IE912658A1

IE912658A1 - 6-alkylpyridazine derivatives, method of preparation and pharmaceutical compositions in which they are present

Info

Publication number: IE912658A1
Application number: IE265891A
Authority: IE
Inventors: Roger Brodin; Jean Paul Kan; Dominique Olliero; Camille Georges Wermuth; Robert Boigegrain
Original assignee: Sanofi Sa
Priority date: 1990-07-31
Filing date: 1991-07-29
Publication date: 1992-02-12
Also published as: HU912555D0; DE69104155T2; IE66376B1; EP0469992B1; FI913656A0; FR2665442A1; HU211645A9; PT98474B; NZ239181A; ATE111900T1; NO179905C; AU638858B2; KR920002550A; FR2665442B1; NO912972L; HUT58706A; NO912972D0; IL99013A0; AU8147691A; ZA916030B

Abstract

Pyridazine derivatives of formula: <IMAGE> in which: - Ar denotes an optionally mono- or disubstituted phenyl group, a pyridyl group or a thienyl group; - R3 denotes a C1-C5 straight or branched alkyl, a -CH2-C6H5 group or a -CH2-CH2-C6H5 group; - R4 denotes the group <IMAGE> in which: - X denotes a C1-C6 straight or branched alkylene - each of R5 and R6 independently denotes hydrogen or a C1-C4 alkyl, or, together with the nitrogen atom to which they are bonded, they form a heterocyclic ring chosen from pyrrolidine, morpholine or piperidine, or else R4 denotes a group chosen from: <IMAGE> in which n is as defined above and R7 denotes H or a C1-C4 alkyl; <IMAGE> in which n is as defined above or <IMAGE> and their salts with inorganic or organic acids. Application: medications useful for the treatment of a cholinergic deficiency.

Description

6-ALKYLPYRIDAZINE DERIVATIVES, METHOD OF PREPARATION AND PHARMACEUTICAL COMPOSITIONS IN WHICH THEY ARE PRESENT SANOFI, a French body corporate, of 40 Avenue George V, 75008 Paris, France.

P 5829 - 1 Pyridazine derivatives have been proposed as drugs for many years, especially those which are active on the cardiovascular system or the central nervous system.

In particular, French patent 2 510 998 and European patent 72 726 disclose pyridazine derivatives which are variously substituted on the pyridazine ring and which all carry, in the 3-position, an amine substituent of the type -NH-alkylene-N in which X and Y are independently hydrogen or an alkyl group or form, with the nitrogen atom to which they are bonded, a heterocycle such as morpholine.

All these compounds are active on the central nervous system as antidepressants.

According to the present invention, it has now been found that by modifying the substituents on the pyridazine ring, compounds are obtained which have lost their antidepressant activity and acquired a valuable activity as Mx-type cholinergic receptor ligands.

The present invention relates to novel pyridazine derivatives of the formula Ar R3 NH-R4 N_N in which - Ar is a phenyl group of the formula (I) - 2 Ri »2 \=. a pyridyl group or a thienyl group; - and R? are each independently hydrogen, a halogen atom, a hydroxyl group, a C1-C4 alkyl group, a C^-C^ alkoxy or the trifluoromethyl group; - Rg is a linear or branched C^-C^ alkyl, a group -CH 10 (¾¾ or a group -CHg-CH^-C^; and - R is the group R, -X-N in which • X is a linear or branched Cj-Cg alkylene and especially either a group -(C^) -, in which n is an integer from 1 to 3; or a group -CH2-C-(CH2)nl1 xi in which n is 0 or 1 and is a C-j-Cg alkyl group; and * r5 and κθ are each independently hydrogen or a linear or branched Cj-C4 alkyl or form, with the nitrogen atom to which they are bonded, a heterocycle selected from pyrrolidine, morpholine or piperidine; or - R^ is a group selected from -(CH2)n-I \ XN i7 in which n is as defined above and R, is hydrogen or a C^-C4, preferably Cj-Cg, alkyl group; (CH2)n zx in which n is as defined above, or and to their salts with mineral or organic acids.

The salts of the compounds of formula (I) according to the present invention include both those with mineral or organic acids which permit appropriate separation or crystallization of the compounds of - 4 formula (I), such as picric acid or oxalic acid, and those with mineral or organic acids which form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogen05 phosphate, methanesulfonate, methylsulfate, maleate, fumarate or naphthalene-2-sulfonate.

According to another feature, the present invention relates to a method of preparing the com- pounds of formula (I), which comprises reacting a 3- 10 chloropyridazine of the formula in which Ar and R3 are as defined above, with an amine of the formula R^NH 2 in which R^ is as defined above, to give the compounds (I) according to the invention and, if desired, converting the resulting compound to a salt with a mineral or organic acid.

The substitution reaction of the 3-chloropyridazine (II) with the amine is carried out at a temperature of between 100 and 150°C, in the absence of a solvent or in the presence of an inert solvent such as n-butanol.

The resulting product of formula (I) is isolated, in the form of the free base or a salt, by the conventional techniques.

When the compound of formula (I) is obtained in the form of the free base, conversion to a salt is - 5 effected by treatment with the chosen acid in an organic solvent. Treatment of the free base, for example dissolved in an alcohol such as isopropanol, with a solution of the chosen acid in the same solvent gives the corresponding salt, which is isolated by the conventional techniques. The hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, methane- sulfonate, methylsulfate, oxalate, maleate, fumarate or naphthalene-2-sulfonate, for example, is prepared in this way. When the reaction is complete, the compound of formula (I) can be isolated in the form of one of its salts, for example the hydrochloride, oxalate or fumarate. In this case, if necessary, the free base can be prepared by neutralization of said salt with a mineral or organic base such as sodium hydroxide or triethylamine, or with an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate.

When Rx and/or Ra are a hydroxyl group, the compound according to the invention is obtained from the compound (I) in which Rx and/or R2 are an alkoxy, all the other substituents being as defined above, by dealkylation using known methods.

The 3-chloropyridazines (II) used as starting materials are prepared from the 2H-pyridazin-3-ones (III) of the formula by reaction with excess phosphorus oxychloride under the action of heat, without a solvent or in the presence of an inert solvent such as acetonitrile.

The 2H-pyridazin-3-ones (III) above are obtained by dehydrogenation of the compounds of formula (IV): ,E ^12658 Ar H for example by reaction with bromine in acetic acid.

The 2,3,4,5-tetrahydropyridazin-3-ones of the formula (IV) and the 2,3-dihydropyridazin-3-ones of formula (III), which are novel and form part of the invention, are prepared by the methods described by SUTTER et al., J. Am. Chem. Soc., 1942, 64 . 533-536, MUKHIRJI D., Science and Culture, 1948, 12, 426, and PINNA G. et al., Il Farmaco, Ed. Sci., 1988, 43 . 539-549.

The intermediates of the formulae (IV) (HI) in which Ar and R3 are as defined above, which are use10 ful for the preparation of (I), are novel and form part of the invention with the exception of the compounds in which Ar is an unsubstituted phenyl and R3 is a methyl group. By way of example, compounds of formulae (IV) and (III) are described in Tables 1 and 2 below.

The chlorinated compounds of formula (II): Ar ί!Λ" N-N (II) which are novel and form part of the invention, are prepared by the customary methods. By way of example, compounds of formula (II) are described in Table 3 below.

Substitution of these chlorinated compounds (II) with an amine makes it possible to obtain the compounds (I), the preparation of which is illustrated by the reaction scheme below. - 8 SCHEME, 1 1) EtONa 05 EtOH Ar-CH2CN 2) R3CO2Et Λ Ar-CH-CN 1 CO-R3 H2S04,H20 H 1) i-PrONa <2) BrCH2C02Et 3) NH2NH2 .H20 Ψ Ar—CH2—CO-R3 (IV) Br2 , AcOH \iz POCI3 Ar (III) (II) H2N-R4 V (I) - 9 Heating a nitrile 1 in the presence of a base and a carboxylic acid ester derivative R3CO2Et gives the 0-ketonitrile 2., which is converted to the corresponding ketone derivative 2 in an acidic medium.

Cyclization to the 2,3,4,5-tetrahydropyridazin3-one is effected by reaction with ethyl bromoacetate in an alcoholic solvent at room temperature, followed by reaction with hydrazine hydrate under the action of heat.

Dehydrogenation of the compound (IV) by reaction with bromine in acetic acid makes it possible to prepare the 2,3-dihydropyridazin-3-one (III).

In the case where n^ = 0, the amines 'R„ in which X is a group -chA25 in which Xx is as defined above, are prepared from a cyano derivative of the formula CN (X^-C-OH by reaction with an amine of the formula HNRsRe, if appropriate in the presence of a salt of a strong acid, such as sodium or magnesium sulfate, at a temperature of between 40 and 80eC, to give the aminonitrile of the formula (Χχ) CN I -C-N R. which is hydrated under the customary conditions, in an acidic medium, to give the corresponding amide of the formula (Χχ)2 which is then reduced by reaction with a metal hydride, such as lithium aluminum hydride or boron hydride, to give the expected amine The following Examples illustrate the invention without however implying a limitation.

EXAMPLE 1 3-(2-Diethylamino-2-methylprop-l-yl) amino-5-(4-fluorophenyl )-6-propylpyridazine A) α-Butyry1-4-fluoropheny1acetonitri1e .9 g of sodium are added to 150 ml of absolute ethanol. While maintaining reflux, a solution of 49.5 g of 4-fluorophenylacetonitrile in 65.2 g of ethyl butyrate is added. The reaction mixture is refluxed for 4 hours and then left to stand overnight at room temperature. The solvents are concentrated under vacuum and the residue is taken up in water and washed with ether. The aqueous phase is cooled in an ice bath - 11 and acidified to pH 5-6 by the addition of concentrated acetic acid to give crystals, which are filtered off, washed with water and dissolved in methylene chloride.

The organic phase is decanted, dried over 05 MgSO4, filtered and concentrated under vacuum. m = 50 g M.p. = 53-54’C B) 1-(4-Fluorophenyl)pentan-2-one g of the product obtained above are treated 10 with 36 ml of water and 148 ml of concentrated sulfuric acid, which is added dropwise at 4°C, with stirring. The mixture is then heated at 80°C for \ hour and cooled, 534 ml of water are then added and the mixture is refluxed overnight.

The mixture is extracted with methylene chloride and the organic phase is decanted, dried over Na2S04, filtered and concentrated under vacuum.

The residue is chromatographed on silica gel using 50/50 eyelohexane/methylene chloride as the eluent. m = 39.2 g C) 5-(4-Fluorophenyl)-6-propyl-2,3,4,5-tetrahydropyridazin-3-one 2.76 g of sodium are dissolved in 115 ml of isopropanol. A solution of 21.56 g of the product obtained above in 30 ml of isopropanol is added, with cooling in an ice bath. The mixture is stirred for one hour at room temperature, a solution of 15 ml of ethyl bromoacetate in 20 ml of isopropanol is then added dropwise and the mixture is left to stand at room temperature for 24 hours.

The residue is taken up in acidified water (HCl - pH = 2) and extracted with methylene chloride.

The organic phase is decanted and dried over MgSO4. It is filtered and concentrated under vacuum. The residue - 12 is taken up in 75 ml of butanol, 11.25 ml of hydrazine hydrate are added and the reaction mixture is refluxed for 4 hours.

The mixture is concentrated under vacuum and the residue is taken up in water and extracted with methylene chloride. The organic phase is decanted, dried over MgSO4, filtered and concentrated under vacuum. m = 13.7 g M.p. = 78-79°C D) 2,3-Dihydro-5-(4-fluorophenyl)-6-propylpyridazin-3one 9.37 g of the product obtained above are dissolved in 40 ml of acetic acid and heated to 80°C. A solution of 7.6 g of bromine in 70 ml of acetic acid is then added dropwise and the reaction mixture is refluxed for 4 hours. It is cooled to 15°C and a precipitate is filtered off. m = 6.6 g M.p. = 193-194*C E) 3-Chloro-5-(4-fluorophenyl)-6-propylpyridazine 4.64 g of the product obtained above are dissolved in 28 ml of acetonitrile and 8.6 ml of phosphorus oxychloride and the reaction mixture is refluxed for 4 hours and then concentrated under vacuum. The residue is taken up in iced water, aqueous ammonia is added and the mixture is then extracted with methylene chloride. The organic phases are decanted, dried over MgSO4, filtered and concentrated under vacuum. The residue is chromatographed on silica gel using 95/5 methylene chloride/ethyl acetate as the eluent. m = 4.35 g M.p. = 64°C - 13 F) Compound 1 g of the product obtained above and 3 g of 1amino-2-diethylamino-2-methylpropane are heated at 120°C, under nitrogen, for 48 hours.

The mixture is concentrated under vacuum and the residue is taken up in a 5% solution of sodium carbonate and extracted with methylene chloride. The organic phase is decanted, dried over MgS04, filtered and concentrated under vacuum. The residue is chroma10 tographed on Merck H silica gel using 96/4 methylene chloride/methanol as the eluent.

The pure product fractions are concentrated under vacuum, the residue is taken up in ether and the addition of a solution of hydrogen chloride in ether makes it possible to prepare the hydrochloride, which is filtered off. m = 1.4 g M.p. = 100-115’C EXAMPLES 2 TO 19 A) The 2,3,4,5-tetrahydropyridazin-3-ones listed in Table 1 below are obtained by following the procedure described in Example 1, steps A, B and C, except that the starting nitrile is replaced with another nitrile derivative, where appropriate, and the carboxylic acid ester is varied. - 14 TABLE 1 Rx r3 M.p.; ‘C Recrystallization solvent H -CH-CH, 131-132 hexane H n-CA 104-105 hexane H i-C3H7 137-138 heptane H i-C4H9 92-93 hexane H neopentyl 155-156 hexane H • 114-115 hexane S -CH2-CH2-CeH5 142-143 Et2O F n-C3H7 78-79 heptane F i-CA 106.5-107,5 heptane Cl -ch3 160-161 Et20 Cl -CH2CH3 121-122 hexane Cl n-CA 118-119 heptane B) The 2,3-dihydropyridazin-3-ones listed in Table 2 below are obtained from the derivatives in Table 1 in the manner described in Example 1, step D, by reaction with bromine followed by dehydrohalogenation. These compounds were all recrystallized from a methylene chloride/hexane mixture. - 15 ~ TABLE 2 (III) Rx r3 M.p.; ’C H -ch2ch3 123-124 H 162-163 H i-c^ 178-179 H i-CA 154-155 H neopentyl 181-182 H -<Α<Α 140-141 H -ch2-ch2-c6h5 169-170 F n-CA 193-194 F l-CA 194-195 Cl -ch3 212-214 Cl -ch2ch3 206-207 Cl n-C3H7 187-188 C) The chlorinated derivatives are prepared from the derivatives in Table 2 by reaction with phosphorus oxychloride in the manner described in Example 1, step E. These chlorine derivatives, which are listed in Table 3 below, were all recrystallized from methylene chloride. - 16 TABLE 3 Rx r3 M.p.; ’C H 49 H n-CA 58 S 1-CA 86-87 H i-CA 70-71 H neopentyl 99-100 H -ch2 99 H -ΑΆ<Α 94-95 F n-CA 64 F i-CA oil Cl -A 127-128 Cl -aa 84-85 Cl n-CA 63 D) Substitution of the chlorinated derivatives with an amine, according to Example 1, step F, makes it possible to prepare the compounds (I) according to the invention, which are listed in Tables 4, 5 and 6 below. - 17 TABLE 4 Exaaple Rx r3 n /85 -N R6 M.p.; *C Recrystallization solvent Salt 2 H -(¾ 2 88 hexane base 3 H n-^H? 2 +% 129 EtOB fuiarate 4 H -CHO 2 -β 241 2HC1 u ΛΛ EtOH base 5 H -ch3 2 -N 0 93 u hexane 6 Cl 3 58 hexane base ±0 ExampleRi r2 r4 H.p.; *c Recrystallization solvent Salt 15 7 H -ch3 π CH2-CH3 154 acetone sesquifunarate 20 8 H iHgH? 1 _0 154 Et2O sesquifunarate 9 H n-C^iy 0 171 Et2O 2HC1 25 Γ 10 H ό 90 Et2O 2HC1 a - 19 TABLE 5 (Cont’d) Example Rl r2 r4 H.p.? 'C Recrystallization solvent Salt N 10 11 H ch3 0 162.5 Et2O difunarate 15 12 H ch3 -CH2^P^ 169.2 iPrOH trifunarate 20 13 8 K4Bg C2«5 N 0 99 Et2O-iPrOH difunarate beaihydrate V axial 25 14 H i-C4Hg C2H5 N 0 151 EtaO-iPrOH difunarate 30 T equatorial - 20 TABLE 6 24 Cl -A -n-(c2h5)2 100-105 Et2O 2HC1 25 Cl -«-(«Α). 95-100 Et2O 2HC1 26 Cl n-c3H7 -»-(CA>2 134-135 Et2O difumarate The compounds according to the invention were studied for their pharmacological properties and in particular for their affinity for the Μ,-type and M,type muscarinic cholinergic receptors.

In vitro, the compounds (I) were tested according to the technique described by L. POTTER et al., J. Pharmacol. Exp. Ther., 1989, 284. 974-978, for their affinity for the Μ,-type receptors, and according to the technique described by HAMMER R. et al., Life Science, 1986, 38, 1653-1662, for their affinity for the Μ,-type receptors.

The compounds according to the invention have a good affinity for the Μ,-type receptors and a marked specificity for the Μ,-type central receptors compared with the Μ,-type receptors.

By way of example, compound 6 showed 50% inhibitory concentrations, expressed in micromol, of 0.16 and 1.5 on the M, and M, receptors respectively.

Likewise, compound 25 showed 50% inhibitory concentrations of 0.04 and 0.9 on the M, and M, receptors respectively.

In vivo, the compounds according to the invention were subjected to the test for the rotations induced by intrastriatal pirenzepine, described by Worms P. et al., Psychopharmacology, 1987, 93, 489-493.

At a dose of 3 mg per kg of body weight, administered orally, the products according to the inven35 - 22 tion strongly inhibit the number of rotations induced by pirenzepine. Thus, by way of example, compound 6 causes a 71% inhibition of the rotations induced by pirenzepine.

Furthermore, the compounds according to the invention have proved to be active on the memory deficiency induced by scopolamine and pentetrazole in the passive avoidance test on rats, described by WORMS P. et al., Psychopharmacol., 1989, 98 . 286-288.

Thus the results of this test show that compound 6 according to the invention opposes the amnesia induced by pirenzepine administered intraperitoneally at a dose of 75 mg/kg, with an EDSO of 0.47 mg/kg, administered orally.

Finally, the compounds according to the invention showed no signs of toxicity at the doses at which they are active.

Consequently, the compounds (I) can be used as drugs.

The results indicated show that the compounds according to the invention have a good affinity for the muscarinic receptors and a good activity in the tests for amnesia induced by scopolamine or pirenzepine. They make it possible to consider using the products according to the invention in all cases where a cholinergic deficiency is evident, especially for the treatment of cognitive memory disorders and degenerative syndromes associated with senescence and with senile dementia.

According to another feature, the present patent application therefore relates to the pharmaceutical compositions in which at least one of the compounds of formula (I) or one of their salts is present as the active principle.

In the pharmaceutical compositions of the - 23 present invention for oral, sublingual, transdermal or rectal administration, the active principles of formula (I) above can be administered to humans in unit forms of administration, mixed with the conventional pharma05 ceutical carriers, especially for the treatment of cognitive memory disorders or degenerative syndromes. Appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspen10 sions to be taken orally, forms for sublingual and buccal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration.

To obtain the desired effect, the dose of active principle can vary between 5 and 1000 mg per day.

Each unit dose can contain from 5 to 200 mg of active ingredient in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times a day.

If a solid composition in the form of tablets is prepared, the main active principle is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.

The tablets can be coated with sucrose or other appropriate substances or they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.

A preparation in the form of gelatin capsules is obtained by mixing the active principle with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

Water-dispersible granules or powders can contain the active principle mixed with dispersants or wetting agents or with suspending agents such as polyIE 912658 - 24 vinylpyrrolidone, as well as with sweeteners or taste correctors.

Rectal administration is effected using suppositories which are prepared with binders melting at the rectal temperature, for example cacao butter or polyethylene glycols.

Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharma10 ceutically compatible dispersants and/or wetting agents, for example propylene glycol and butylene glycol.

The active principle can also be formulated as raicrocapsules, if appropriate with one or more carriers or additives.

As a pharmaceutical preparation, it is possible to prepare gelatin capsules containing Compound 6 0.010 g Lactose 0.050 g Magnesium stearate 0.005 g by intimately mixing the above ingredients and pouring the mixture into hard gelatin capsules.

Claims

CLAIMS:

1. A compound of the formula Ar R 3 _Z \_NH-R4 (I) in which - Ar is a phenyl group of the formula a pyridyl group or a thienyl group; - R x and R a are each independently hydrogen, a halogen atom, a hydroxyl group, a Cj-C, alkyl group, a C x -C 4 alkoxy or the trifluoromethyl group; - R 3 is a linear or branched C 1 -C s alkyl, a group -CH 2 C 6 H 5 or a group -CH 2 -CH 2 -C 6 H 5 ; and - R„ is the group -X-N R s r 6 in which • X is a linear or branched C i -C 6 alkylene and - 26 • R 5 and R s are each independently hydrogen or a linear or branched C 1 -C 4 alkyl or form, with the nitrogen atom to which they are bonded, a heterocycle selected from pyrrolidine, morpholine or piperidine; or - R 4 is a group selected from -(CH 2 ) n R7 in which n is as defined above and R 7 is hydrogen or a C x -C 4 , preferably C x -C 2 , alkyl group; in which n is as defined above, -ch 2 -( f N-C 2 H 5 <^N-(CH 2 )

2. And its salts with mineral or organic acids. - 27 2. A comp - X X or Xl -CH 2 -C-(CH 2 )nlXl in which n 1 is 0 or l and X 3 is a group; and R c and R r are as defined in claim 1. □ b

3. An intermediate for the preparation of ( formula ound accordinq to claim 1, wherein R, 3 4 N R C R C in which : 5 b represents either a group -(CH 2 ) n - , an integer from 1 to 3 ; a group represents in which n is : 3 -C 3 alkyl ), of the (IV) in which Ar and R 3 are as defined in claim 1 exception of the compound (IV) in which R x = R 3 = CH 3 .

4. An intermediate for the preparation of (I formula with the = H and ), of the (III) in which Ar and R 3 are as defined in claim l, with the exception of the compound (III) in which R x = R 2 = H and R^ = CH 3 .

5. . An intermediate for the preparation of (I), of the formula Cl (II) in which Ar and R 3 are as defined in claim 1.

6. A method of preparing a compound according to claim 1, which comprises reacting an amine of the formula H 2 N-R 4 in which R 4 is as defined in claim 1, with a 3-chloro pyridazine derivative of the formula in which Ar and R 3 are as defined in claim 1, and, if desired, converting the resulting compound to a salt with a mineral or organic acid.

7. a pharmaceutical composition in which a compound of formula (I) according to claim 1 is present as the active principle.

8. - A pharmaceutical composition according to claim 7 in the form of a dosage unit in which the active principle is mixed with at least one pharmaceutical excipient.

9. A compound of the formula (I) as defined herein, substantially as herein described in the Examples.

10. A method of preparing a compound of the formula (I) as defined herein, substantially as herein described in any of 5 the Examples.

11. A compound of the formula (I) as defined herein whenever prepared by a method according to Claim 6 or Claim 10.

12. An intermediate of the formula (IV), (III) or (II) as 10 herein defined, for the preparation of a compound of the formula (I) as herein defined, substantially as herein described in Example 1.

13. A method of preparing a compound of the formula (IV), (III) or (II) as herein defined, substantially as herein 15 described in Example 1.

14. A pharmaceutical composition according to Claim 6, substantially as herein described.

15. A compound of the formula (I) as defined herein for use as an Mj-type cholinergic receptor ligand.

16. 20 16. The features described in the foregoing specification, or any obvious equivalent thereof, in any novel selection.