(3-endo-D-camphoryl)-urea 67 percent of the theory), having a decomposition point of 190. [a] =-17.7.

EXAMPLE 8 Preparation of 1- (p-toluene sulfonyl -3 3-endo-D- camphoryl)-urea 1 g. mixture of 3-endo-tosylureido-D-borneol-isoborneol isomers (according to specific rotation, 58 percent cis and 42 percent trans) is dissolved in ml. of absolute acetone and treated dropwise with stirring at room temperature with an amount of chromic acid standard solution (26.7 g. of chromium trioxide dissolved in 23 ml. of cone. H 50 and sufficient water to make 100 ml. of solution) suflicient to color the supernatant solution orange-brown.

Thereafter, the reaction mixture is diluted with ml. of water to dissolve the green chromium salts present. The crystalline oxidation product is removed by filtration, washed well with water and recrystallized from methanol/ water to yield 0.83 g. (83 percent of the theory) of l-(ptoluenesulfonyl)-3-(S-endo-D-camphoryl)-urea. The IR spectrum of the product is identical with that of the product obtained in accordance with Example 7.

EXAMPLE 9 Preparation of l-(p-toluenesulfonyl)-3-(3-endo-D- camphoryl) -urea 1.06 g. of sodium p-toluenesulfonamide are suspended in 30 ml. of absolute dimethylformamide and treated at 20 with 0.97 g. of D-camphoryl-(3) isocyanate with stirring at 20 for an additional 15 hours. The solvent is evaporated and the oily residue is dissolved in 20 ml. of 0.5 N caustic soda. The resulting alkaline solution is acidified with dilute hydrochloric acid, whereby the product precipitates. The precipitate is isolated, washed with water and recrystallized from methanol/water to yield 1.6 g. (88 percent of the theory) of l-(p-toluenesulfonyl)-3-(3- endo-D-camphoryD-urea, having a decomposition point of 190.

EXAMPLE 10 Preparation of 1-(p-toluenesulfonyl)-3-(3-endo-L- camphoryl -urea In an analogous manner to Example 2, 15 g. of 3-endoamino-L-camphor D-camphor-lO-sulfonate are reacted with 15 ml. of p-tosylisocyanate to yield 10.4 g. of l-(ptoluenesulfonyl)-3-(3-endo-L-camphoryl)-urea, having a decomposition point of 190; [a] =-|-17.5 (in chloroform, c.=3).

The 3-endo-amino-L-camphor D-camphor-lO-sulfonate can be prepared according to the following procedure:

In a manner analogous to that of the J. Org. Chem. 28, 304 (1963), 3-isonitroso-L-camphor is prepared from L- camphor. According to the procedure of Example 18, paragraph 2, B-endo-amino-L-camphor is obtained therefrom as a crude product in ethereal solution. The ethereal solution is reacted with methanolic solution of D-camphor-lO-sulfonic acid whereby the salt precipitates. The resulting 3-endo-amino-L-camphor D-camphor-lO-sulfonate has a decomposition point of 199; [a] =14.8 (in methanol, c.=6).

EXAMPLE 1 1 Preparation of N-(p-toluenesulfonyl-carbamoyl)-endo-D- bornano- 3 ,2' 4,5 -oxazolidin-2-one A suspension of 20 g. of endo-D-bornano-[3',2':4,5]- oxazolidin-Z-one in m1. of absolute xylene is heated at reflux with 24 ml. of p-toluenesulfonylisocyanate for a period of 3 hours. The xylol is thereafter evaporated, and the residue is extracted several times with a total of 200 ml. of ether and thereafter recrystallized to yield N-(ptoluenesulfonyl carbamoyl -endo-D-bornano- [3,2' 4,5 oxazolidin-Z-one having a decomposition point of 155, [Sig 155 (chloroform, c.=3) from acetone/petroleum e er.

The starting material can be prepared according to the following procedure:

To a suspension of 70 g. of 3-endoamino-D-borneo1 and g. of lead carbonate in 200 ml. of toluene are slowly dripped with stirring 280 ml. of a 20 percent solution of phosgene in toluene. Upon completion of the reaction, the mixture is stirred for an additional hour, filtered and the filtrate is washed with hot toluene. The filtrate is evaporated and the residue recrystallized from acetonepetroleum ether to yield endo-D-bornano-[3',2':4,5]-oxazolidin-Z-one which decomposes at 168, [e1 +87 (alcohol, c.=3).

9 EXAMPLE 12 Preparation of 1-(p-toluenesulfonyl)-3-(3-endo-D,L- camphoryD-urea 13.5 g. of 3-endo-amino-D,L-camphor hydrochloride are reacted with 15 m1. of p-tosylisocyanate according to the procedure of Example 2 to yield 15.3 g. of 1-(ptoluenesulfonyl)-3-(3-endo-D,L-camphoryl)-u1'ea having a decomposition point of 164.

The 3-endo-amino-D,L-camphor hydrochloride can be prepared according to the following procedure:

15 g. of isonitroso-D,L-camphor are dissolved in 120 ml. of sodium hydroxide solution (15 g. sodium hydroxide). The solution is charged with 18 g. of zinc dust. The resulting oily 3-endo-amino-D,L-camplror is dissolved in ether, and the ethereal solution is dried with potassium carbonate. Thereafter, the solution is treated to a strong acetic reaction with ether saturated wih hydrochloric acid. The resulting precipitate is separated and washed with divided portions of ether, to yield 13.5 g. of 3-endo-amino- D,L-camphor hydrochloride having a decomposition point EXAMPLE 13 Tablets of the following composition are prepared rutilizing conventional procedures:

Mg. 1-(p toluenesulfony1) 3 (2 endo-hydroxy-3- endo-D-bornyl)-urea 50 Avicel 90 Corn starch 9.9 Magnesium stearate 0.1

Total 150 1 0 We claim: 1. A compound of the formula NHCONHSOz-CH1 References Cited UNITED STATES PATENTS 2,968,158 1/ 1961 Ruschig et a1 260-553D 3,334,302 8/1967 Beregi et al. 260--553D 3,352,884 11/1967 Fonkcn et a1. 260-553D 2,928,871 3/1960 Aeschlimann et a1. 260553D LEON ZITVER, Primary Examiner G. A. SCHWARTZ, Assistant Examiner U.S. Cl. X.R.

260563 P, 453 A, 307 C; 424322