CA1135689A

CA1135689A - Substituted phenol ester containing compounds

Info

Publication number: CA1135689A
Application number: CA000345303A
Authority: CA
Inventors: Arthur Scherm; Dezsoe Peteri; Klaus Hummel
Original assignee: Merz and Co GmbH and Co KG
Current assignee: Merz and Co GmbH and Co KG
Priority date: 1979-02-08
Filing date: 1980-02-08
Publication date: 1982-11-16
Also published as: PL123379B1; SE8000962L; AR228251A1; AU532208B2; ATA70380A; PL221888A1; IL59337A; NL8000826A; CH644092A5; AT374797B; BE881626A; SE450381B; GB2041937A; DK53680A; IT8019782A0; FR2448532B1; GR73905B; GB2041937B; FR2448532A1; JPS6126993B2

Abstract

ABSTRACT
A process for producing pharmaceutically active compounds of the general formula Wherein R1 = a) where n = 3 - 12 m = O - 1 z = O - 1 b) where m = O - 1 and z = O - l c) Cumyl d) p-Chlorobenzoyl e) 1-Piperidinyl f) 2-Pyrimidinyl or, g) Hydrogen, when R2 equals cycloalkyl or cycloalkylene (-CH2-)n, and R2 = a) (-CH2-)n, where n = O or 4 b) Halogen c) C1-C6-Alkyl or cycloalkyl d) Methoxy e) Ethoxy f) trifluoromethyl g) Nitro or, h) Hydrogen and R3 = a)

Description

ll~S6~9 MERZ-4-CANADA

The invention relates to new pharmaceutically effective compounds and their pharmaceutically applicable salts formed with organic acids as well as to a process for the manufacture of these compounds.
It is known that atherosclerosis is caused by the accumula-tion of lipids in the aorta and the coronary, cerebral and peri-pheral arteries. This results in an increased risk of throm-boses or artery obstruction. Dependent on the nature of the increased plasma protein level, either the elevated cholesterol or triglyceride level is of importance. In this connection even cholesterol levels exceeding 200-300 mg/100 ml serum and tri-glyceride levels of 45-66 mg/100 ml serum are considered to be extremely elevated.
The two most widely known classes of active substances used in the treatment of hyperlipidemias comprise the ethyl ester of

2-(p-chlorophenoxy)-isobutyric acid - known as clofibrate - and its salts as well as nicotinic acid which influence the serum lipids by different modes of action. While in test animals doses of 30-500 mg/kg body weight mainly effect a lowering of the cholesterol level in addition to a slight reduction of the free fatty acids, 3-pyridyl carbinol, nicotinic acid and its salts bring about a great reduction of the free fatty acids already at a low dosage between 0.5 and 30 mg/kg body weight.
None of the substances has, however, a significant reducing influence on triglycerides~ 8esides that, due to its unpleasant and known side effects (flush, headache, nausea, vomiting) nicotinic acid can only be conditionally used so that thereapy often has to be discontinued prematurely.

.~ ~

~3S6l~

Additionally, it is known that clofibrate, in fact, effects a fall of the initial values of triglycerides (TG) and pre-B-lipoproteins by up to 50%, this degree of lowering not being achieved in the case of cholesterol. In about 20% of the cases the cholesterol (CH) in the B- and ~-lipoproteins is even further increased. Nicotinic acid and its derivatives, on the contrary, act predominantly on elevated cholesterol values and free fatty acids, whereas the decrease of the endogenous re-synthesis of the triglycerides via inhibition of tissue lipoly-sis is only a secondary effect (cf. Verhandlungen der Deutschen Gesellschaft f~r innere Medizin, 82. Kongress, gehalten zu Weisbaden vom 25. bis 29.4.1976, Teil I, J.F. Bergmann Verlag M~nchen).
Moreover, FR-PS 6975 mentions the 3-pyridyl carbinol ester of clofibric acid as effective lipid- and cholesterol-lowering component. This compound, although being predominantly used in the form of nicotinate, can only be administered in low dosage due to the high portion of its pyridine component and the thus resulting side effects. It is, therefore, of only little thera-peutic benefit.
All the aforementioned substances effect a significant reduction of only one of the lipid components, e.g., the tri-glycerides, while the other lipid components are therapeutic-ally not or only slightly influenced. This therapeutic effect can only be achieved by a dose increase.
Therefore, the objective was to find other compounds having a lowering effect on several lipid components but without dose increase.
Unexpectedly, this requirement is met by the claimed new compounds having the general formula explained in claim 1. The ~13Sfi~ M~RZ-4-CANADA

compounds according to the invention exhibit a strong effect on both increased serum triglyceride and cholesterol values.
In comparison with nicotinic acid and the ethyl ester of 2-(p-chlorophenoxy)-isobutyric acid the dosages are incomparably lower so that possible side effects are reduced to minimum.
The new compounds are solid substances.
In the following the manufacture of the new compounds is described:

Example 1: Preparation of p-cyclohexylphenyl nicotinate 17.6 g l100 mmol) of cyclohexylphenol and 19 g (106 mmol) of nicotinic acid chloride hydrochloride was mixed with 250 ml of dry pyridine and kept at 40C for 4 hours. Subsequently, the mixture was cooled in the ice bath, and water added in portions. After addition of 10 ml of water a clear solution was obtained. Water (50 ml) was admixed until strong turbidity appeared. After stirring the mixture for a longer period of time the product crystallized in the ice bath. The precipitate was sucked off, freed from pyridine by washing with water and dried. A second fraction was obtained from the filtrate by further addiing water (60 ml).
Yield: 70% of the theoretical value. Fp.: 103~C
Analysis calculated found C76.86 76.83 H6.76 6.76 N4.98 5.05 Example ~: Preparation of p-(t-adamantylphenyl)-nicotinate 11.4 g (S0 mmol) of p-1-adamantylphenol and 10 g (56 mmol) of 113~g nicotinic acid chloride hydrochloride was mixed with 150 ml of dry pyridine and kept at 45~C for 4 hours. By adding 40 ml of water and stirring in the ice bath the product formed a pre-cipitate which was sucked off, washed with water and dried.
Yield: 78% of the theoretical value. Fp.: 199~C
Analysis calculatedfound C79.27 78.01 H6.90 6.82 N4.20 4.50 Example 3: Preparation or 2-(p-chlorophenoxy)-isobutyric acid-p-(1-adamantylacetyl)-phenyl ester 6.75 9 (25 mmol) of p-(1-adamantylacetyl)-phenol and 6 9 (25.7 mmol) of 2-(p-chlorophenoxy)-isobutyric acid chloride was mixed with 60 ml of dry pyridine and kept at 40C for 4 hours. After addition of 40 ml of water a crystalline product was obtained which was sucked off, washed with water and dried.
Yield: 77% of the theoretical value. Fp.: 114C
Analysis calculated found C 72.03 72.12 H 6.64 6.61 Example 4: Preparation of p-cyclododecylphenyl nicotinat~

8 9 (30.8 mmol) of p-cyclododecylphenol and 5.9 q (33.2 mmol) of nicotinic acid chloride hydrochloride was mixed with 140 ml of dry pyridine and kept at 30C for 15 hours. Subsequently, 42 ml of water was added slowly drop by drop, and the mixture cooled to 0C. The crystallized precipitate was sucked off, freed from ~' 3S~Ei9 MF,RZ-4-CANADA

pyridine by washing with water and dried.
Yield: 85% of the theoretical value. Fp.: 98UC
Analysis calculated found C 79.91 79.01 H 8.50 8.54 Example 5: Preparation of p-(cyclohexylacetyl)-phenyl nicotinate 11 g (50 mmol) of p-cyclohexylacectylphenol and 9.6 g (54 mmol) of nicotinic acid chloride hydrochloride was mixed with 160 ml of dry pyridine and stirred for 8 hours at 40~C. Subsequently, water (66 ml) was added drop by drop until the solution was turbid. The solution was placed in the ice bath, the precipi-tate sucked off, freed from pyridine by washing with water and dried.
Yield: 55% of the theoretical value. Fp.~ 103~C
Analysis calculated found C 74.30 74.07 H 6.50 6.51 Example 6: Preparation of o-cyclohexylphenyl nicotinate hydrochloride 15 g (85 mmol) of o-cyclohexylphenol and 16.5 g (93 mmol) of nicotinic acid chloride hydrochloride was mixed with 200 ml of dry pyridine and stirred for 24 hours at 30~C. After cooling precipitated pyridine hydrochloride was sucked off and 300 ml of water added. The precipitated raw prod~ct was washed with 200 ml portions of water, dissolved in alcohol and reduced by means of a rotary evaporator. The remaining viscous oil was ~3~6~9 dissolved in 500 ml of dry ether and hydrochlorinated with HCl gas. Subsequently, the mixture was filtered, washed with ether and dried.

Yield: 52% of the theoretical value. Fp.: 151-2C

Analysis calculated found C68.03 68.11 H6.29 6.30 Cl11.18 11~20 Example 7: Preparation of 5,6,7,8-tetrahydro-1-naphthyl nicotinate 7 g (47 mmol) of 5,6,7,8-tetrahydro-1-naphthol and 9 g (50 mmol) of nicotinic acid chloride hydrochloride was mixed with 130 ml of dry pyridine and stirred for 24 hours at 30 degrees centi-grade. After cooling precipitated pyridine hydrochloride was sucked off, and the filtrate mixed with 300 ml of water. The precipitated raw product was washed with 200 ml portions of water and recrystallized from methanol.

Yield: 65% of the theoretical value Melting point: 86 degrees centigrade Analysis calculated found C75.88 75.81 H5.93 6.07 1135~ MERZ-4-CANADA

Toxicity tests:
Table 1 No. of LDso Human merap.
~ound R1 R2 R3 Mouse daily dose Index (mg~kg) (mg) _ 2 I Cyclohexyl ~ ridinoyl-(3) ZZ00 300 0,13 1 1-Adamantyl H Pyridinoy1-(3) 3200 300 0,093 = ===___ = ____ ~ -- =_= = = =====
2-0-Chlorophenoxy isobutyric acid ethyl ester (standard) 1500 1500 1,0 Nicotinic acid (standard) 4000 3000 0,75 Table 1 shows that the toxicity values are in a comparable range thus resulting in excellent values for the therapeutic index~

Evidence of effectiveness:
Additionally, experiments on female Wistar rats were carried out. For a period of 3 weeks the animals received a special diet with a very high fat content. Starting from the second week, half the rats were treated with a dosage of 100 mg/kg body weight. After the third week blood samples were taken 18 hours after administration of the last dose. Trigly-ceride and cholesterol concentrations were compared with that of the untreated animals. Cholesterol and triglycerides were determined with the aid of the Boehringer enzymatic test. As summarized in Table 2, highly significant reductions of both parameters were achieved. Table 2 also show that the separate administration of clofibrate and nicotinic acid was by far less effective.

~3S6~'3 Table 2 Red. ofRed. of triglycer-~ f R1 R2 R3 choles-ides in %
compound terol in %
1l-Adamantyl H Pyridincyl-(3) 28 47 _ 2 Cyclohexyl H Pyridinoyl-(3) 45 4 Cumyl H Pyridinoyl-(3) 24 7 p-Chloro- H Pyridinoyl-(3) 29 benzoyl 8 1-Adamantyl- H 2-Methyl-2-(p- 27 35 acetyl chlorcphenoxy) propionyl _ _ Nicotinic acid (100 mg/kg) 7 2-(p-Chloro-phenoxy iso- (100 mg/kg) _ 8 butyric acid ethyl ester Subject matter of the invention are therefore new compounds of the general 20formula:

R
R~ 0 - R3 /CH--(CH2)-- C 11 ;
Wherein Rl = a) (CH ) H where n = 3 - 12 2 m = 0 - 1 z = O -- 1 b) ~ 2 m ( ~ where m - 0 - 1 ~356~

c) Cumyl d) p-Chlorobenzoyl e) 1-Piperidinyl f) 2-Pyrimidinyl g) Hydrogen, when R2 equals cycloalkyl or cyclo-alkylene (~CH2~)n' and R~ = a) (-CH2-)n, where n = 0 or 4 b) Halogen C ) C1 -C6-Alkyl d) Methoxy e) Ethoxy f) Trifluoromethyl g) Nitro O
and R3 = a) - C - ~

b) 2-Methyl-~-(p-chlorophenoxy)-propionyl and their pharmaceutically applicable salts formed with organic or inorganic acids.
Additionally, the invention relates to a process for the manufacture of the compounds according to claim 1, characterized in that known esterification methods are used such as, e.g., the reaction of 1 mol of nicotinic acid chloride with 1 mol of starting phenol in the presence of at ieast 1 mol of an acid-binding substance, e.g., pyridine. The preparations according to the invention consist of compounds according to claim 1 and usual pharmaceutical adjuvants.
The compounds according to the invention may be processed into pharmaceutical agents containing a carrier or a diluent in addition to the active substance. They can be administered by`

` MERZ-4-C~NAD~
1~3S6~3 the oral and the parenteral route.
Solid preparations for oral administration are capsules, tablets, pills, powders, granulates. In such solid prepara-tions the active substance is mixed with at least one inert diluent such as cane sugar, lactose or starch. Additional sub-stances may be added such as lubricants or buffers. The tablets or pills may be subject to enteric-coating.
Liquids for oral application are emulsions, solutions, suspensions containing the commonly used inert diluents such as water. Additionally, such liquid agents may contain wetting~
emulsifying and dispersing agents as well as sweetening, flavor-ing and odorous substances.
Preparations for parenteral application are, among others, sterile, aqueous or non-aqueous solutions, suspensions or emul-sions. Substances known for this form of presentation are used as carrier material.
Dependent on mode of application and d~ration of treatment, the dosage of the active substances in the preparationS may vary.

'.

~3s~g ( ME~Z-4 CANADA

SUPPLEMENTARY DISCLOSURE
-FURTHER EXAMPLES

Example 8: 2-t-butyl-4-eyelohexylphenyl nieotinate 12 g (52 mmol) of 2-t-butyl-4-eyelohexylphenol and 10 g (56 mmol) of nieotinie aeid chloride hydrochloride was mixed with 150 ml of dry pyridine and stirred for 48 hours at 35C. After cooling preeipitated pyridine hydrochloride was sucked off and the filtrate mixed with 75 ml of water. The precipitated raw pro-duct was freed from pyridine by washing with water and re-erystallized from alcohol.
Yield: 73% of the theoretieal value. m.p.: 115C.
Analysis calculated found C 78.33 78.03 H 8.01 7.88 N 4.15 4.07 The eompound had an LD50 in the rat in mg/kg of 1700, an ED50 in the rat in mg/kg of 30 and a therapeutie index of 56. At a dosage of 25 mg/kg, the percentage cholesterol reduction - with this compound was 9% and the reduction in triglycerides was 8~ in the rat.

Example g: p-cumylphenyl nicotinate 42.4 g (200 mmol) of p-cumylphenol and 40 g (220 mmol) nicotinie acid ehloride hydroehloride was mixed with 600 ml dry pyridine and stirred for 24 hours at 40C. After eooling preeipitated pyridine hydrochloride was sucked off and the filtrate mixed with 150 ml of water. The precipitated raw product was washed with two 100 ml portions of water and recrystallized from methanol.
Yield: 70% of the theoretical value. m.p.: 56C.
Analysis calculated found C79.49 79.59 B5.99 6.06 , ~ /o ( ~RZ-4 CANADA
11356~9 At a dosage of 100 mg/kg of this compound, the cholesterol reduction was 24% and the triglycerides reduction was 1% in the rat.

Example 10: p-chlorobenzoylphenyl nicotinate 15 g (64.5 mmol) of p-chlorobenzoylphenol and 12 g (68 mmol) of nicotinic acid chloride hydrochloride was mixed with 200 ml dry pyridine and stirred for 24 hours at 40C. After cooling 200 ml water were added and the precipitated pro-duct washed twice with 80 ml of water and recrystallized from methanol, Yield: 80% of the theoretical value. m.p.: 172C.
Analysis calculated found C - 67.55 67.41 H 3.56 3.64 At a dosage of 100 mg/kg of this compound, the cholesterol reduction was 29% in the rat.

Example 11: 2-chloro-4-cyclohexylphenylnicotinate 6.4 g (28 mmol) 2-chloro-4-cyclohexylphenol and 5.9 g (33 mmol) nicotinic acid chloride hydrochloride was mixed with 100 ml dry pyridine and kept at 40C for 48 hours. By adding 200 ml of water and stirring in an ice bath, the product formed a precipitate which was sucked off, washed with water and dried.
Yield: 72% of the theoretical value. m.p. 68C.
Analysis calculated found C 68.46 68.66 H 5.71 5.73 Cholesterol reduction is 29%, triglycerides reduction is 2 at a dosage of 100 mg/kg in the rat.

ME~Z-4 CANADA
1135~39 Example 12: 2-nitro-4-cyclohexylphenylnicotinate 8 g (36 ~mol) 2-nitro-4-cyclohexylphenol and 6.9 g (39 mmol) nicotinic acid chloride hydrochloride was mixed with 100 ml dry pyridine and kept at 40C for 24 hours. By adding 30 ml of water and stirring in an ice bath, the product formed a precipitate which was sucked off, washed with water and dried. The product was recrystallized from 75 ml methanol.
Yield: 77% of the theoretical value. m.p.: 113C.
Analysis calculated found C66.25 66.27 H5.52 5.63 N8.59 8.69 Example 13: 2-chloro-4-(1-adamantyl)phenylnicotinate 13 g (49.5 mmol) 2-chloro-4-(1-adamantylphenyl) and 9.7 g (54.5 mmol) nicotinic acid chloride hydrochloride was mixed with 100 ml dry pyridine and kept at 75C for 72 hours. By adding 150 ml of water and stirring in an ice bath, the produce formed a precipitate which was sucked off, washed with water and dried. The product was re-crystallized from 100 ml ethanol.
Yield: 84.5% of the theoretical value. m.p.: 185C.
Analysis calculated found C71.83 71.89 H6.03 5.98 N3.81 3.83 Cholesterol reduction is 22%, triglycerides reduction is 14% at a dosage of 100 mgtkg in the rat.

1~

1~3S6~9 EXAMPLE 14, 4-(1-PIPERIDINO)-PHENYLNICOTINATE
Eight (8) grams (45 MMOL) of 4-(1-piperidino)-phenol and 8,5 G (48 ~OL) of nicotinic acid chloride hydrochloride were mixed with 150 ML dry pyridine and maintained at 40 degrees centigrade for 24 hours. Then 80 ML of water was added slowly and, after further addition of 60 ML water, the mixture was cooled in an icebath. The precipitate was removed by suction filtration, freed from pyridine by washing with water, and dried.

YIELD: 60% of the theoretical. MP: 126C
ANALYSIS

CALCULATED FOUND
CARXON: 72,34 72,24 H 6,38 6,40 N 9,90 9,92 EXAMPLE 15, 2-(P-CHLOROPHENOXY)-ISOBUTYRIC ACID-4-CYCLOHEXYL-PHENYLESTER
Seven (7) grams (40 ~OL) of 4-cyclohexylphenol and 10 G (43 MMOL) of p-chlorophenoxyisobutyric acid chloride were mixed in 70 ML of dry pyridine and maintained at 40C for 24 hours. Then 20 ML of water was added slowly and the reaction mixture cooled in an icebath. The precipitate was removed by suction filtration, freed from pyridine by washing with water and dried.

YIELD: 81% of the theoretical. MP: 100C

A~ALYSIS

CALCULATED FOUND
CARBON:70,8771,02 H 6,71 6,83 -13~-

Claims

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

1. Process for the manufacture of a substituted phenol ester having the general formula:

Wherein R1= a) where n = 3 - 12 m = 0 - 1 z = 0 - 1 b) where m = 0 - 1 and z = 0 - 1 c) Cumyl d) p-Chlorobenzoyl e) piperidinyl or, f) Hydrogen, but R1 can only equal hydrogen when R2 equals cycloalkyl or cycloalkylene (-CH2-)n, and R2 = a) (-CH2-)n, where n = 0 or 4 b) Halogen c) C1-C6-Alkyl or cycloalkyl d) Methoxy e) Ethoxy f) Trifluoromethyl g) Nitro or, h) Hydrogen and R3 = a) or, b) 2-Methyl-2-(p-chlorophenoxy)-propionyl, -14- (Claims page 1) and their pharmaceutically applicable salts formed with organic or inorganic acids, comprising the steps of (a) reacting a nicotinic acid halide or 2-methyl-2-(p-chlorophenoxy)-propionyl halide with a starting substituted phenol of the formula at an elevated temperature and (b) isolating the desired product of the formula first above given as the free base or as an acid addition salt thereof.

2. Process of Claim 1 wherein the elevated temperature is at least about 30 degrees centigrade and wherein the reaction is conducted using an acid chloride in the presence of an acid-binding substance.

3. Process of Claim 2 wherein the acid-binding substance is pyridine.

4. A process of Claim 1 wherein cyclo-hexylphenylnicotinate or an acid addition salt thereof, or cyclododecylphenyl-nicotinate, or 5,6,7,8-tetrahydro-1-naphthyl-nicotinate, or (1-adamantylphenyl)-nicotinate, or (cyclohexylacetyl)-phenyl-nicotinate, or 2-(chlorophenoxy)-isobutyric acid-(l-adamantylacetyl)-phenylester is produced starting from about one mol of the appropriate starting phenol and about one mol of the selected nicotinic acid or 2-methyl-2-(p-chlorophenoxy)-propionyl chloride in the presence of at least one mol of an acid-binding substance.

-15- (Claims page 2)

5. A process of Claim 2, wherein cyclohexylphenylnicotinate or an acid addition salt thereof, or cyclododecylphenyl-nicotinate, or 5,6,7,8-tetrahydro-1-naphthyl-nicotinate, or (l-adamantylphenyl)-nicotinate, or (cyclohexylacetyl)-phenyl-nicotinate, or 2-(chlorophenoxy)-isobutyric acid-(l-adamantyl-acetyl)-phenylester is produced starting from about one mol of the appropriate starting phenol and about one mol of the selected nicotinic acid or 2-methyl-2-(p-chlorophenoxy)-propionyl chloride in the presence of at least one mol of an acid-binding substance.

6. A process of Claim 3, wherein cyclohexylphenylnicotinate or an acid addition salt thereof, or cyclododecylphenyl-nicotinate, or 5,6,7,8-tetrahydro-1-naphthyl-nicotinate, or (l-adamantylphenyl)-nicotinate, or (cyclohexylacetyl)-phenyl-nicotinate, or 2-(chlorophenoxy)-isobutyric acid-(l-adamantylacetyl)-phenylester is produced starting from about one mol of the appropriate starting phenol and about one mol of the selected nicotinic acid or 2-methyl-2-(p-chlorophenoxy)-propionyl chloride in the presence of at least one mol of an acid-binding substance.

-16- (Claims page 3)

7. Process for the production of cyclohexylphenylnicotinate or an acid addition salt thereof which comprises the step of reacting nicotinic acid chloride with cyclohexylphenol in the presence of an acid-binding substance.

8. Process for the production of cyclohexylphenylnicotinate which comprises the step of reacting nicotinic acid chloride with cyclohexylphenol in the presence of an acid-binding substance.

9. Process for the production of p-cyclohexylphenylnicotinate which comprises the step of reacting nicotinic acid chloride with p-cyclohexylphenol in the presence of an acid-binding substance.

lO. Process for the production of cyclohexylphenylnicotinate hydrochloride which comprises the step of reacting nicotinic acid chloride with cyclohexylphenol in the presence of an acid-binding substance.

ll. Process for the production of o-cyclohexylphenylnicotinate hydrochloride which comprises the step of reacting nicotinic acid chloride with o-cyclohexylphenol in the presence of an acid-binding substance.

12. Process for the production of cyclododecylphenyl-nicotinate which comprises the step of reacting nicotinic acid chloride with cyclododecylphenol in the presence of an acid-binding substance.

13. Process for the production of p-cyclododecylphenyl-nicotinate which comprises the step of reacting nicotinic acid chloride with p-cyclododecylphenol in the presence of an acid-binding substance.

-17- (Claims page 4)

14. Process for the production of 5,6,7,8-tetrahydro-1-naphthylnicotinate which comprises the step of reacting nicotinic acid chloride with 5,6,7,8-tetrahydro-1-naphthol in the presence of an acid-binding substance.

15. Process for the production of (1-adamantylphenyl)-nicotinate which comprises the step of reacting nicotinic acid chloride with 1-adamantylphenol in the presence of an acid-binding substance.

16. Process for the production of p-(1-adamantyl)phenyl nicotinate which comprises the step of reacting nicotinic acid chloride with p-(1-adamantyl)phenol in the presence of an acid-binding substance.

17. Process for the production of (cyclohexylacetyl)-phenyl-nicotinate which comprises the step of reacting nicotinic acid chloride with (cyclohexylacetyl)-phenol in the presence of an acid-binding substance.

18. Process for the production of p-(cyclohexylacetyl)-phenyl-nicotinate which comprises the step of reacting nicotinic acid chloride with p-(cyclohexylacetyl)-phenol in the presence of an acid-binding substance.

19. Process for the production of 2-(chlorophenoxy)-isobutyric acid-(1-adamantylacetyl)-phenylester which comprises the step of reacting 2-methyl-2-(p-chlorophenoxy)-propionyl chloride with 1-(adamantylacetyl)-phenol in the presence of an acid-binding substance.

20. Process for the production of 2-(chlorophenoxy)-isobutyric acid-p-(1-adamantylacetyl)-phenylester which comprises the step of reacting 2-methyl-2-(p-chlorophenoxy)-propionyl chloride with 1-p-(adamantylacetyl)-phenol in the presence of an acid-binding substance.
-18- (Claims page 5)

21. A substituted phenol ester whenever prepared according to the method of Claim 1 or an obvious equivalent.

22. A substituted phenol ester whenever prepared according to the method of Claim 2 or an obvious equivalent.

23. A substituted phenol ester whenever prepared according to the method of Claim 3 or an obvious equivalent.

24. A substituted phenol ester whenever prepared according to the method of Claim 4, 5, or 6 or an obvious equivalent.

25. The compound cyclohexylphenylnicotinate or an acid addition salt thereof whenever prepared according to the method of Claim 7 or an obvious equivalent.

26. The compound cyclohexylphenylnicotinate whenever prepared according to the method of Claim 8 or an obvious equivalent.

27. The compound p-cyclohexylphenylnicotinate whenever prepared according to the method of Claim 9 or an obvious equivalent.

28. The compound cyclohexylphenylnicotinate hydrochloride whenever prepared according to the method of Claim 10 or an obvious equivalent.

29. The compound o-cyclohexylphenylnicotinate hydrochloride whenever prepared according to the method of Claim 11 or an obvious equivalent.

30. The compound cyclododecylphenylnicotinate whenever pre-pared according to the method of Claim 12 or an obvious equivalent.

-19- (Claims page 6)

31. The compound p-cyclododecylphenylnicotinate whenever prepared according to the method of Claim 13 or an obvious equivalent.

32. The compound 5,6,7,8-tetrahydro-1-naphthylnicotinate whenever prepared according to the method of Claim 14 or an obvious equivalent.

33. The compound (1-adamantylphenyl)-nicotinate whenever prepared according to the method of Claim 15 or an obvious equivalent.

34. The compound p-(1-adamantyl)phenyl-nicotinate whenever prepared according to the method of Claim 16 or an obvious equivalent.

35. The compound (cyclohexylacetyl)-phenylnicotinate whenever prepared according to the method of Claim 17 or an obvious equivalent.

36. The compound p-(cyclohexylacetyl)-phenylnicotinate whenever prepared according to the method of Claim 18 or an obvious equivalent.

37. The compound 2-(chlorophenoxy)-isobutyric acid-(1-adamantylacetyl)-phenylester whenever prepared according to the method of Claim 19 or an obvious equivalent.

38. The compound 2-(chlorophenoxy)-isobutyric acid-p-(1-adamantylacetyl)-phenylester whenever prepared according to the method of Claim 20 or an obvious equivalent.

-20- (Claims page 7) SVPPLEMENTARY DISCLOSURE CLAIMS

39. Process for the production of 2-t-butyl-4-cyclohexyl-phenyl nicotinate which comprises the step of reacting nicotinie acid chloride with 2-t-butyl-4-cyclohexylphenol in the presence of an acid-binding substance.

40. Process for the production of p-cumylphenyl nieotinate whieh comprises the step of reacting nicotinic acid chloride with p-cumylphenol in the presence of an acid-binding substance.

41. Process for the produetion of p-chlorobenzoylphenyl nicotinate which comprises the step of reacting nicotinic acid chloride with p-chlorobenzoylphenol in the presence of an acid-binding substance.

42. The compound 2-t-butyl-4-cyclohexylphenyl nicotinate whenever prepared according to the method of Claim 39 or an obvious equivalent.

43. The compound p-cumylphenyl nicotinate whenever pre-pared according to the method of Claim 40 or an obvious equivalent.

44. The compound p-chlorobenzoylphenyl nicotinate whenever prepared according to the method of Claim 41 or an obvious equivalent.

-21- (Claims page 8)

45. Process for the production of the compound 4-(1-piperidino)-phenylnicotinate which comprises the step of reacting nicotinic acid chloride with 4-(1-piperidino)-phenol in the presence of an acid-binding substance.

46. Process for the production of the compound 2-(p-chloro-phenoxy)-isobutyric acid-4-cyclohexylphenylester which comprises the step of reacting 2-(p-chlorophenoxy)-isobutyric acid chloride with 4-cyclohexylphenol in the presence of an acid-binding substance.

47. The compound 4-(1-piperidino)-phenylnicotinate whenever prepared according to the method of claim 45 or an obvious equivalent.

48. The compound 2-(p-chlorophenoxy)-isobutyric acid-4-cyclohexylphenylester whenever prepared according to the method of claim 46 or an obvious equivalent.

-22- (Claims page 9)