Acylamino pyrazolyl compounds of the formula: ##STR1## wherein Ar represents an optionally substituted pyrazolyl group, the acylamino group --NR.sup.1 COR.sup.2 being attached to a carbon atom of the pyrazolyl ring, which have anti-allergic activity, methods of making the compounds and pharmaceutical formulations containing the compounds.

This invention relates to heterocyclic chemical compounds and more 
particularly to certain novel 5-membered heteroaryl derivatives having 
nitrogen atoms as the sole heteroatoms in the ring, substituted by an 
acylamino group which are useful for the chemotherapy of immediate 
hypersensitivity conditions and/or which are useful as intermediates in 
preparing the active derivatives. The invention also includes processes 
for preparing the active compounds of the invention. Furthermore, the 
invention includes within its scope pharmaceutical compositions containing 
the pharmacologically active compounds and methods of treatment of 
animals, including humans, comprising administering thereto an effective 
dose of the compound or compounds or of pharmaceutical compositions 
comprising the active compound or compounds. 
A number of acylamino derivatives of five membered heteroaryl systems 
similar to the compounds of the invention have been previously described 
-- see for example Helv. Chim. Acta., 48, 524 (1965). However, it is to be 
noted that such prior disclosures of this type of compound have either 
disclosed a utility quite different from that possessed by the compounds 
of the invention or have been publications of academic interest only in 
which no utility whatsoever has been disclosed. 
According to the present invention there is provided a novel heteroaryl 
derivative of the formula: 
##STR2## 
wherein Ar represents an optionally substituted pyrazolyl group, the 
acylamino group --NR.sup.1 COR.sup.2 being attached to a carbon atom of 
the pyrazolyl ring, R.sup.1 is C.sub.1-10 alkyl, C.sub.3-6 alkenyl, 
C.sub.3-6 alkynyl, C.sub.2-6 alkoxyalkyl, C.sub.2-6 carboxyalkyl, 
C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, C.sub.3-10 
cycloalkyl-C.sub.1-6 alkyl, optionally substituted phenyl-C.sub.1-6 alkyl 
or optionally substituted phenyl-C.sub.2-6 alkenyl; and R.sup.2 is 
C.sub.1-8 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.3-10 
cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-6 alkyl, optionally substituted 
phenyl, optionally substituted phenyl-C.sub.1-6 alkyl, optionally 
substituted phenyl-C.sub.2-6 alkenyl, C.sub.1-4 alkoxycarbonyl-C.sub.1-8 
alkyl, C.sub.2-8 carboxyalkyl or C.sub.3-6 acyloxyalkyl; or R.sup.1 and 
R.sup.2 together form a lactam ring having 5 to 7 ring atoms; provided 
that: 
When Ar is a 5-pyrazolyl group, the 1-position of the prazolyl group cannot 
be substituted by a phenyl group when R.sup.1 and R.sup.2 are both methyl. 
The pyrazolyl nucleus is preferably substituted by one or two groups 
selected from C.sub.1-4 alkyl, benzyl, phenyl and halogen. 
Preferred R.sup.1 substituents are C.sub.1-10 alkyl, C.sub.3-6 alkenyl, 
C.sub.3-8 cycloalkyl, and benzyl optionally substituted by halogen. 
Preferred R.sup.2 substituents are C.sub.1-8 alkyl, C.sub.2-6 alkenyl, 
C.sub.3-10 cycloalkyl, phenyl, benzyl, C.sub.1-4 alkoxycarbonyl-C.sub.4-8 
alkyl, C.sub.2-8 carboxyalkyl and C.sub.3-6 acyloxyalkyl. 
The term "C.sub.1-6 alkyl" as used herein means a straight or branched 
chain alkyl group containing from 1 to 6 carbon atoms such as methyl, 
ethyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-amyl, s-amyl, 
n-hexyl, 2-ethylbutyl or 4-methylamyl. 
Similarly the term "C.sub.1-4 alkyl" as used herein means a straight or 
branched chain alkyl group containing from 1 to 4 carbon atoms, namely 
methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, s-butyl, t-butyl. 
"C.sub.1-4 hydroxyalkyl" and "C.sub.3-6 acyloxyalkyl" mean the 
aforementioned C.sub.1-4 alkyl groups substituted with an hydroxy group 
and acyloxy group respectively. "C.sub.2-6 alkoxyalkyl" and "C.sub.1-6 
haloalkyl" mean the aforementioned C.sub.1-6 alkyl groups substituted with 
an alkoxy group or one or more halogen atoms, such as methoxyethyl, 
ethoxyethyl, ethoxybutyl, dibromomethyl, trifluoromethyl, 1-chloroethyl, 
1,1-dichloroethyl, 1-iodobutyl or pentafluoroethyl. 
The term "C.sub.3-6 alkynyl" is used herein to indicate an alicyclic 
hydrocarbon group having 3 to 6 carbon atoms which contains a --C.tbd.C-- 
group. However, it should be noted that the --C.tbd.C-- group cannot be 
directly adjacent the nitrogen atom of the acylamino group. Similarly, 
C.sub.3-6 alkenyl groups may not contain a --C.tbd.C-- group directly 
adjacent the nitrogen atom. 
"C.sub.3-10 cycloalkyl" means a saturated ring having from 3 to 10 carbon 
atoms in the ring such as cyclopropyl, cyclobutyl, cyclopentyl, 
cyclooctyl, or adamantyl. "C.sub.3-10 cycloalkyl-C.sub.1-6 alkyl" means 
the aforementioned saturated rings attached to a C.sub.1-6 alkylene 
bridge. 
The term "optionally substituted phenyl" as used herein means a phenyl 
group unsubstituted or substituted by one or more groups which do not 
substantially alter the pharmacological activity of the compounds of 
formula (I), such as halogen, trifluoromethyl, methyl, methoxy, or nitro 
groups. 
The term "C.sub.2-6 carboxyalkyl" as used herein means a C.sub.1-5 alkyl 
group substituted by a carboxylic acid group. Examples of such groups are 
carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl. 
Preferred compounds of the invention are pyrazoles having the structural 
formula: 
##STR3## 
where R.sup.3 is a substituent selected from hydrogen, C.sub.1-4 alkyl and 
optionally substituted phenyl and R.sup.4 is a substituent attached at one 
of the carbon atoms of the pyrazole nucleus and being selected from 
formyl, carboxyl, hydroxy, C.sub.1-4 hydroxyalkyl, C.sub.1-4 alkyl, 
C.sub.3-10 cycloalkyl, C.sub.3-6 acyloxyalkyl, optionally substituted 
phenyl and halogen, or is hydrogen. 
In another embodiment, compounds of the invention are formula (II) 
compounds wherein R.sup.3 is selected from C.sub.1-4 alkyl and phenyl and 
R.sup.4 is selected from hydrogen, C.sub.1-4 alkyl, phenyl and halogen. 
Preferably the acylamino group is attached at the 3- or 5-position of the 
pyrazole nucleus. 
Particularly interesting pyrazoles of formula (II) are those wherein 
R.sup.3 is C.sub.1-4 alkyl, for instance methyl; R.sup.4 is hydrogen; 
C.sub.1-4 alkyl or phenyl; and NR.sup.1 COR.sup.2 is a 5- substituent in 
which R.sup.1 is C.sub.3-6 alkyl, for instance n-butyl and n-hexyl; allyl 
or benzyl and R.sup.2 is C.sub.3-6 alkyl; for instance i-propyl and 
n-hexyl; allyl; benzyl or C.sub.3-5 cycloalkyl. Compounds of formula (I) 
may be prepared by: 
(a) acylating an alkyl derivative of formula: 
EQU ArNHR.sup.1 (V) 
where Ar and R.sup.1 are as defined previously or; 
(b) alkylating an acyl derivative of formula: 
EQU ArNHCOR.sup.2 (VI) 
where Ar and R.sup.2 are as defined previously. 
The acylation of the compound of formula (V) may be carried out with an 
acid halide having the formula R.sup.2 CO--X wherein X is chlorine or 
bromine and R.sup.2 is defined above in the presence of a proton acceptor, 
such as pyridine or triethylamine, in an inert solvent, such as benzene. 
The acylation may also be carried out by heating the alkyl derivative of 
formula (V) with a suitable acid anhydride, (R.sup.2 CO).sub.2 O, in an 
inert solvent. 
When alkyl derivatives of formula (V) are acylated in which Ar is a 
heteroaryl nucleus wherein the ring nitrogen atoms are unsubstituted or 
substituted only by hydrogen, there is a possibility of acylation of a 
ring nitrogen atoms as well as the exocyclic amino group NHR.sup.1. In 
such cases, if desired, the acyl group may be removed from the ring by 
hydrolysis which occurs preferentially at the ring nitrogen atom. 
Those skilled in the art will immediately appreciate that a wide variety of 
other acylating conditions can be used (see, for example, "The Chemistry 
of Amides" 1971 by A. J. Beckwith; "Survey of Organic Synthesis", 1970 by 
Buehler and Pearson; "Organic Functional Group Preparations" 1968 by 
Sandler and Karo; "Reagents for Organic Synthesis" 1968 by Fieser and 
Fieser, etc.). 
Compounds of formula (VI) can be alkylated by dissolving the amide in a 
suitable inert, anhydrous, polar solvent such as dimethylformamide, 
forming an alkali metal salt thereof with an alkali metal hydride, 
preferably sodium hydride, and then treating the salt with an alkylating 
agent of formula R.sup.1 X.sup.1 where X.sup.1 is a reactive atom such as 
a halogen atom or a reactive group such as an alkyl sulphate group. 
Of course, alkylating agents and alkylating reaction conditions other than 
those specified above can be utilised, the nature of these being readily 
apparent to those acquainted with the art. 
The derivatives of formulae (V) and (VI) can be derived from the 
corresponding amines of formula ArNH.sub.2 by standard alkylation or 
acylation techniques. 
The amines of formula ArNH.sub.2 are either known compounds, see, for 
example, Ang. Chem. Int. 13. 206 (1974), or can be prepared by 
modification of known synthetic methods. In the case of pyrazole amines 
prepared by reaction of 2-chloroacrylonitrile with monosubstituted 
hydrazines, it will be appreciated that the reaction may produce 3- or 5- 
aminopyrazoles. Evidence to date-- see Synthesis (1976) 52 by G. Ege-- 
indicates that the most likely reaction product is the 3-aminopyrazole and 
this assumption has therefore been followed in the present specification. 
However, the evidence for this structure is not unequivocal and, if 
subsequent research should determine that the 5-aminopyrazole is actually 
produced, it will be understood that products derived from the foregoing 
reaction will be similarly 5-substituted. 
The intermediates of formula (VI) except when Ar is a pyrazolyl substituted 
by a pyridyl group, are novel and are provided in a further aspect of the 
invention. 
Compounds of formula (I) have been shown to be useful in the prophylactic 
and therapeutic treatment of immediate hypersensitivity diseases including 
asthma and in the alleviation of status asthmaticus. The compounds have 
low toxicity. 
The compounds or compositions of the present invention may be administered 
by various routes and for this purpose may be formulated in a variety of 
forms. Thus the compounds or compositions may be administered by the oral 
and rectal routes, topically, parenterally, e.g. by injection and by 
continuous or discontinuous intra-arterial infusion, in the form of, for 
example, tablets, lozenges, sub-lingual tablets, sachets, cachets, 
elixirs, suspensions, aerosols, ointments, for example, containing from 1 
to 10% by weight of the active compound in a suitable base, soft and hard 
gelatin capsules, suppositories, injection solutions and suspensions in 
physiologically acceptable media, and sterile packaged powders adsorbed 
onto a support material for making injection solutions. Advantageously for 
this purpose, compositions may be provided in dosage unit form, preferably 
each dosage unit containing from 5 to 500 mg. (from 5.0 to 50 mg. in the 
case of parenteral administration, from 5.0 to 50 mg. in the case of 
inhalation and from 25 to 500 mg. in the case of oral or rectal 
administration) of a compound of formula (I). Dosages of from 0.5 to 300 
mg/kg per day, preferably 0.5 to 20 mg/kg of active ingredient may be 
administered although it will, of course, readily be understood that the 
amount of the compound or compounds of formula (I) actually to be 
administered will be determined by a physician, in the light of all the 
relevant circumstances including the condition to be treated, the choice 
of compound to be administered and the choice of route of administration 
and therefore the above preferred dosage range is not intended to limit 
the scope of the present invention in any way. 
In this specification, the expression "dosage unit form" is used as meaning 
a physically discrete unit containing an individual quantity of the active 
ingredient, generally in admixture with a pharmaceutical diluent therefor, 
or otherwise in association with a pharmaceutical carrier, the quantity of 
the active ingredient being such that one or units are normally required 
for a single therapeutic administration or that, in the case of severable 
units such as scored tablets, at least one fraction such as a half or a 
quarter of a severable unit is required for a single therapeutic 
administration. 
The formulations of the present invention normally will consist of at least 
one compound of formula (I) mixed with a carrier, or diluted by a carrier, 
or enclosed or encapsulated by an ingestible carrier in the form of a 
capsule, sachet, cachet, paper or other container or by a disposable 
container such as an ampoule. A carrier or diluent may be a solid, 
semi-solid or liquid material which serves as a vehicle, excipient or 
medium for the active therapeutic substance. 
Some examples of the diluents or carriers which may be employed in the 
pharmaceutical compositions of the present invention are lactose, 
dextrose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, 
white soft paraffin, kaolin, fumed silicon dioxide, microcrystalline 
cellulose, calcium silicate, silica, polyvinylpyrrolidone, cetostearyl 
alcohol, starch, modified starches, gum acacia, calcium phosphate, cocoa 
butter, ethoxylated esters, oil of thoobroma, arachis oil, alginates, 
tragacanth, gelatin, syrup B.P., methyl cellulose, polyoxyethylene 
sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, 
sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and 
propellants such as trichloromonofluoromethane, dichlorodifluoromethane 
and dichlorotetrafluoroethane. In the case of tablets, a lubricant may be 
incorporated to prevent sticking and binding of the powdered ingredients 
in the dies and on the punch of the tabletting machine. For such purpose 
there may be employed for instance aluminium, magnesium or calcium 
stearates, talc or mineral oil.

The following Examples will further illustrate the invention. 
EXAMPLE 1 
(a) 1-Methyl-3-Aminopyrazole 
2-Chloroacrylonitrile (175 g, 2 mol) was added slowly to a solution of 
methyl hydrazine (92 g, 2 mol) and potassium carbonate (280 g, 2 mol) in 
water (1,000 ml) cooled at 0.degree. C. under nitrogen. The solution was 
maintained at 0.degree.-5.degree. C. for 11/2 hours and then heated at 
40.degree.-50.degree. C. for 2 hours. Continuous extraction of the 
reaction mixture with ethyl acetate, and evaporation of the dried extract, 
gave 1-methyl-3-aminopyrazole, b.p. 62.degree.-66.degree. C./5 mm, 146 g, 
as a pale yellow oil. 
Analysis: C.sub.4 H.sub.7 N.sub.3 requires: C 49.5; H 7.3; N 43.3%. Found: 
C 49.3; H 7.5; N 43.5%. 
(b) N(1-Methylpyrazol-3-yl)-2-Methylpropanamide 
isoButyric anhydride (23.8 g, 0.15 mol), and 3-amino-1-methylpyrazole (11.7 
g, 0.12 mol) were heated together at 78.degree. C. in benzene for 2 hours. 
Solvent and excess of reagent were removed in vacuo and the residue 
distilled at 124.degree.-128.degree. C./0.05 mm. The distillate, 14.4 g, 
solidified on standing and a sample separated from ether/petrol 
(40.degree.-60.degree. C.) as needles, m.p. 82.degree.-83.degree. C. 
(c) N-Benzyl-N(1-methylpyrazol-3-yl)-2-Methylpropanamide 
The pyrazole (3 g, 0.018 mol) in dry DMF (20 ml) was maintained at 
0.degree. C. during the addition of 50% sodium hydride (1 g, 0.021 mol). 
After a further 1 hour at 0.degree. C., benzylbromide (3.5 g, 0.0205 mol) 
was added and the mixture allowed to cool to room temperature during 2 
hours. Water was added and the oil which separated was isolated in ether. 
Evaporation of the dried extract gave a solid which was recrystallized 
from ether/petrol (40.degree.-60.degree. C.) as white needles, 2.9 g, m.p. 
81.degree.-82.degree. C. 
Analysis: C.sub.15 H.sub.19 N.sub.3 O requires: C 70.1; H 7.45; N 16.35%. 
Found: C 70.0; H 7.45; N 16.6%. 
EXAMPLES 2 to 35 
The following pyrazoles were prepared using similar procedures to that 
described in Example 1. All references to boiling points are to air-bath 
temperatures. 
N-butyl-N-(1-methylpyrazol-3-yl)acetamide. b.p. 170.degree. C./0.1 mm. 
N-butyl-N-(1-methylpyrazol-3-yl)-2-methylpropanamide. m.p. 
43.degree.-47.degree. C. 
N-butyl-N-(1-methylpyrazol-3-yl)cyclohexane carboxamide. m.p. 
82.degree.-84.degree. C. 
1-ethoxycarbonyl-N-(1-methylpyrazol-3-yl)heptanamide. m.p. 
83.degree.-84.degree. C. 
N-benzyl-N-(1-methylpyrazol-3-yl)benzamide. m.p. 129.degree.-130.degree. C. 
N-decyl-N-(1-methylpyrazol-3-yl)benzamide. m.p. 65.degree.-67.degree. C. 
N-butyl-N-(1-methylpyrazol-3-yl)benzamide. m.p. 63.degree.-65.degree. C. 
N-methyl-N-(1-methylpyrazol-3-yl)-2-methylpropanamide. m.p. 
40.degree.-42.degree. C. 
N-butyl-N-(1-methylpyrazol-3-yl)cyclobutyl carboxamide. m.p. 
69.degree.-71.degree. C. 
N-hexyl-N-(1-methylpyrazol-3-yl)acetamide. b.p. 165.degree.-170.degree. 
C./0.1 mm. 
N-methyl-N-(1-methylpyrazol-3-yl)adamantane carboxamide. m.p. 
112.degree.-114.degree. C. 
N-butyl-N-(1-methylpyrazol-3-yl)crotonamide. m.p. 35.degree.-38.degree. C. 
N-benzyl-N-(1-methylpyrazol-3-yl)-2-methylpropanamide. m.p. 
81.degree.-82.degree. C. 
2-acetoxy-N-(1-methylpyrazol-3-yl)propanamide. b.p. 170.degree. C./0.5 mm. 
N-methyl-N-(1-methylpyrazol-3-yl)cyclohexane carboxamide. m.p. 
66.degree.-69.degree. C. 
1-carboxy-N-(1-methylpyrazol-3-yl)heptanamide. m.p. 132.degree.-136.degree. 
C. 
N-(o-Chlorobenzyl)-N-(1-methylpyrazol-3-yl)benzamide. m.p. 
148.degree.-149.degree. C. 
N-methyl-N-(1-methylpyrazol-3-yl)heptanamide. m.p. 23.degree.-25.degree. C. 
N-methyl-N-(1-methylpyrazol-3-yl)phenylacetamide. m.p. 
49.degree.-51.degree. C. 
N-hexyl-N-(1-methylpyrazol-3-yl)heptanamide. b.p. 160.degree. C./0.2 mm. 
N-hexyl-N-(1-methylpyrazol-3-yl)phenylacetamide. b.p. 190.degree. C./0.5 
mm. 
2-Acetoxy-N-butyl-N-(1-methylpyrazol-3-yl)propanamide. m.p. 
50.degree.-52.degree. C. 
1-carboxy-N-(1-methylpyrazol-3-yl)propanamide. m.p. 168.degree.-170.degree. 
C. 
N-(1-methylpyrazol-3-yl)-N-(2-propenyl)cyclohexane carboxamide. m.p. 
82.degree.-83.degree. C. 
N-(1-hexyl)-N-(1-methylpyrazol-3-yl)-2-methylpropanamide. m.p. 
34.degree.-35.degree. C. 
N-(4-bromophenyl)methyl-N-(1-methylpyrazol-3-yl)acetamide. m.p. 
59.degree.-60.degree. C. 
N-phenylmethyl-N-(1-phenylpyrazol-3-yl)cyclohexane carboxamide. m.p. 
109.degree.-110.degree. C. 
N-(1-butylpyrazol-3-yl)-N-(hexyl)cyclopropane carboxamide. b.p. 150.degree. 
C. @ 0.13 mm Hg. 
N-(1-butyl)-N-(1-methylpyrazol-3-yl)cyclopentane carboxamide. m.p. part 
62.degree.-64.degree. C. and part 68.degree.-69.degree. C. 
N-(1-butylpyrazol-3-yl)-N-(methyl)cyclopropane carboxamide. b.p. 
130.degree. C. @ 0.15 mm Hg. 
N-(1-methylpyrazol-3-yl)-N-(phenylmethyl)cyclopentane carboxamide. m.p. 
88.degree. C. 
N-methyl-N-(1-phenylpyrazol-3-yl)acetamide. m.p. 67.degree.-67.5.degree. C. 
N-(1-hexyl)-N-(1-phenylpyrazol-3-yl)cyclohexane carboxamide. m.p. 
57.degree.-58.degree. C. 
N-(2-methylprop-1-yl)-N-(1-methylpyrazol-3-yl)heptanamide. b.p. 
123.degree.-126.degree. C. 
EXAMPLE 36 
N-Phenylmethyl-N-1,3,5-trimethylpyrazol-4-ylheptanamide 
1,3,5-Trimethyl-4-pyrazoleamine (4.17 g) in pyridine (40 cc.) was treated 
with heptanoic anhydride (8.9 g) and stirred at room temperature 
overnight. Water was then added and the resulting solid was collected, and 
recrystallised from chloroform/hexane, 6.4 g, m.p. 78.degree.-79.degree. 
C. 
1,3,5-Trimethylpyrazol-4-ylheptanamide (2.37 g) was dissolved in dry DMF 
(40 ml) at 0.degree. C. and sodium hydride (0.58 g, 50% dispersion) was 
added slowly. After 1 hour at 0.degree. C., benzyl bromide (11.88 g) was 
added. After a further hour water was added and the product was isolated 
in ethyl acetate. Evaporation of the extract gave an oil b.p. 170.degree. 
C. (air-bath)/0.15 mm. 
Analysis: C.sub.20 H.sub.29 N.sub.3 O requires: C 13.35; H 8.9; N 12.8%. 
Found: C 13.55; H 9.1; N 12.7%. 
EXAMPLE 37 
N-(n-Butyl)-N-(1,3,5-trimethylpyrazol-4-yl)cyclohexane carboxamide 
4-Amino-1,3,5-trimethylpyrazole (4.17 g) was reacted with cyclohexane 
carboxylic acid chloride (5.37 g) in dry pyridine (40 ml) for 21/2 hours 
at room temperature. Water was added with resultant precipitation of 
N-(1,3,5-trimethylpyrazol-4-yl)cyclohexane carboxamide, 4.7 g., m.p. 
182.degree. C. 
The amide (2.5 g) was suspended in dry DMF (50 cc) and sodium hydride (0.61 
g, 50% dispersion) was added slowly. After 1 hour the mixture was cooled 
in ice and butyliodide (2.13 g) was added. After 3 hours water was added 
and the product was isolated in ethyl acetate as an oil, b.p. 135.degree. 
C. (air-bath/)/0.05 mm, 2.7 g. 
Analysis: C.sub.17 H.sub.29 N.sub.3 O requires: C 70.1; H 10.0; N 14.4%. 
Found: C 70.3; H 9.8; N 14.4%. 
EXAMPLE 38 
N-(2-Chlorophenyl)methyl-N-(1,3,5-trimethylpyrazol-4-yl)cyclohexane 
carboxamide. m.p. 121.degree.-122.degree. C. was prepared as in Example 
36. 
EXAMPLE 39 
N-(4-Chlorophenyl)methyl-N-(1,3,5-trimethylpyrazol-4-yl)heptanamide. b.p. 
187.degree.-191.degree. C.(air-bath)/0.15 mm was similarly prepared. 
EXAMPLE 40 
5-Amino-1-methyl-3-phenylpyrazole was prepared according to Gazz. Chim. 
Ital. 98, 569 (1968) m.p. 128.degree.-129.degree. C. 
EXAMPLE 41 
N-(1-Hexyl)-N-(1-methyl-3-phenylpyrazol-5-yl)cyclopentane carboxamide 
5-Amino-1-methyl-3-phenylpyrazole (3.75 g) in dry pyridine was treated with 
cyclopentane carboxylic acid chloride (3.14 g) and kept at room 
temperature for 2 hours. The solvent was then removed in vacuo and the 
residue dissolved in ethyl acetate. The washed and dried solution was then 
evaporated to leave a solid 4.8 g, m.p. 160.degree. C. 
The amide (2.0 g) was alkylated with hexyliodide as described in previous 
Example 37. The product was isolated as a solid. m.p. 
27.degree.-37.degree. C. 
EXAMPLE 42 
N-methyl-N-(1-methyl-3-phenylpyrazol-5-yl)cyclopentane carboxamide. m.p. 
65.degree.-69.degree. C. was prepared as described in Example 41. 
EXAMPLE 43 
N-(2-Butyl)-N-(1-methylpyrazol-3-yl)heptanamide 
3-Amino-1-methylpyrazole (9.7 g) in DMF (100 cc) and 2-bromobutane (10 cc) 
was treated with potassium carbonate and heated at 100.degree. C. for 5 
hours. Water was then added and the product was isolated in ether, 6.07 g, 
b.p. 80.degree. C./0.25 mm. 
The amine (1.53 g) in dry pyridine (10 cc) was treated with heptanoic 
anhydride (2.66 g) stirred at room temperature for 15 hours, and then for 
4 hours at 50.degree. C. and 3 hours at 120.degree. C. The product was 
isolated in the normal way as an oil. b.p. 138.degree.-141.degree. C. 
(air-bath/0.1 mm. 1.5 g. 
Analysis: C.sub.15 H.sub.27 N.sub.3 O requires: C 67.9; H 10.3; N 15.8%. 
Found: C 67.7; H 10.3; N 15.7%. 
EXAMPLE 44 
N-Cyclohexyl-N-(1-methylpyrazol-3-yl)pentanamide m.p. 
97.5.degree.-98.degree. C. was prepared as described in Example 43. 
EXAMPLE 45 
N-(2-Butyl)-N-(1-methylpyrazol-3-yl)cyclohexane carboxamide m.p. 
98.degree.-99.degree. C. was similarly prepared. 
EXAMPLE 46 
N-Butyl-N-(1-methyl-4-chloropyrazol-3-yl)cyclohexane carboxamide 
N-Butyl-N-(1-methylpyrazol-3-yl) cyclohexane carboxamide (1.3 g, 0.0049 m) 
in dry benzene (15 cc) was cooled at 0.degree. C. while sulphuryl chloride 
(0.67 g, 0.0049 m) was added slowly. The cooling bath was then removed and 
the solution was kept at room temperature for 12 hours. The solvent was 
then evaporated and the residue crystalled from ether/petrol 
(40.degree.-60.degree. C.) as white prisms, 1.0 g, m.p. 
110.degree.-112.degree. C. 
EXAMPLE 47 
N-Hexyl-N-(1-methyl-4-chloropyrazol-3-yl)acetamide b.p. 130.degree. C. (air 
bath)/1 mm; m.p. &lt;room temperature, was similarly prepared. 
EXAMPLES 48-53 
The amides of Examples 5, 17 and 24 were alkylated with methyl iodide or 
n-butyl bromide in the presence of sodium hydride using the procedure 
generally outlined in Example 1 to give the following alkylated products: 
1-Ethoxycarbonyl-N-methyl-N-(1-methylpyrazol-3-yl)-heptanamide; 
1-Carboxy-N-methyl-N-(1-methylpyrazol-3-yl)-heptanamide; 
1-Carboxy-N-methyl-N-(1-methylpyrazol-3-yl)-propanamide; 
1-Ethoxycarbonyl-N-n-butyl-N-(1-methylpyrazol-3-yl)-heptanamide; 
1-Carboxy-N-n-butyl-N-(1-methylpyrazol-3-yl)-heptanamide; 
1-Carboxy-N-n-butyl-N-(1-methylpyrazol-3-yl)-propanamide. 
The following Examples 54-60 illustrate pharmaceutical formulations 
containing the active compound 
N-(n-butyl)-N-(1,3,5-trimethylpyrazol-4-yl)-cyclohexane carboxamide. 
EXAMPLE 54 
Soft gelatin capsules were prepared using the following ingredients: 
______________________________________ 
Quantity (mg/capsule) 
______________________________________ 
Active compound 20 
Propyl gallate 0.03 
Fractionated Coconut Oil B.P.C. 
70 
______________________________________ 
The above ingredients were mixed and filled into soft gelatin capsules, the 
main shell components of which were gelatin and glycerine. 
EXAMPLE 55 
Hard gelatin capsules were prepared using the following ingredients: 
______________________________________ 
Quantity (mg/capsule) 
______________________________________ 
Active compound 25 
Silicon dioxide (fumed) 
25 
Lactose 50 
Butylated hydroxyanisole B.P. 
0.02 
______________________________________ 
The butylated hydroxyanisole was dissolved in the active ingredient and the 
solution so formed adsorbed onto the silicon dioxide (fumed). The lactose 
was then added and the whole mixed. Finally, the mixture was filled into 
hard gelatin capsules. 
EXAMPLE 56 
An ointment was made up from the following ingredients: 
Active compound: 2% by weight 
Butylated hydroxyanisole B.P.: 0.04% by weight 
White soft paraffin: q.s. 100% 
The hydroxyanisole was dissolved in the melted paraffin and the active 
compound then added in, and the mixture allowed to cool. 
EXAMPLE 57 
A topical cream containing 1% of the compound was prepared as follows: 
______________________________________ 
grams: 
______________________________________ 
Active compound 1 
Cetomacrogol 1000 3 
Cetostearyl alcohol 10 
Liquid Paraffin 7 
Butylated hydroxyanisole B.P. 
0.04 
Distilled Water to 100.0 
______________________________________ 
The active compound was mixed with the hydroxyanisole and suspended in the 
liquid paraffin. The cetostearyl alcohol was added and the mixture heated 
to 70.degree. C. with stirring. The cetomacrogol 1000 was then dissolved 
in 60 g. of water heated to 70.degree. C. The cetostearyl alcohol and 
liquid paraffin active compound mixture were then poured into the aqueous 
cetomacrogol 1000 solution with stirring and the stirring continued until 
the cream was cold. The cream was then made up to weight with water and 
passed through a stainless steel colloid mill set at a gap of 15/1000 
inch. 
EXAMPLE 58 
Suppositories containing 30 and 60 mg. of the compound were prepared as 
follows: 
Active compound: 3 g 
Henkel base: 97 g 
The active compound was mixed with the Henkel base which had been 
previously melted using the minimum amount of heat possible. The mixture 
was then poured into suppository moulds of a nominal capacity of 1 g. or 2 
g. as desired, to produce suppositories each containing 30 mg. or 60 mg. 
of the active compound. 
EXAMPLE 59 
An aerosol was prepared containing the following ingredients: 
______________________________________ 
Quantity per ml. 
______________________________________ 
Active compound 10.00 mg. 
Propylene glycol 10.00 mg. 
Dichlorotetrafluoroethane 
500 mg. 
(Propellant 114) 
Dichlorodifluoromethane 
900 mg. 
(Propellant 12) 
______________________________________ 
The active compound was mixed with the propylene glycol and the mix added 
to the propellant 114, the mixture cooled to -15.degree. to -20.degree. C. 
and transferred to a filling device. At the same time a mixture of 
propellants 114 and 12, previously cooled to -15.degree. to -20.degree. C. 
was fed into a second filling device. A metered amount of propellant from 
the second filling device was introduced into a stainless steel container, 
followed by the required amount of material from the first filling device. 
The valve units were then fitted and sealed to the container. These valve 
units were equipped with metering device so that approximately 0.15 mg. of 
the active compound is released by a single actuation of the valve. 
EXAMPLE 60 
Tablets were prepared using the following components: 
Active compound: 15.00 mg. 
Microcrystalline Cellulose: 240.00 mg. 
Sodium Carboxymethyl Starch: 20.00 mg. 
Magnesium Stearate: 2.5 mg. 
Butylated Hydroxyanisole B.P.: 0.002 mg. 
The hydroxyanisole was dissolved in the active compound, the solution 
adsorbed onto the microcrystalline cellulose. This was mixed with the 
sodium carboxymethyl starch and the magnesium stearate then mixed in. 
Finally, the mixture was compressed to form tablets.