DE2621828A1 - PYRIDOCHINOLINS, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

I.C.I. Case no.PH.27874

Imperial Chemical Industries Limited, London / England

Pyridoquinolines, processes for their preparation and pharmaceuticals containing these compounds

Priority England No. 21 290/75 from 19-5-1975

The invention relates to pyridoquinoline derivatives that have an inhibiting Show activity against the effects produced by the combination of reagin-like antibodies with their antigens be evoked.

The invention relates to pyridoquinoline derivatives in general Formula:

-2-

609849/0994

wherein the benzene ring A represents a group of the formula:

away

or

OH

or

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or

OH

where a in the formulas II to V denotes the common bond between the pyridine ring and the benzene ring A in the formula I, R denotes hydrogen or has the same meaning as R ² and R denotes a group of the formula -CHR ^ R , in which R ^ is hydrogen or a C, _O -alkyl group, for example a methyl group, and R is a. Cp g-alkanoyloxy, Cpc-alkoxycarbonyl, Cq _1Q -phenylalkoxycarbonyl, Cp λ-alkanoyl, benzoyl, C ₁ , y-dialkylcarbamoyl ^or cyano group and where the benzene ring B optionally has one or two substituents from group C. , g-alkyl and C._g-alkoxy groups and halogen atoms.

The compounds of the present invention represent compounds of the following Formulas:

VI

(1,7-phenanthroline derivatives) and

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-4-

0R ^J

VII

(Pyrido [2,3-gjquinoline derivatives}

and

VIII

(4,7-phenanthroline derivatives)

and

0R ^J

OH

IX

(Pyrido [3.2 g of quinoline derivatives)

1 2
in which B, R and R have the meanings given above,

-5-

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The compounds according to the invention can be in various tautomeric Forms are available. For example, in the case of compounds of the formula VI, the tautomeric form has the following formula:

For simplification, the compounds according to the invention are used
herein as quinoline derivatives (ie, compounds of Formulas VI
to IX).

Suitable substituents R are, for example, propionyloxy, isobutyryloxy, Pivaloyloxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, Isopropoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, Acetyl, benzoyl, diethylcarbamoyl and cyano groups.

The ring B can optionally carry one or two substituents, for example from the group consisting of methyl, n-propyl, η-butyl and
n-propoxy groups and fluorine, chlorine and bromine atoms are selected
are.

According to a particular embodiment of the invention, compounds of formulas VI or IX are considered in which

1 2
B, R and R have the meanings given above.

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According to a further preferred embodiment of the invention, compounds of the formula VI are contemplated in which B, R and R have the meanings given above.

Has a preferred group of compounds according to the invention

1 ?

the formula VI, in which R is hydrogen, R is a

3 4 " ³ I.

Group of the formula -CHR ^ R, wherein R "is hydrogen or a Means methyl group and R stands for an isobutyryloxy, pivaloyloxy or Äthoxycarbonylgruppe ^ and where the benzene ring B carries a C.λ-alkyl or propoxy group.

Another object of the invention is a method for production of the compounds according to the invention, which is characterized in that a compound of the general formula;

OH

XI

in which the benzene ring D represents a group of the formula;

XII

or

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-7-

C0 ₂ ® Μ®

XIII

OH

or

XIV

or

XV

stands, where a. in the formulas XII to XV the common bond between the pyridine ring and the benzene ring D in the formula XI

© means that B has the meaning given above and M for a reactive cation, with a halogen derivative of the formula

2 2

R Hai, in which R has the meaning given above and Hai for a chlorine, bromine or iodine atom is reacted in a suitable organic solvent.

Suitable organic solvents are, for example, hexamethylphosphorus

© acid triamide or dimethylformamide. For example, M can be a

-8th-

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Alkali metal ion, for example a sodium or potassium ion, or a tri-C ^ f-alkylammonium ion, for example a triethylammonium ion. The process is suitably carried out at room temperature or at moderately elevated temperature, for example from 90 to 110 ⁰ C.

The process according to the invention usually gives in each case a mixture of the following two products:

1) from the product in which R stands for hydrogen, and

2) from the product in which R has the same meaning as R ² .

The mixture can be prepared by conventional means such as chromatography or fractional crystallization. If mainly the product (1) is to be obtained, then should be about 2.2 equivalents of the compound of formula

XI and about 2.3 equivalents of the compound of the formula R Hai be used. On the other hand, if the product (2) is mainly to be obtained, then about 2.2 equivalents should be obtained of the compound of formula XI and about 4 equivalents of the

bond of the formula R Hai can be used.

The starting materials of the formula XI are salts that are used in conventional Manner can be obtained from the corresponding dicarboxylic acids. According to the information in GB-PS 1 308 787.

The biological activity of the compounds according to the invention has been shown to be able to do so in the rat to inhibit passive cutaneous anaphylaxis caused by reagin-like antibodies to egg albumin using

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Bordetella pertussis as an adjuvant is induced .. The melstsn the compounds of the invention are bsi diesss: - Ssst a ri-i _"s when administered intravenously weräeiio Diejenigan _P CLIA" boi intravenous administration actively SINCL are not bsi psroraler administration active. Furthermore, many of the compounds according to the invention with intravenous activity are also perorally active. The activity of each compound in the test depends on its chemical structure. Generally speaking, the compounds of the invention are active at a dose of 0.5 to 5 mg / kg when administered intravenously and / or at a dose of 2.5 to 20 mg / kg when administered orally. No toxic or other undesirable side effects have been observed with the compounds at dosages at which they are active in the above test.

Special compounds according to the invention which wt? ^: Gene their high oral activity in the above test are of particular interest are 6-n-butyl-4,10-dihydroxy-2,8-di- (pivaloyloxymethoxycarbonyl) -1,7-phenanthroline and 6-n-butyl 2,8-di- (ethoxycarbonylmethoxycarbonyl) -4,1O-dihydroxy-1,7-phenanthroline.

If the compounds according to the invention are used in warm-blooded mammals, e.g. in humans, for the treatment of essential (non-allergic) asthma or one caused by an antigen-antibody reaction caused disease or such a syndrome, e.g. from allergic asthma, hay fever, urticaria or a autoimmune disease are to be used, then it is recommended that the compounds be administered in the following manner:

a) orally three times a day at a dose of 50 to 300 mg each time; or

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- ίο -

b) intravenous (where applicable ·} with a full daily dose before .. 5 to 25 mg »

The invention also relates to medicaments which are characterized in that they contain at least one compound of the formula I in which a, A, R ^! , R ^, R ^ and R are as defined above and contain an inert, non-toxic pharmaceutically acceptable diluent or carrier.

The medicaments according to the invention can be made using conventional Diluents or carriers can be prepared by known methods. Oral preparation forms can e.g. Unit dosage forms for oral administration, e.g. Tablets or capsules, or they may be in the form of solutions, suspensions, emulsions or syrups. Suitable Forms of preparation for intravenous administration are e.g. sterile solutions or suspensions.

The medicaments according to the invention can, in addition to the compound of the formula I or a non-toxic pharmaceutically acceptable base addition salt thereof, one or more known active ingredients from the group of β-adrenergic stimulants, for example isoprenaline, adrenaline, orciprenaline or isoethacin, or a pharmaceutically acceptable acid addition salt of which, e.g. a sulfate, and prostaglandins with bronchodilatory activity, e.g. prostaglandin E ^ and E ₂ , and phosphodiesterase inhibitors from the group of the following compounds:

a) 3-acetamido-6-methyl-8-n-propyl-s-triazolo [4,3-a] pyrazine;

b) 2-Amino-4,6-di-C ₁ _ ^ - alkyl-5-oxo-4,5-dihydro-s-triazolo- [1,5-ajpyrimidines, e.g. Z-Amino-G-methyl ^ - oxo ^ -n pyl-4,5-dihydro-s-triazolo [1,4-a] pyrimidines;

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- 11 -

c) theophylline and related 3,5-di-C ₁ _ -alkylxanthine _Zt; and

d) 6,8-Di-C ₁ ^ -alkyl-5,6-dihydro-5-oxo-s-triazolo [4,3-c] pyrimidines, for example 5,6-dihydro-5-oxo-6, 8-di-n-propyl-striazolo [4,3-c pyrimidine,

contain.

The medicaments according to the invention can contain 1 to 50% by weight of a Compound of formula I or a non-toxic pharmaceutical acceptable base addition salts thereof.

The invention is illustrated in the examples. example 1

A mixture of the disodium salt of 6-n-butyl-2,8-dicarboxy- · 4,10-dihydroxy-1,7-phenanthroline (2 g), hexamethylphosphoric acid triamide (10 ml) and Chlorine thy Ip ivalat (3 g) was added at room temperature Stirred for 43 h. The mixture was dissolved in water (200 ml) and extracted with chloroform (3 × 100 ml). The chloroform extract was washed with water (2 × 100 ml), over Magnesium sulfate, filtered and the filtrate was evaporated to dryness under reduced pressure. The leftover Oil was deactivated by dry column chromatography on silica gel 60 (Merck) (400 g) which had previously been deactivated with water (10% w / w) and then with a solvent system (10% of a mixture from toluene / acetone, volume ratio 1; 1) had been treated, cleaned. The product was treated with toluene / acetone (volume ratio 1: 1) and the eluate was filtered. That The filtrate was evaporated under reduced pressure. The residue obtained was replaced by acetone by adding petroleum ether (bp.

-12-, 609849/099 ^

60 to 80 ⁰ C) crystallized. In this way 6-n-butyl-4,1O-dihydroxy-2,8-di- (pivaloyloxymethoxycarbonyl) -1,7-phenanthroline, melting point 97 to 99 ° C., was obtained.

Example 2

The procedure was as in Example 1 with the exception that the chlorine ethyl pivalate was replaced by an equivalent amount of α-chloroethyl pivalate was replaced and that the reaction mixture was stirred for 4 days at room temperature. The product was determined by chromatography in a manner similar to that described in Example 1, isolated. In this way was 6-n-butyl-4,1O-dihydroxy-2,8-di- (a-pivaloyloxyäthoxycarbonyl) -i, 7-phenanthroline, M.p. 65 to 68 ° C.

The cc-chloroethyl pivalate used in the above procedure was manufactured as follows:

To a mixture of pivaloyl chloride (24.1 g) and paraldehyde (26.4 g) was added anhydrous zinc chloride (20 mg). After the exothermic reaction had ended, the mixture was ^{heated to 75 to 80 °} C. for 30 minutes. The mixture was then fractionally distilled under reduced pressure. The fraction with a bp of 42 to 54 ° C at 14 mm pressure was collected. In this way, α-chloroethyl pivalate was obtained.

Example 3

A mixture of 6-n-butyl-2,8-dicarboxy-4,10-dihydroxy-i, 7-phenanthroline (712 mg), triethylamine and dry dimethylformamide (14 ml) was stirred at room temperature for 2 hours. Chloromethyl pivalate (782 mg) was added and the mixture was stirred and heated to 90-110 ° C for 18 hours. The mixture was

-13-

cooled, diluted with ethyl acetate (100 ml) and the solution became washed with saturated sodium chloride solution (3 × 15 ml). The organic solution was dried with magnesium sulfate and then filtered. The solvent was distilled off under reduced pressure. The residue obtained was dissolved in ethyl acetate (5 ml) and resolved by chromatography on 12 silica-GF plates purified using a mixture of toluene and acetone (volume ratio 1: 1). The product range (Rp 0.76) was removed and stirred for 18 hours with ethyl acetate eluted. The ethyl acetate eluate was filtered and the filtrate was evaporated to dryness under reduced pressure. Of the obtained residue was dissolved in chloroform. The solution was centrifuged, decanted and reduced to a low volume constricted. It was then diluted with petroleum ether (boiling point 40 to 60 ° C.). The mixture was centrifuged and the supernatant Liquid has been decanted. The residue was washed with petroleum ether (boiling point 40 to 60 ° C.) and dried in vacuo. on in this way was 6-n-butyl-4,10-dihydroxy-2,8-di- (pivaloyloxymethoxycarbonyl) -1,7-phenanthroline, M.p. 97 to 99 ° C.

Examples 4 and 5 (Example 4)

The procedure was as in Example 3, with the exception that the chloromethyl pivalate by an equivalent amount of chloromethyl propionate was replaced. In this way 6-n-butyl-4,10-dihydroxy-2,8-di- (propionyloxymethoxycarbonyl) -1,7-phenanthroline, M.p. 60 to 70 ° C.

(Example 5)

A fast moving tape was separately eluted and chromatographed purified, whereby a second product was obtained-

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262Ί828

de, which consisted of 6-n-butyl-10-hydroxy-2,8-di- (propionyloxymethoxycarbonyl) -4-propionyloxymethoxy-1,7-phenanthroline. NMR Spectrum (in CDCI-,): (All chemical shifts are given in Å values) 8.00 (s, 1H, H-5); 7.78, 7.92 (two s, 2H, H-3 and H-9); 6.10 (s, 6H, 2 CO ₂ CH ₂ O plus ArOCH ₂ O); 3.28 (t, 2H, ArCH ₂ C ₃ H ₇ ); 2.45 (g, 6H, 3 COCH ₂ CH ₃ ); 0.9-2-0 (m, 3 COCH ₂ CH ₃ plus ArCH ₂ CH ₂ CH ₂ CH ₃ ).

Example 6

The procedure was as in Example 3, with the exception that the chloromethyl pivalate was replaced by an equivalent amount of chloromethyl isobutyrate. There was thus obtained 6-n-butyl-4,10-dihydroxy-2,8-di- (isobutyryloxymethoxycarbonyl) -1,7-phenanthroline. NMR spectrum (in CDCI ^): (all chemical shifts are given in S values) 10.2 (bs, 1H, NH in 1-position); 9.26 (brs, 1H, NH in 7-position); 8.40 (s, 1H, H-5); 7.22 (s, 1H, H-9); 7.15 (d, 1H, H-3); 6.04 (eg, 4H, ester CH ₂ ); 2.40-300 (m, 4H, ArCg ₂ C ₃ H ₇ plus 2 COCH (CH ₃ ) ₂ ); 1.30-1.90 (m, 4H, ArCH ₂ CH ₂ CH ₂ CH ₃ ); 1.20 (d, 12H 2 CH (CH ₃ ) ₂ ); 1.01 (t, 3H, ArCH ₂ CH ₂ CH ₂ CH ₃ ).

Example 7

The procedure was as in Example 3, with the exception that the 6-n-butyl-2,8-dicarboxy-4,10-dihydroxy-1,7-phenanthroline was replaced by an equivalent amount of 2,8-dicarboxy-4, 10-dihydroxy ~ 6-methyl-1,7-phenanthroline was replaced. There was thus obtained 4,10-dihydroxy-6-methyl-2,8-di- (pivaloyloxymethoxycarbonyl) -1,7-phenanthroline. NMR spectrum (in CDCl ₇ ): (all chemical shifts are given in S values) 10.14 (bs, 1H, NH in 1-position); 9.06 (brs, 1H, NH in 7-position); 8.30 (s, 1H, H-5); 7.12 (s, 1H, H-9); 7.04 (s, 1H, H-3); 6.06 (two s, 4H,

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Ester CH ₂ ); 2.56 (s, 3H, CH _3); 1.10 (s, 18H, 2 t-Bu). Example 8

The procedure was as in Example 3, with the exception that the chloromethyl pivalate was replaced by an equivalent amount of ethyl bromoacetate. The product was extracted with chloroform. The product was obtained after chromatography on silica plates using a mixture of toluene and acetone (volume ratio 1: 1) extracted in chloroform and precipitated with petroleum ether (b.p. 40 to 6O ⁰ C.). In this way 6-n-butyl-2,8-di- (ethoxycarbonylmethoxycarbonyl) -4,10-dihydroxy-1,7-phenanthroline, melting point 185 ° to 195 ° C., was obtained.

Examples 9-13

The procedure was as in Example 8 with the exception that the Ethyl bromoacetate was replaced by an equivalent amount of an alkyl bromo or chloroacetate. There were the following compounds obtain:

(Example 9)

6-n-Butyl-4,10-dihydroxy-2,8-di- (methoxycarbonylmethoxycarbonyl) -1,7-phenanthroline, melting point 193 to 195 ^° C., from methyl chloroacetate.

(Example 10)

6-n -Butyl-4,10-dihydroxy-2,8-di- (n-propoxycarbonylmethoxy carbonyl ) -1,7-phenanthroline, melting point 186 to 188 ° C., from n-propylchloroacetate. 1

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(Example 11)

6-n-butyl-4,1O-dihydroxy-2,8-di- (isopropoxycarbonylmethoxycarbonyl) -1,7-phenanthroline, Mp. 159 to 161 ° C, from isopropyl chloroacetate.

(Example 12)

6-n-butyl-2,8-di- (t-butoxycarbonylmethoxycarbonyl) -4,1O-dihydroxy-1,7-phenanthroline, Mp. 171-173 ° C, from t-butyl bromoacetate.

(Example 13)

2,8-di- (benzyloxycarbonylmethoxycarbonyl) -6-n-butyl-4,1O-dihy-

Example 14

droxy-1,7-phenanthroline, melting point 155 to 16O ° C, from Benzylchlorace-

The procedure was as in Example 1, with the exception that the chloromethyl pivalate was replaced by an equivalent amount of N, N-diethyl chloroacetamide. The reaction mixture was poured into water (200 ml) and extracted with chloroform (3 × 50 ml). The chloroform extract was washed with water (50 ml), dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The obtained residue was stirred with petroleum ether (bp. 60 to 80 ⁰ C), filtered and the solid residue obtained was crystallized from toluene. In this way 6-n-butyl-2,8-bis- (diethylcarbamoylmethoxycarbonyl) -4,10-dihydroxy-1,7-phenanthroline, melting point 203-206 ° C., was obtained.

Example 15

The procedure was as in Example 14, with the exception that the

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NjN-diethylchloroacetamide was replaced by an equivalent amount of chloroacetone. In this way, 2,8-di- (acetylmethoxycarbonyl) -6-n-butyl-4,10-dihydroxy-1,7-phenanthroline, melting point 260 to 262 ^° C. after crystallization from dioxane, was obtained.

Example 16

In a manner similar to that described in Example 15, using an equivalent amount of phenacyl bromide in place of chloroacetone, 2,8-di- (benzoylmethoxycarbonyl) -6-n-butyl-4,10-dihydroxy-1,7-phenanthroline was obtained. Mp. 217 to 219 ° C after
Crystallization from toluene.

Example 17

The procedure was as in Example 3, with the exception that the chloromethyl pivalate was replaced by an equivalent amount of chloroacetonitrile. After 18 hours of heating the reaction mixture to 90 to 110 ⁰ C, the mixture was cooled, poured into water (50 ml) and extracted with ethyl acetate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate, whereby 6-n-butyl-2,8-di- (cyanomethoxycarbonyl) -4,10-dihydroxy-1,7-phenanthroline, melting point 225 to 227 ° C., was obtained.

Example 18

The procedure was as in Example 3, with the exception that equivalents Amounts of 2,8-dicarboxy-10-chloro-4,6-dihydroxypyrido- [3.2-g] quinoline and ethyl bromoacetate instead of 6-n-butyl-2,8-dicarboxy-4,10-dihydroxy-1,7-phenanthroline and chloromethyl pivalate were used. In this way 10-chloro-2,8-di- (ethoxycarbonylmethoxycarbonyl) -4,1O-dihydroxypyrido [3.2-g] quinoline, Mp 175-178 ° C.

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Example 19

The procedure was as in Example 1, with the exception that the chloromethyl pivalate was replaced by an equivalent amount of ethyl 2-bromopropionate. In this way, mp 6-n-butyl-2,8-di- (a-äthoxycarbonyläthoxycarbonyl) -4, 1O-dihydroxy-1,7-phenanthroline,. 122 to 124 ⁰ C, was obtained.

Example 20

The procedure was as in Example 3, with the exception that equivalents Amounts of 2,8-dicarboxy-4,10-dihydroxy-6-n-propoxy-1,7-phenanthroline and of ethyl bromoacetate instead of 6-n-butyl-2,8 «dicarboxy-4,1O-dihydroxy-1,7-phenanthroline or chloromethyl pivalate were used. In this way, 2,8-di- (ethoxycarbonylmethoxycarbonyl) -4,10-dihydroxy-6-n-propoxy-1,7-phenanthroline, Mp. 194 to 196 ° C (after crystallization from acetone / petroleum ether with a boiling point of 40 to 60 ° C) obtained.

Example 21

The procedure was as in Example 3, with equivalent amounts of 2,8-dicarboxy-4,10-dihydroxy-6-methyl-1,7-phenanthroline and of ethyl bromoacetate instead of 6-n-butyl-2,8-dicarboxy-4,10-dihydroxy-1,7-phenanthroline and chloromethyl pivalate, respectively, were used. In this way, 2,8-di- (ethoxycarbonylmethoxycarbonyl) -4,10-dihydroxy-6-methyl-1,7-phenanthroline, Mp. 169 to 171 ° C. (after crystallization from acetone).

Example 22

A mixture of 50 parts by weight of 6-n-butyl-4,10-dihydroxy-2,8-di- (pivaloyloxymethoxycarbonyl) -1,7-phenanthroline and 25 parts by weight of mannitol was in such amounts in hard gelatin caps

609849/0994 " ¹⁹ ~

be filled that capsules with 25 to 500 mg of active ingredient received became. In this way, capsules suitable for therapeutic peroral administration were obtained.

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Claims (8)

Patentans ν r u che i1.) Pyridoquinoline derivatives of the general formula: 0R ^J wherein the benzene ring A represents a group of the formula: or III -21- 4 9/0994 - 21 - IV or OH where a in the formulas II to V denotes the common bond between the pyridine ring and the benzene ring A in the formula I, R denotes hydrogen or has the same meaning as R ² and R ² denotes a group of the formula -CHR ⁵ R stands in which R- ^{5 is} hydrogen or a C _{1 O} -alkyl group, for example a methyl 4th
group, and R stands for a Cpc-alkanoyloxy, Cp_g-alkoxycarbonyl, Co ^ Q-phenylalkoxycarbonyl, Cp ^ -alkanoyl, benzoyl, C ^^ - dialkylcarbamoyl or cyano group and where the benzene ring B optionally has an or can carry two substituents from the group C ^ / - alkyl and C, / - alkoxy groups and halogen atoms. 2. Compounds according to claim 1, characterized in that Br stands for a methyl group. 3. Compounds according to claim 1 or 2, characterized in that g e - λ
indicates that R represents a propionyloxy, Isc butyryloxy, pivaloyloxy, methoxycarbonyl, ethoxycarbonyl, -22-609849 / 0994 n-propoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, Acetyl, benzoyl, diethylcarbamoyl or cyano group stands. 4. Compounds according to any one of claims 1 to 3, characterized in that the benzene ring B is one or two substituents from the group methyl, n-propyl, n-butyl and carries n-propoxy groups and fluorine, chlorine and bromine atoms. 5. 6-n-Butyl-4,1O-dihydroxy-2,8-di- (ρivaloyloxymethoxycarbonyl ) -1,7-phenanthroline. 6. 6-n-Butyl-2,8-di- (ethoxycarbonylmethoxycarbonyl) -4,10-dihydroxy-1,7-phenanthroline. 7. A process for the preparation of compounds according to claim 1, characterized in that a compound the general formula: XI in which the benzene ring D represents a group of the formula: XII 609849/0994 -23- or XIII XIV or XV CO ₂ stands, where a in formulas XII to XV is the common bond denotes between the pyridine ring and the benzene ring D in the formula XI, B has the meaning given in claim 1 and M stands for a reactive cation, with a halogen derivative of 2 2 Formula R Hai, in which R has the meaning given in claim 1 and Hai stands for a chlorine, bromine or iodine atom, in a suitable organic solvent. 8. Medicament, characterized in that there is at least one compound according to claim 1 and an inert one non-toxic pharmaceutically acceptable diluent or contains carrier. 6 0 Q R & Q / OQQiL PATENT LAWYERS U3Ot3 / ü33 «} _D _ _{ING H} FiNCKE, D'PL.-ING. H. BOHR DIPi,! ING. S. STAEGER. DR. Tar nat. R. KNEISM.