CA1129881A - Benzamidoalkyl mercaptans - Google Patents

Abstract

Abstract Novel benzamidoalkyl mercaptans having the formula wherein R is hydrogen, halogen, lower-alkyl, lower-alkoxy, amino, carboxy or trifluoromethyl, "alk" is a straight or branched divalent alkylene radical of 2 to 4 carbon atoms and n is one to three, except where R
is hydrogen, n is three and "alk" represents -CH2-CH2- are found to be useful as mucolytic agents in combating lung mucus.

Description

~988~L
The present invention is concerned with certain mercaptans possessing mucolytic activ;ty and is particularly concerned with certain novel benzamidoalkyl mercaptans, compositions thereof and methods for employing the mercaptans as mucolytic agents in con~rolling and combatlny mucus bu;ld-up in an animal exhibiting or suffering from lung congestion.
A.L. Sheffner, Ann. N.Y. Acad. Sci. 106, 298-310 (1963) discloses sulfhydryl-containing compounds having mucolytic activity and established - the use of mucin mucoprotein as a tes~ media. None of the compounds disclose~ by Sheffner were of the benzamidoalkyl mercaptan type. T.A.
10 Martin et al., in U.S. Patent 4,005,222 disclose mucolytic anilido alkyl mercaptans distinguishable in part from compounds of the instant invention in having the nitrogen interposed between carbonyl and phenyl rather than between carbonyl and alkyl.
Benzamicloethyl mercaptan is a known compound, A.A. Goldberg et al., J. Chem. Soc. 1948, 1919-26, but there has been no disclosure of mucolytic activity.
The compounds of the present invention are novel benzamido-alkyl mercaptans illustrated generally by the followin~ formula:
o ,~ C-NH-alk-SH

( )~ Formula I

wherein;
R is selected from hydrogen, halogen, lower-alkyl, lower-alkoxy, amino, carboxy or trifluoromethyl, -alk- is a straight or branched divalent alkylene radical of

2 to 4 carbon atoms, and n is 1 to 3, and when n is more than 1, R may be the same or different in various positions relative to one another on the ring, ..~; .

the compound wherein R is hydrogen, n is three and -alk- is -CH2-CH2-being excluded since this is a known compound.
The compounds have mucolytic activity and are useful in d;ssolviny and diluting mucus in warm-blooded animals exhibiting or su~ferlng -From lung congestions.
In another aspect, the present invention provides a method of preparing the benzamidoalkyl mercaptans defined above, said method comprising either:
~ a) reacting a salt of the formula:

S -alk -NH2 o HX
(R)n with alkali, wherein R, n and alk are as defined above and X is halogen or (b) reacting an isothiouronium salt of the formula:

~ ~ C - NH - alk - S - C - NH2 ? HX
(R)n with alkali wherein R, n, alk and X are defined above; or (c) reacting an acid of the formula COOH
(R)n with a compound of the formula HS - alk - NH2 . HX
where R, n, alk and X are as defined above with pyridine and phosphorus trichloride.

813~

The compounds described hereinafter and represented by the foregoing Formula I have been shown by a modification of the method of S.J. Corne et al., J. Phys. 242, 116 (1974) as described hereinbelow to have mucolytic activity in animals.
Compounds For which mucolytic activity was found to be of the same order of magnitude as N-acetyl-L-cysteine on rat stomach mucus are the preferred compounds which are as follows:
(1) 4-chlorobenzamido-ethylmercaptan (2) 4-methylbenzamido-ethylmercaptan

(3) 4-methoxybenzamido-ethylmercaptan The method used to establish mucolytic activity in compounds of the present invention is as follows: Female - 2a -~2~

Sprague-Dawley (charles River Labs) 1~0-180 g. rats are fasted 16 hours on wireJ housed two animals per cage. To minimize coprophagia, the lights are left on during the fast. Two cc. of water are given orally to each rat to minimize internal debris. Thirty minutes later the rats are sacrificed by cervical dislocation. The stoma~hs are removed, trimmed of excess tissue and the epithelial portion discarded. The glandular portion is cut suffi-ciently along the greater and lesser curvature to cause eversion of the stomacn before placing it in the drug solution. Stomachs with a fecal odor or containing visible-fecal matter are discarded. Stomachs ;are placed in 10 cc. of solution (50% PEG-300-H20) containing 2.5 mg.
test compound/ml. for 40 minutes. After drug treatment the stomachs are placed in 10 cc. Alcian Blue (Solution 1) for 90 minutes where the dye complexes with the stomach mucus. After two successive 10-minute washes in 10 cc.
o~ 0.25 M. sucrose (Solution 2), the stomachs are placed in 10 cc. of 0.5 MgCl2 (Solution 3) for one hour to remove the complexed dye. The MgCl2 supernatant is shaken with 10 cc. diethyl ether in a 60 cc. separatory funnel to remove lip*ids. The aqueous phase is drained into a Spectronic 20 Tube and th*e percent transmission is read at 605 m~ in a Spectronic 20 Spectrophotometer. The per-cent transmission is converted to ~g/ml of Alcian Blue from a standard curve (P. Whiteman, Biochem~ J. 131, 351-57 ~1973). Each drug or drug vehicle (control) is tested on three stomachs. Mean differences between treated and control values are expressed as percentages.
Solution 1 Alcian Blue, 0.05% w/v (1 liter) 54.8 g. sucrose (0.15 M) 6.8 g. sodium acetate 900. cc. deionized water Dissolve with a magnetic stirrer and adjust to pH 5.8.
Add 500 mg. Alcian Blue 8GN (MathesonJ Coleman & Bell ~8E13). Fill to one liter in a volumetric flask. Refrig-erate. Use only for one week.

* Trade Mark ~lZ98E3~

Solution 2 - Sucrose, 0.25 M (1 liter) Add 85.6 g. of sucrose to 1 liter volumetric flask. Fill to volume with cleionized water. Use only for one week.
Solution 3 - Magnesium Chloride. 0.5 M (1 liter) Qdd 101.7 g. MgC12r6H20 (A.C.S.) to a one liter volumetric flask. Fill to volume with deionized water.
Therefore, the present invention is directed to providing certain novel benzamidoalkyl mercaptans having mucolytic activity in a warm-blooded animal and to using them in combating mucus in an animal suffering from or exhibiting lung congestion.
The compounds may be used in the form of nov~-l pharmaceutical compositions for combating mucus in warm-blooded animals.
Advantages of the present invention will be apparent to one skilled in the art and still others will become apparent from the following description of the best mode of carrying out the present invention and from the appended claims.
In the definition of the symbols and in Formula I given above and where they appear elsewhere throughout the claims and specification hereof, the terms have the following significance.
The "lower-alkyl" and "lower-alkoxy" substituents each have from one to four carbon atoms which can be arranged as straight or branched chains. Examples are methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy.
~(R)n refers to 1 to 3 substituents of R in various available positions on the phenyl nucleus and when more than one substituent is present, may be the same or different and may be in various position combinations relative to each other.

- ~Lz~

The term "alk" represents a selection from among ethylene (-CH2CH2-) J propylene (-CH2CH2CH2-), lJ2-propylene (-ICHCH2-), 2J3-butylene (-~H -CH-).
CH3 CH3 C~3 Methods of Preparation The mercaptans of the present invention are prepared by one of three known methods as represented by the following equations.
METHOD (1) Via carbothioic acid ester acid salts (R)n C-Cl + HS-alk-NH2~HCl O O
(R)n C S-alk-NH2 HCl ~ ~ C-NH-alk-SH

METHOD (2) Via isothiouronium salts (.R)n ~ C-Cl + ~E~-alk-cl ---~ ~ (R)n O S
(R)n C-NH-alk-Cl + NH2-C-NH2 O NH
(R)n ~ C-NH-alk-S-C-NH2~HCl 3 KOH ~ C-NH-alk-SH
H20 ( R~n, 38~

MæTHOD (3) PCl3 ~ COOH + HS-alk-~H2~HCl Pyridine (R ~
O
C-~H-alk-SH
( R)n Description of preparation of intermediates in Method (1) follows.

2~

Preparation Benzenecarbothioic Acid, 2-Aminoeth~,rl Ester, Mono-hydrochloride.
A mixture of benzoylchloride, 15 ml~ (ca 0.13 mole) and 2-aminoethanethiol hydrochloride, 4.54 g. (0.04 mole) 5 was heated (protected from moisture) over a stream jet for 2 hours. Slight cooling produced a mass of crystals.
After trituration with 60-110C. ligroine filtration and drying, the crystals melted at 177-180C. Several recrystallizations from anhydrous ethanol produced a 10 colorless solid which melted at 178.5-lfg.5C. Nuclear Magnetic Resonance (NMR), Mass Spectrophotometer (MS), and Infra Red (IR) analyses all supported structure of the title compound. Yield was 5.1 g (59.1%).
Analysis:Calculated for CgHl2ClNOS: C,49.65; H,5.55, N,6.43 Found : C,49,58; H,5.59;
N,6.49 Preparation 2

4-Methylbenzenecarbothioic Acid, 2-Aminoethyl Ester Monohydrochloride.
A mixture of freshly distilled p-toluoyl chloride, b.p. 122C./32 mm. Hg., 30 ml. (ca 0.18 moles) and 2-amino-ethanethiol hydrochloride, 9.68 g. (0.085 moles) was heated (protected from moisture) over a steam jet for 2.25 hours.
A solid crystalline mass formed on completion of the 25 reaction. The mass was cru~hed and carefully triturated wi~h warm 60-110C. ligroine, and crystal~ were separated by filtration and washed with warm ligroine. After two recrystallizations from anhydrous ethanol, the product, 19.07 g. (97%), melted at 206.5-208C. ~ MS and IR
30 analyses all supported the structure of the title compound.
Analysis: calculated for CloHl4NOClS C,51.83; H,6 09;
Found : C~51.57; H,~;.o6;
~,6.11 ~Z~81~

Preparation ~
4-Methoxybenzenecarbothioic Ac_d, 2-Aminoethyl Ester, Monohydrochloride.
A mixture of p-anisoyl chloride, 23 ml (ca 0.135 mole) and 2-aminoethanethiol hydrochloride, 7.4 g (o.065 mole) was heated (protected from moisture) over a steam jet for about 2 hours. The resultant crystalline mass was cru~hed and carefully triturated with warm 60-110C. ligroine and crystals were separated by filtration and washed with warm ligroine. After two recrystallizations from anhydrous ~thanol~ the product, 14.6 g (90.6~ melt~d at 191.5-193 C.
NMR, ~ and IR analyses all supported the structure of the title compound.
Analysis: calculated for CloHl4ClN04S: C,48.48; H,5.69;
N,5-65 Found : C,48.42, H,5.73;
~,5.66 Preparation 4 When in the procedure of Preparation 1, benzoyl chloride is replaced by equal molar amounts of 3,4 J 5-trimethoxybenzoyl chloride, 3-trifluoromethylbenzoyl chloride, 3,4-dimethylbenzoyl chloride, 4-carboxybenzoyl chloride, there are obtained 3J4,5-trimethoxybenzenecarbothioic acid, 2-amino-ethyl ester, hydrochloride, 3-trifluoromethylbenzenecarbothioic acid, 2-amino-ethyl ester, hydrochloride, 3,4-dimethylbenzenecarbothioic acid, 2-aminoethyl ester, hydrochloride, 4-carboxybenzenecarbothioic acid, 2-aminoethyl ester hydrochloride.
Preparation 5 When in the procedure of Preparation 1, 2-amino-ethanethiol hydrochloride is replaced by equal molar amounts of 3~aminopropanethiol hydrochloride, there is obtained 9~

Benzenecarbothioic acid-~-aminopropylester hydro-chloride.
Preparation 6 When in the procedure of Preparation l, ~-amino-ethanethiol hydrochloride is replaced by equal molar amounts of 3-aminopropanethiol hydrochloride and benzoyl chloride is replaced by p-toluoyl chloride J or p-anisoyl chloride there are obtained 4-methylbenzenecarbothioic acid, 3-aminopropyl ester, hydrochloride, 4-methoxybenzenecarbothioic acid, 3-aminopropyl ester, hydrochloride.
The following examples of preparation of compounds are only intended to illustrate the present invention and are not to be construed as limiting the invention in any respect.

88~L

Example l 4-Chlorobenzamido-ethylmercaptan.
To a ~olution of 2-aminoethanethiOl hydrochloriae 22.7 g. (0.02 mole) in ~00 ml. of dry pyridine was ~dded with stirring, phosphorus trichloride, 1~.7 g. (0.1 m~le3 in 50 ml. dry pyridine. Slight exothermic reaction was noted. After ~tirring an additional ~0 min., p-chlorobenzoic acid, 31.2 g. (0.2 mole) in lO0 ml. of dry pyridine was added.
The reaction mixture was heated to reflux for 4 hrs, cool~d and poured onto 400 g. of ice. The reaction mix~ure was extracted 4 times with 100 ml. portions of methylene ~hloride.
The combined 2xtract was wa~hed twice with 200 ml. ice water, 4 times with lO0 ml. of 5~ sodium carbonate and twice more with 200 ml. of ice water~ After drying over magnesium ~ulfate, the washed extract was concentrated by evaporation to a cream colored oil which solidified on ~tanding. The 601id was 6tirred in warm water, filtered and the residue washed twice with 200 ml. water and air dried to give 29 g.
of crude material~ ~he crude was dissolved in 400 ml. Df methanol and 200 ml. of 10% 60dium carbonate ~olution added.
The solution was filtered and cooled overnight in a refrig-erator. Tan a rphous material was filtered off and discarded. Volume of ~he ~iltered solution was adjusted to 1 liter. The solution wa~ allowed to ~tand at 0 C. for 96 hrs. and the precipitate was collected by filtration and dried. Yield o~ off-white product which melted at 73-78 C.
was 5 g. (15%).
Analysis: calculated for C~HloClNOS: C~50.12; ~,4.67; ~,6.49 Found : C,50.00, H,4.63; ~J6>5 Example 2 ~0 When in the procedure ~ Example 1, 4-chlorobenzoic acid is replaced by equal molar amounts of the following:
4-~luorobenzoic acid, 4-bromobenzoic acid, 2-chlorobenzoic acid, and ~5 3,4,5-trichlorobenzoic acid, there are obtained ~z~

4-fluorobenzamido-ethylmercaptan 4-bromobenzamido-ethylmercaptan - 2-chlorobenzamido-ethylmercaPtan, ~nd 3,4,5-trichlorobenzamido-ethylmercaptan.

4-Chlorobenzamido-proPylmercaptan.
~hen in the procedure vf Example 1, 2~mîn~propan~-thiol hydrochloride is ~ubstituted $or 2-amin~e~hanethl~l in ~qual ~olar amounts, the title compound is ~btained.
~
When in the pr~cedure oi Example 2, 2-aminopropane-thiol hydrochloride is eubstituted for 2-amin~ethane~hi~l hydrochloride in equal m~lar amount, there are obtain~d:
4-fluorobenzamido-propylmercaptan 4-bromobenzamido-propylmercaptan 2-chlorobenzamido-propylmercapt~n, and ~,4,5-trichlorobenzamido-propy}mercaptan~
Example 5 (a) Isothiouronium_Salt of N-(2-mercaptoethyl)benzamide.
A mixture of ~-(2-chloroethyl)benzamide, 18.~ g.
(0.10 mole) and thioureaJ 9.1 g. (0.12 mole) in 120 ml.
anhydrous ethanol were refluxed under nitrogen, excluding moisture, overnight. Solvent was removed by distillation and the resulting isothiouronium hydrochloride salt of N-(2-mercaptoethyl)benzamideJ 25.2 g. (94.7%)J melted at 169-173C.
(b) Benzamido-ethylmercaptan.
The product of (a) was added to 300 ml. solution of potassium hydroxide (2 moles) and warmed at about 90 C0 for 2-3 hours. The solution was cooledJ washed with ether and acidified to p~ 3. The resultant turbid solution was extracted with several portions of chloroform and the combined extracts dried over magnesium sulfate. T~e solution was evaporated under reduced pressure to give a light syrup which was then diluted while warmed with 6~
110C. ligroine. The solid obtained was recrystallized 13LZ~

from benzene-ligroine to yield a colorless, crystalline solid melting 62.5~65.5C. which weighed 13.1 g. (42.30 .
Analysis: Calculated for CgHllNOS: C,59.62; H,6.11; ~J7.7~
Found : C,59.50; H,5-98; N,7-59 Example 6 4-Methylbenzamido-ethylmercaptan.
To a solution of potassium hydroxide, 6.2 g. (0.11 mole) in 200 ml. of oxygen-free water was added in one portion 4-methylbenzenecarbothioic acid, 2-aminoethyl ester monohydrochloride, 12.0 g. (0.052 mole). Nitrogen was bubbled through the suspension which was maintained at reflux temperature for 1.5 hours. A small amount of insoluble material was filtered off and discarded. The alkaline filtrate was extracted with chloroform. The aqueous alkaline solution was then acidified with conc.
hydrochloric acid and again extracted with chloroform.
The chloroform extracts were combined and dried and con-centrated to a thin syrup. Addition of 60-110 C. ligroi~e caused precipitation of crystalline solid, 9.31 g., melting at 110-113C. Yield of product after a single recrystallization from benzene-ligroine (1:5) was 7.41 g.
(76.3%), melting at 112.5-114C.
Analysis: Calculated for CloHl3S~0: C,61.50; H,6.71;
~,7-17 Found : C,61.~4; H,6.65;
N,7.16 Example 7 4-Methoxybenzamido-ethyl Mercaptan.
To a solution of potassium hydroxide, 5.6 g. (0.10 mole) in 170 ml. of oxygen-free water under a nitrogen atmosphere was added 4-methoxybenzenecarbothioic acid, 2-aminoethyl ester, monohydrochloride, 7.01 g. (0.0283 mole). The temperature was raised to and held at reflux for 1.5 hr. Tetrahydrofuran, 30 ml. was added during the ~ast 30 minutes to effect full solution. After cooling, the solution was extracted while alkaline with chloroform, then acidified and extracted again. The extracts were ~L~2988~

combined, dried, concentrated and then diluted with ligroine. The solid obtained was recrystallized from benzene 60-110C. ligroine. The yield was 3.97 g~ (57.7%
based 2-aminoethanethiol hydrochloride), melting at 107-1~8~5oc~
Analysis Calculated for CloHl3N02S: C,56.85; Hl6.20;
N,6.63 Found ~ C,56.90; H,6.16;
N,6.64 Example 8 When in the procedure of Example 7, 4-methoxybenze~e-carbothioic acid, 2-aminoethyl ester, monohydrochloride is replaced by equal molar quantities by the following:
3,4,5-trimethoxybenzenecarbothioic acid, 2-amino-ethyl ester, hydrochloride, ~-trifluoromethylbenzenecarbothioic acid, 2-amino-ethyl ester, hydrochloride, 3,4-dimethylbenzenecarbothioic acid, 2-aminoethyl ester, hydrochloride, 4-carboxybenzoylcarbothioic acid, 2-aminoethyl ester hydrochloride, there are obtained 3,4,5-trimethoxybanzamido-ethylmercaptan, 3-trifluoromethylbenzamido-ethylmercaptan, 3,4-dimethylbenzamido-ethylmercaptan, 4-carboxybenzamido-ethylmercaptan.
Example ~
When in the procedure of Example 7, 4-methoxybenzene-carbothioic acid, 2-aminoethyl ester monohydrochloride is replaced by equal molar amounts of benzenecarbothioic acid-3-aminopropyl ester hydrochloride, 4-methylbenzenecarbothioic acid, 3-aminopropyl ester, hydrochloride, or 4-methoxybenzenecarbothioic acid, 3-aminopropyl ~5 ester, hydrochloride, 9~

there are obtained benzamido-propyl mercaptan, 4-methylbenzamido-propyl mercaptan, 4-methoxybenzamido-propyl mercaptan.
` Example 10 (a) Isothiouronium Salt of N-~2-mercaptoethYl)-4-aminobenzamide.
When in the procedure of Example 5(a).N-(2-chloro-ethyl)4-aminobenzamide is substituted in equal molar amount for N-(2-chloroethyl)benzamide, the title compound is obtained.
(b) 4-Aminobenzamide-ethylmercapt n.
When in the procedure of Example 5(b)the isothiouronium salt of N-(2-mercaptoethyl)-4-aminobenzamide is substituted for isothiouronium salt of ~-(2-mercapto-ethyl)benzamide in equal molar amount, 4-aminobenzamide-ethyl-mercaptan is obtained.

8~

The pharmaceutical compositions of this invention comprise halobenzamidoethyl (and propyl) mercaptans in an amount sufficient to provide effective action against lung congestion in mammalian subjects when applied topically as an inhalant together with an acceptable carrier therefor.
The compounds of Formula I are administer~d in an amount sufficient to induce liquefaction of mucus in the respiratory tract of warm-blooded animals in need thereof.
Intratracheal administration of the compounds of Formula I
are effected by various inhalation or instillation means such as nose drops~ sprays, aerosols and the like.
Examples of pharmaceutically acceptable liquid carriers are water and polyethyleneglycol-300. Another suitable means of administration is by insufflation of micronized particles or ultra-fine powder utilizing only the energy of the inspiratory action or by use of aerosol propellants.
Generally, the amount of the compound in the inhalant composition will vary from about 0.5 to 50 weight ~.
Solutions or suspensions having about 0.5 to 20~ by weight, preferably 5-10 wt. ~, of the mucolytic agent of Formula I
are suitable for application by spraying with an atomizer, nebulizer, aerosol and the like. Dusts containing about 25-75~ or more active agent in micronized form are also suitable, about 50~ being preferable.
It will be readily apparent to those skilled in the medical arts that the correct dosage of a compound to be employed with any particular mammalian subject is determine by the severity of the condition requiring mucolytic therapyJ
as well as the age, sex, weight and general physical condition of the subject. Individual doses ranging from

5-100 mg for inhalation by man are suitable and may be required for the mucolytic effect.
The pharmaceutical compositions may take the form of dilution of the micronized compounds in dust~ or solutions and suspensions in liquids suitably dispensed for inhalation.

A. owder for Administration via Inhaler Device.
4-chlorobenzamido ethyl mercaptan of Example 1, micronized 2.5 g.
Lactose powder 2.5 g.
The powders are blended aseptically and filled into hard gelatin capsules each containing 50 mg o the mixture.
This is suitable for dispersion into the inspired breath by means of a breath-operated inhalex device containing means for rupture of the capsule wall prior to dosing.
Various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, compositions and methods of the present :Lnvention without departing from the spirit and scope thereof, and it is therefore understood that the invention is to be limited only by the scope of the appended claims.

Claims (9)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a benzamidoalkyl mercaptan of the general formula:

Ia or a pharmaceutically acceptable salt thereof; wherein R is hydrogen, halogen, lower-alkyl, lower-alkoxy, amino, carboxy or trifluoromethyl, "alk" represents a straight or branched alkylene radical of 2 to 4 carbon atoms and n is one to three, but excluding the compound where R is hydrogen, n is three and "alk" represents -CH2-CH2-, which comprises either:
(a) reacting a salt of the formula:

with alkali, wherein R, n and alk are as defined above and X is halogen or (b) reacting an isothiouronium salt of the formula:

with alkali wherein R, n, alk and X are defined above; or (c) reacting an acid of the formula with a compound of the formula HS - alk - NH2 ? HX
where R, n, alk and X are as defined above with pyridine and phosphorus trichloride.

2. A compound of the formula Ia given in claim 1 or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process according to claim 1 in which (R)n is 4-chloro 4-methyl or 4-methoxy and alk is -CH2CH2-.

4. A process according to claim 1 in which p-chlorobenzoic acid is reacted with a mixture of 2-aminoethanethiol, dry pyridine and phosphorus trichloride and neutralising the reaction mixture so obtained.

5. 4-Chlorobenzamido ethylmercaptan whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

6. A process according to claim 1 which comprises reacting 4-methyl-benzenecarbothioic acid and 2-aminoethyl ester monohydrochloride with alkali.

7. 4-Methylbenzamido ethylmercaptan whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

8. A process according to claim 1 which comprises reacting 4-methoxybenzenecarbothioic acid and 2-aminoethyl ester monohydrochloride with alkali.

9. 4-Methoxybenzamido -ethyl mercaptan whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.