GB1598900A

GB1598900A - Heterocyclic amino derivatives

Info

Publication number: GB1598900A
Application number: GB2145178A
Authority: GB
Original assignee: Lilly Industries Ltd
Current assignee: Lilly Industries Ltd
Priority date: 1978-05-23
Filing date: 1978-05-23
Publication date: 1981-09-23

Description

(54) HETEROCYCLIC AMINO DERIVATIVES (71) We, LILLY INDUSTRIES LIMITED, a British company, of Lilly House, Hanover Square, London, W1R OPA, formerly of Henrietta House, Henrietta Place, London, W1, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to heterocyclic amino derivatives, more particularly to carbamates and ureas thereof, and to methods of preparing such derivatives. The derivatives have useful pharmacological activity and the invention further provides pharmaceutical formulations containing the derivatives and use of the derivatives in the treatment of non-human animals suffering from or susceptible to allergic conditions.

According to the invention there is provided a heterocyclic amino derivative of formula

wherein Ar represents a 5-membered heterocyclic nucleus selected from 2-furyl, 2thienyl, 5-pyrrolyl, l-(C~, alkyl)-3-pyrazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl and 5-tetrazolyl, the heterocyclic nucleus being optionally substituted by hydrogen, C1 6 alkyl or R4; R1 is hydrogen, Cl-s alkyl, C2~6 alkenyl, Cs-6 alkynyl, C cycloalkyl or CH2R4; R2 represents the group OR or NHR3; R8 is 01-8 alkyl, C26 alkenyl, C3-s cycloalkyl, adamantyl, R4 or CH2R4 and R4 is phenyl optionally substituted by one or more groups selected from halogen, trifluoromethyl, 01-4 alkyl, C1~4 alkoxy and nitro; provided that (i) when the heterocyclic nucleus is 2-furyl or 2-pyrrolyl, and R2 is OR , R is not hydrogen; (ii) when Ar is unsubstituted 2-thienyl, R1 is not hydrogen; (iii) when the heterocyclic nucleus is 1,2,4- or 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl or 5-tetrazolyl, R1 is not hydrogen; (iv) when the heterocyclic nucleus is 1,2,Sthiadiazolyl, R2 is OR3; (v) when Ar is unsubstituted 2-thienyl, R is methyl or benzyl and R2 is OR3, R3 is not methyl; (vi) when Ar is 3-methyl-2-thienyl, R1 is hydrogen and R2 is NHR3, R3 is not phenyl; (vii) when Ar is 3,4-diphenylpyrrol-2-yl, R1 is hydrogen and R2 is NHR3, R3 is not ethyl or phenyl; (viii) when Ar is unsubstituted 1,2,4-thiadazol-5-yl and R1 is methyl, R3 is not ethyl; (ix) when Ar is 5-phenyl-1,3,4-oxadiazol-2-yl, R1 is methyl and R2 is NHR8, R3 is not phenyl; and (x) when Ar is unsubstituted 5-tetrazolyl, R1 is benzyl and R2 is OR3, R3 is not ethyl.

The term "C1-8 alkyl" as used herein means a straight or branched chain alkyl group containing from 1 to 6 carbon atoms such as methyl ethyl, isooropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-amyl, s-amvl, n-hexyl, 2-ethylbutyl and Gmethvlamyl.

Similarity, the term "C1-4 alkyl" as used herein means a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, namely methyl, ethyl, isopropyl, n-proovl, n-butyl, isobutyl, s-butyl, t-butyl.

"C@-@ cycloalkyl" means a saturated cycloalkyl ring having from 3 to 8 carbon atoms in the ring, such as cyclopropyl, cyclonentyl, cyclohexvl and cvclooctvl.

Preferred carbamates (i.e. compounds of formula (I) wherein R2 is OR ) and preferred ureas (i.e. compounds of formula (I) wherein R2 is NHR ) of the invention are those having one or more of the following features: (A) Ar is optionally substituted by hydrogen, C1-5 alkyl or phenyl; (B) R1 is C1-R alkyl; (C) R is allyl; (D) Rl is Dropvnyl; (E) R1 is benzyl; (F) R is C16 alkyl; (G) R3 is allyl; (H) R3 is C5-6 cycloalkyl; (I) R3 is adamantyl; (T) R3 is phenyl; (K) R9 is benzyl; (L) R1 is phenyl optionally substituted by one or two groups selected from halogen, trifluoromethyl, methyl, methoxy and nitro; and (M) R4 is phenyl, (N) R1 is hydrogen.

The preferred furan derivatives of the invention are the carbamates of formula (II):

where R1 is C1-6 alkyl, allyl, propynyl or benzyl, R3 is C1~ alkyl, allyl, cyclopentyl or adamantyl and R5 is hydrogen or C1, alkyl.

The preferred thiophene derivative of the invention is l-n-butyl-3-(2-phenyl-5- thienyl) urea.

The preferred pyrrole derivatives of the invention are the carbamates of formula

where RI is CI-, alkyl and R3 is C2, alkyl or C,, cycloalkyl.

The preferred pyrazole carbamates of the invention are those of formula (IV):

where R1 is 01-4 alkyl or benzyl and R3 is C1--g alkyl, phenyl or benzyl.

The preferred pyrazole ureas of the invention are those of formula (V):

where R1 is hydrogen, 01-4 alkyl or benzyl and R3 is C1-6 alkyl or phenyl.

The preferred 1,2,4-oxadiazole derivatives of the invention are those of formula (VI):

where R1 is 01-4 alkyl or benzyl, R2 is NHR3 or OR3 and R3 is C1--6 alkyl, cyclohexyl or phenyl. The most preferred carbamates of formula (VI) are those wherein R3 is 01-4 alkyl. The most preferred ureas of formula (VI) are those wherein R1 is n-butyl or benzyl and R3 is n-butyl, cyclohexyl or phenyl.

The preferred 1,3,4-oxadiazole derivatives of the invention are the carbamates of formula (VII):

where R1 is n-butyl or benzyl and R3 is 01-4 alkyl.

The preferred 1,2,4-thiadiazole derivative of the invention is ethyl N-n-butyl-(3methyl-1,2,4-thiadiazol-5-yl)carbamate.

The preferred tetrazole derivatives of the invention are the carbamates of formula (VIII):

where Rl is n-butyl or benzyl and R3 is C2~, alkyl or phenyl.

The present invention also provides a method of preparing a heterocyclic amino derivative of formula (I), which comprises: (1) reacting a compound of formula (IX):

wherein Ar and R1 are as defined above, with a compound of formula R3 Z (a) wherein (i) Q is hydrogen, R3, is R3 or hydrogen and Z is -NCO, or (ii) Q is COCI, R3 is R3 and Z is NH2; so as to produce a compound of formula (I) in which R2 is NHR3, followed, when R3, is hydrogen, by alkylation to convert R3' to R3; or (b) wherein Q is hydrogen, Z is LCO2- where L is a good leaving group preferably chlorine, and R3' is R3, so as to produce a compound of formula (I) in which R2 is OR3, followed where necessary when R1 is hydrogen by alkylation to form a compound of formula (I) wherein R2 is OR3 and Rl is other than hydrogen; or (2) reacting a compound of formula Ar-CO-X where Ar is as defined above and X is OH or a good leaving group, preferably chlorine, with diphenylphosphonic azide or an alkali metal azide, provided that when X is OH reaction with an alkali metal azide is preceded by reaction with a compound of formula LCOOR6 where L is a good leaving group, preferably chlorine, and R5 is Cut~6 alkyl; followed by reaction with a compound of formula R30H wherein R3 is as defined above to give a compound of formula (I) wherein R1 is hydrogen, followed, where necessary, by alkylation to give a compound of formula (I) wherein R1 is not hydrogen.

The preferred method of preparation of ureas of formula (I) involves reaction of an amine of formula (IX) in which Q is hydrogen with an isocyanate of formula R3NCO:

The reaction can be carried out in any suitable anhydrous inert solvent, e.g. benzene or toluene. Similar reaction conditions to those described in U.K. Patent Specification No. 1,327,042 may be used.

In a modification of the above isocyanate method the isocyanate of formula R3NCO can be replaced by isocyanic acid (UNCO) conveniently prepared in situ from an alkali metal isocyanate, e.g. potassium isocyanate and a carboxylic acid such as acetic acid. The reaction product is a urea of formula (X):

which is then alkylated with an alkylating agent, preferably in the presence of a base.

It should be noted that the term "alkylation" is used herein a broad sense to indicate the addition of moieties such as C,~,; alkenyl phenyl or benzvl as well as the Cl~s alkyl, Ca-a cycloalkyl or admantyl moieties. One method of alkylating a compound of formula (X) comprises forming the sodium salt thereof with sodium llydride in dirnethylformamide and then treating the salt with an alkyl halide or sulphonate. In those cases where R1 is hydrogen, it is found that selective alkylation occurs initially on the -NH, group.

Some of the intermediates of formula ArNIIR1 are novel and may be prepared by reduction of an amide with e.g. LiAIH, as follows ArNHCOR5

ArNHCH2Re where R6 is hydrogen, C1~7 alkyl, Cl~s alkenyl, 01- alkynyl, or R4. Others of the intermediates of formula ArNHRl are described in Belgian Patent Specification Nos.

842,577, 842,578 and 842,579.

When a carbamoyl chloride of formula (IX), i.e. a compound of formula (IX) wherein Q is COOl, is reacted with an amine of formula R3NH2, the reaction may be accomplished by the use of excess amine and/or the presence of an acid acceptor such as triethylamine which will not react with the carbamoyl chloride.

Reaction of a compound of formula (IX) wherein Q is hydrogen with a compound of formula LC02R3 yields a carbamate of formula (I). L is preferably chlorine and the reaction may be effected in a suitable solvent e.g. in dry pyridine or in dry benzene in the presence of a suitable proton acceptor such as triethylamine.

Reaction of a compound of formula ArCOGl with an alkali metal azide, e.g.

NaN,, may be effected in a suitable solvent mixture such as 1,2-dichloroethane/water, followed by separation and drying of the organic phase before reaction with an alcohol of formula R30H to give a carbamate of formula (I) wherein R1 is hydrogen. A compound of formula ArCOX, where X is -OCOOR', may be generated prior to reaction with the alkali metal azide by reaction of an acid of formula ArCOOH with a Cl-a alkyl chloroformate in an inert solvent such as 1,2-dichloromethane.

Alternatively, an acid of formula ArCOOH may be reacted directly with diphenylphosphonic azide and an alcohol of formula R30H in the presenc of a proton acceptor such as triethylamine, if desired in an inert solvent such as 1,2-dichloroethane, or dichloromethane, to yield a carbamate of formula (I) wherein R1 is hydrogen.

Resulting carbamates of formula (I) wherein R1 is hydrogen may be converted to the corresponding derivatives wherein R1 is other than hydrogen by treatment with suitable alkylating agents such as iodides of formula R1I (where R1 is other than hydrogen). It is considered unnecessary to give specific examples of suitable reagents or reaction conditions since these will be well known to those skilled in the art.

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 intraarterial infusion, in the form of, for example, tablets, lozenges, sublingual 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 30 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 adminisered 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 dosage preferred 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 contining 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 more 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 empoule. 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, polyvinylpyrrolidine, cetostearyl alcohol, starch, modified starches, gum acacia, calcium phosphate, cocoa butter, ethoxylated esters, oil of theobroma, arachis oil, alginates, traganth, gelatin, syrup B.P., methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and pr6peffants 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 invention will be better understood from the following illustrative Examples.

EXAMPLE 1.

Iso-propyl 2-furylcarbamate.

2-Furoyl chloride (26. g., 0.2 mole) was stirred in 1,2-dichloroethane (75 ml), cooled to OOC and a solution of sodium azide (15 g., 0.23 mole) in water (60 ml) added over 5 minutes. Benzyl trimethylammonium chloride (1 g) was added and the mixture stirred at room temperature for 2 hours. The phases were separated and the organic phase dried over Molecular Sieves 3A. The dried organic phase was then added dropwise with stirring to a mixture of isopropanol/toluene (100 my/100 ml) at 85 CC. Gassing and gentle reflux continued for 6 hours, after such time the resulting yellow solution was cooled and evaporated (rotary) to give a yellow oil which was distilled in vacuo to yield the desired product as a pale yellow liquid (21.2 g), b.p.

86"C/2 mm. The product tended to discolour in the presence of air and light and was stored in a refrigerator prior to use. On storage the product became completely crystalline with melting point 50 C. Alternatively, it was found that the yellow oil, prior to distillation, could be crystallised from petroleum ether 60/800C to give material with identical melting point, SOOC.

EXAMPLES 2 AND 3.

The following compounds were prepared by similar methods to that of Example 1: n-Propyl 2-furylcarbamate boiling point 100-G/5 mm.

l-Ethylpropyl 2-furylcarbamate boiling point 1320 C/S mm.

melting point 50etc.

EXAMPLE 4.

Cyclopentyl 2-furylcarbamate.

2-Furoic acid (44.8 g, 0.04 mole) was stirred in 1,2-dichloroethane (300 ml) and was cooled to 000. Triethylamine (64 ml, 0.464 mole) was added, followed by dropwise addition of ethyl chloroformate (43 ml, 0.51 mole) maintaining the temperature at 000. After further stirring at O"C for 30 minutes, a solution of sodium azide (35 g, 0.54 mole) in water (150 ml) was added dropwise. After stirring for 2 hours and allowing the temperature to rise to room temperature, further water (200 ml) was added to give two clear phases. The organic phase was separated, dried over Molecular Sieves 3A and added dropwise, with stirring, to cyclopentanol (85 ml) heated on a steam bath. Gassing was complete after 4 hours and the resultant orange-red solution was cooled and evaporated (rotary) to give an oil which readily crystallised. Recrystallisation from petroleum ether (60/800C) gave the title product as orange-yellow crystals (62.0 g, m.p. 80"C.).

EXAMPLE 5.

Isopropyl 5-t-butyl-2-furylcarbamate b.p. 1040C/0.25 mm was prepared in a similar manner to Example 4.

EXAMPLE 6.

t-Butyl 2-furylcarbamate.

2-Furoic acid (56 g, 0.5 mole) was mixed with triethylamine (70 ml, 0.5 mole) and tert.butylalcohol (100 ml) in 1,2-dichloroethane (300 ml) and cooled to OOC.

Diphenylphosphonic azide (108 ml, 0.5 mole) was added gradually with stirring and the clear pale straw-coloured solution gradually heated (oil bath, 101100C). Gassing commenced at 65"C, becoming steady and brisk at 80"C with the temperature of the solution finally rising to 850C. After 4 hours gassing was complete and the brownish solution was poured onto ice/water. The organic phase was separated and washed successively with N/10 hydrochloric acid solution, then saturated sodium bicarbonate solution. The washed organic phase was evaporated (rotary) to give a brownish oil which readily crystallised. The product was recrystallised from 60/8 C petroleum ether to yield the desired compound as pale yellow crystals (63.4 g, m.p. 960C).

EXAMPLE 7.

Isopropyl 5-methyl-2-furylcarbamate.

Diphenyl phosphonic azide (21.6 ml) was added slowly to a stirred mixture of 5-methyl-2-furoic acid (12.6 g, 0.1 mol) and triethylamine (14 ml) in iso-propanol (30 ml) at G"C. and the clear yellow solution was heated to 900C on a steam bath.

After heating for 2 hours the solution was poured onto ice-water and extracted with dichloromethane. The extract was washed with dilute HC1 and saturated sodium bicarbonate solution and evaporated to give the product as a yellow oil (8.8 g) which slowly crystallised (m.p. 450C).

EXAMPLE 8.

Cyclopentyl 5-methyl-2-furylcarbamate (m.p. 830C) was prepared in a similar manner to Example 7.

EXAMPLE 9.

Isopropyl N-butyl-2-furylcarbamate.

The isopropyl carbamate from Example 1 (16.9 g, 0.1 mole) was dissolved in dry dimethylformamide (50 ml) and added dropwise with stirring to a suspension of sodium hydride (50% oil dispersion 4.8 g, 0.1 mole) in dry dimethylformamide (75 ml) with cooling to 100C. After gassing was complete, n-butyl iodide (19.q g, 0.1 mole) was added dropwise with continued stirring. After warming to room tem- perature over 1.5-2 hours, the mixture was treated with a few drops of ethanol to destroy any remaining sodium hydride, then poured onto ice/water and extracted into dichloromethane at pH 7 after pH adjustment with a few drops of glacial acetic acid. The organic extract was evaporated (rotary) to give a light brown mobile liquid which was fractionally distilled in vacuo to give the required compound as a colourless liquid (16.5 g), b.p. 940C/2 mm.

Analysis: Cl2EgNO3 req: C, 64.0; H, 8.50; N, 6.22% Found: C, 64.1; H, 8.37; N, 6.46% EXAMPLES 10-27.

The following compounds were prepared by methods similar to that of Example 9:

EXAMPLE R5 R1 R3 | b.p./mmHg 10 H IrHexyl i-Propyl 940C/0.08 11 H Benzyl i-Propyl 1120C-/0.1 12 H n-Butyl n-Propyl 940C/1.0 13 H n-Butyl CH(C,Hs)2 1230C/1.0 14 H n-Butyl cyclopentyl 890C/0.08 15 H Ethyl cyclopentyl 800C/0.15 16 H n-Hexyl cyclopentyl 1140C/0.1 17 H Allyl cyclopentyl 920C/0.2 18 H Benzyl cyclopentyl 1420C/0.1 19 H n-Butyl t-butyl 800C/0.5 20 Methyl n-Butyl cyclopentyl 1200C/O.5 21 Methyl Methyl cyclopentyl 860C/0.2 22 Methyl Ethyl cyclopentyl 900C/0.15 23 Methyl n-Propyl cyclopentyl 950C/0.15 24 Methyl n-Hexyl cyclopentyl 1200C/0.1 25 Methyl Allyl cyclopentyl 1000C/0.2 26 Methyl Benzyl cyclopentyl 142 C/0.09 27 t-Butyl n-Butyl i-propyl 900C/0.3 EXAMPLE 28.

Cyclohexyl N-butyl-2-furylcarbamate.

Crude cyclohexyl 2-furylcarbamate was prepared in a similar manner to that of Example 1 and alkylated without further purification using the method described in Example 9 to yield the title product (b.p. 114 C/0.15 mm Hg).

Analysis: C, 67.8; H, 8.90; N, 5.16% A6H23NOs requires C, 68.0; H, 8.75; N, 5.29% EXAMPLE 29.

Methyl N-butyl-2-furylcarbamate.

Ethyl 2-furylcarbamate was prepared by a modification of Example 6 because of the low boiling point of methanol. 2-Furoic acid (22.4 g, 0.2 mole) was mixed in toluene (300 ml) with triethylamine and diphenyl phosphonic azide at OOC, then gradually warmed to 900C over 30 minutes, by which time there was gentle gassing. At this point methanol (10 ml) was added at such a rate that the temperature of the reaction mixture did not fall below 85"C. After 4 hours, gassing had ceased and work up was similar to Example 6. The resultant brownish viscous oil was ex tracted with hot 40/60"C petroleum ether and evaporated (rotary) to yield methyl 2furylcarbamate as a pale yellow oil (8.3 g) which crystallised on storage at 5"C, but melted again at room temperature.

This carbamate was reacted as in Example 9 using n-butyl iodide to give the title compound, b.p. 76 C/0.5 mm.

Analysis: CloHlNOs req: C, 60.9; H, 7.67; N, 7.10% Found: C, 61.2; H, 7.76; N, 6.89% EXAMPLE 30.

l-Adamantyl N-ethyl-2-furylcarbamate.

Crude l-adamantyl 2-furylcarbamate was prepared in a similar manner to that of Example 6 and alkylated using the method described in Example 9 to give the title compound, b.p. 1240C/0.01 mmHg.

Analysis: found C, 72.1; H, 8.76; N, 0.37% ClgH2TNO3 requires C, 71.9; H, 8.57; N, 4.42% EXAMPLES 31 AND 32.

The following compounds were prepared in a similar manner to that of Example 30: 2-Propenyl N- (2-propynyl ) 2-furylcarbamate b.p. 87 0C/0.O4 mm Cyclopentyl N-methyl-5-phenyl-2-furylcarbamate b.p. 113 0C/0.07 mm EXAMPLE 33.

Butyl-N- (5-phenyl-2-thienyl) carbamate.

Diphenylphosphonic azide (6.74 g, 0.0245 mole) was added to a solution of 5-phenyl-2-thiophenecarboxylic acid (5.0 g, 0.0245 mole), n-butanol (3.62 g, 0.049 mole), and triethylamine (2.47 g, 0.0245 mole) in dichloromethane (30 ml) cooled in an ice bath. The mixture was heated gently and refluxed for 3 days. The solution was diluted with ethyl acetate and washed with 2M aqueous NaOH, aqueous NasCl, dried and evaporated. The dark brown residue was eluted with CHOW, from a short silica gel column and the eluent collected and evaporated to a viscous red liquid which crystallised from ethanol-water. Recrystallisation from petroleum spirit (60-800 C) gave the title product in the form of buff coloured needles (5.14 g, 77%, m.p. 7475 C).

Analysis: Found C, 65.05; H, 5.93; N, 5.22; 0, 11.92; S, 11.64% 0,,H17NO2S required C, 65.44; H, 6.22; N, 5.09; 0, 11.62; S, 11.6% EXAMPLE 34.

l-Butyl-3- (2-phenyl-5-thienyl) -urea.

Triethylamine (2.38 g, 0.024 mole) was added to a stirred suspension of 5-phenyl2-thiophene amine hydrochloride (5.0 g, 0.024 mole) in dry benzene (150 ml). n-butyl isocyanate (2.33 g, 0.024 mole) was added and the mixture was heated under reflux for 6 hours giving a clear solution. The mixture was cooled, petroleum spirit (60- 800C) was added, and the crystals whth formed were washed with dilute HG1 and recrvstallised from ethanol-water to give the title product as white needles, m.p. 149 151"C.

EXAMPLES 35 to 39.

The following compounds were prepared by similar methods to that of Example 29:

b.p.* C/ EXAMPLE R R pressure mmHg 35 Methyl Cyclohexyl 150 C/0.1 36 n-Butyl Ethyl 90-95 C/0.5 37 n-Butyl n-Butyl 114-1180C/O.1 38 n-Butyl Cyclopentyl 1150C/0.05 39 n-Butyl Cyclohexyl 1050C/0.1 * temperatures given are air-bath temperatures.

EXAMPLE 40.

Phenyl N-(l-methyl 3-pyrazoloyl)carbamate.

Phenyl chloroformate (31.8 g, 0.2 mole) was added dropwise to a stirred solution of 3-amino-l-methyl pyrazole (19.4 g, 0.2 mole) and triethylamine (20.2 g, 0.2 mole) in dry benzene (50 ml) cooled to 5--100C. After 2 hours at room temperature water was added followed by petroleum ether (4(00C). The resulting crystalline title product was filtered, dried in vacuo, and recrystallised from ethyl acetate-ethanol to yield white needles, (m.p. 145-1470C).

EXAMPLES 41 AND 42.

The following compounds were prepared in a similar manner to Example 40 and recrystallised from the solvents shown: Methyl N-(1-methyl-3-pyrazolyl)carbamate m.p. 136---137OC (EtOAc) n-Butyl N- ( 1-methyl-3-pyrazolyl) carbamate m.p. 68700 C (Et2O-Petrol) EXAMPLE 43.

Benzyl N-butvl-N (1 -methyl-3 -pyrazolyl) carbamate.

A solution of benzyl N(1-methyl pyrazol-3-yl)carbamate (4.5 g, 0.019 mole) (prepared by the method of Example 40), in dry dimethvlformamide (15 ml) was added to a stirred suspension of sodium hydride (50 /, dispersion in oil, 1.0 g, 0.021 mole, previously washed with petrol (4060"C) under nitrogen) in dimethylformamide (25 ml) cooled to 5--10"C. After 1 hour at room temperature the mixture was cooled again and n-butyI iodide (3.9 g, 0.021 mole) added. The mixture was stirred for 1 hour at room temperature and then poured onto water (100 ml). The product was extracted into ether, washed with saturated brine solution, dried over anhydrous sodium sulphate, filtered and evaporated. Distillation of the residual oil yielded the title product as a colourless viscous liquid (4.95 g, 88%, b.p. 120 C at 0.05 mmHg).

Analvsis: found C, 67.12; H, 7.20; N, 14.61; 0, 10.91% C1sH21N8O2 required C, 66.87; H, 7.37; N, 14.62; 0, 11.13% EXAMPLES 44 TO 51.

The following compounds were prepared by similar methods to that of Example 43. In some cases the products were solids and were recrystallised from the solvents shown:

EXAMPLE R R *b.p. C/mmHg m.p. (solvent) 44 n-Butyl Methyl 95-100 / 0.1 45 n-Butyl n-Butyl - 0-50C (Petrol 40-60 ) 46 i-Butyl n-Butyl 110 / 0.1 47 Benzyl butyl 150 / 0.5 36-380C (Petrol 4060o) 48 Methyl Benzyl - 42-430C (Et2O-Petrol 40-60 ) 49 Benzyl Benzyl - 44-450C (EtoH-H1o) 50 n-Butyl Phenyl - 38-40 C (Petrol 40-60 ) 51 Benzyl Phenyl 110 / 0.02 60-64 C (Et2O) * temperatures given are air-bath temperatures.

EXAMPLE 52.

N- (1-methyl-3-pyrazolyl)N-butylamine.

N-( l-methyl-3-pyrazolyl)propanamide (25.5 g, 0.15 mole) in dry tetrahydrofuran (150 ml) was added to a stirred suspension of lithium aluminium hydride (7.2 g, 0.2 mole) in dry tetrahydrofuran (150 ml) cooled in an ice bath under nitrogen.

After refluxing the mixture for 4 hours, ethyl acetate was added to destroy excess lithium aluminium hydride and the solution was filtered The filtrate was diluted with diethyl ether, washed with water, dried, filtered and evaporated. The residual yellow oil was distilled to yield the title product as a colourless liquid (20.5 g, 91%, b.p.

60-65 C at 0.4 mmHg).

Analysis: found: C, 62.57; H, 9.63; N, 27.17%.

C8H15N3 required: C, 62.71; H, 9.87; N, 27.42%.

EXAMPLES 53 AND 54.

The following compounds were prepared by similar methods to that of Example 52: N-(1-methyl-3-pyrazolyl)-N-phenylmethylamine m.p. 49-51 C.

N-methyl-N-(l-methyl-3-pyrazolyl)amine b.p. 690,C at 2.3 mmHg.

EXAMPLE 55.

l-Butyl-3-(1-methyl-3-pyrazolyl)-3-phenylmethyl urea.

A solution of N-phenyl l-methyl-3-pyrazolyl (3.9 g, 0.021 mole) and n-butyl isocyanate (2.07 g, 0.021 mole) in dry benzene (100 ml) was heated under reflux for 2 hours and then evaporated. The residual solid was dissolved in diethvl ether, washed with 2M aqueous hydrochloric acid, saturated aqueous sodium chloride, dried over anhydrous sodium sulphate, filtered and evaporated. Recrystallisation from chloraform-petroleum spirit (60-800 C) gave the title product as a white crystalline solid (59%, m.p. 61----620C).

EXAMPLES 56 to 62.

The following compounds were prepared by similar methods to that used in Example 55 and, where necessary, recrystallised from the solvents shown:

EXAMPLE R R m.p. Yield % 56 H n-Hexyl 42 C (Et2O) 60 57 H Phenyl 137-138 C (CHCl3-petrol 79 60-80 ) 58 Methyl n-Butyl 100C 60 59 Methyl Phenyl 61-630C (EtoH-H,o) 76 60 n-Butyl Methyl 33-370C 88 61 n-Butyl n-Butyl OOC (Petrol 40-600) 65 -62 n-Butyl Phenyl 54-570C (EtOH-H20) 68 EXAMPLE 63.

Phenyl N-butyl-N- (3-methyl- 1,2,4oxadiazol-5-yl) carbamate.

A mixture of phenyl chloroformate (3.9 g, 0.025 mole) and N-butyl (3-methyl1,2,4-oxadiazol-5-yl)amine (3.5 g, 0.023 mole) in anhydrous pyridine (30 ml) was stirred at room temperature for 24 hours. The pyridine solvent was removed under reduced pressure by azeotroping with water. The product was extracted into ether, washed with water, dried, and evaporated to a yellow oil. Distillation yielded the title product as a colourless viscous liquid (5.62 g, 91%, b.p. 125130 at 0.0-1 mmHg).

Analysis: found: C, 61.17; H, 6.08; N, 15.02; 0, 17.57% Cl4HI7N302: required: C, 61.08; H, 6.23; N, 15.26; 0, 17.43% EXAMPLES 64 to 67.

The following compounds were prepared by methods similar to those of Example 63:

EXAMPLE R1 R3 b.p.*/pressure mmHg Yield % 64 Methyl n-Butyl 90-100 C/0.02 40 65 Methyl Phenyl 125-130 C/0.01 87 66 n-Butyl Ethyl 90-950C/0.02 42 67 Benzyl Ethyl 110-1150C/0.05 58 * temperatures given are air-bath temperatures.

EXAMPLE 68.

l-Methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)3-n-butyl urea.

A solution of N-methyl (3-methyl-1,2,4-oxadiazol-5-yl)amine (2.5 g, 0.022 mole) and n-butyl isocyanate (2.2 g, 0.022 mole) in dry benzene (50 ml) was heated under reflux for 5 hours and then evaporated. The solid residue was recrystallised from ethanol-water to give the title product as white needles (37%, m.p. 35- 38 C).

EXAMPLES 69 to 71.

The following compounds were prepared by similar methods to that of Example 68 and recrystallised where necessary from the solvents shown:

EXAMPLE R1 R2 m.p. Yield % 69 n-Butyl Phenyl 47-49 C .(Et2O-water) 29 70 n-Butyl Cyclohexy 27-340C (Et20-petrol 78 406oo) 71 Benzyl n-Butyl 39 EXAMPLE 72.

Ethyl N-butyl-N-(5-phenyl-1,3,4-oxadiazol-2-yl)carbamate.

A mixture of ethyl chloroformate (2.9 g, 0.027 mole), triethylamine (2.7 g, 0.027 mole) and N-butyl-(5-phenyl-1,3,4-oxadiazol-2-yl)amine (5.3 g, 0.0244 mole) in dry benzene (50 ml) was stirred at room temperature for 24 hours. Water was added and the product extracted into diethyl ether, washed with 2M Howl, saturated aqueous sodium chloride, dried and evaporated. Distillation yielded the title product as a colourless liquid (1.76 g, 23%, b.p. 125 C at 0.02 mmHg).

Analysis: found C, 61.99; H, 6.79; N, 14.57; 0, 16.58% Cl3Hl9N Os required C, 2.27; H, 6.62; N, 14.52; 0, 16.59% EXAMPLES 73 AND 74.

The following compounds were prepared by similar methods to that described in Example 63, reacting 2-amino-5-phenyl-1,3,4,-oxadiazole with the appropriate chloroformate:

EXAMPLE R3 m.p. (solvent) Yield % 73 Ethyl 126-1320C (CHCl3-Petrol 56 (60-80 ) 14 n-Butyl 138-14()0C (EtOAc) 56 EXAMPLES 75 to 77.

The following compounds were prepared by alkylation of the products described in Examples 73 and 74 by methods similar to that described in Example 43:

EXAMPLE EXAMPLE R1 R m.p. or b.p. Yield % 75 n-Butyl n-Butyl b.p. 130 C/0.01mmHg 52 76 Benzyl Ethyl m.p 88-920C 58 Benzyl n-Butyl m.p. 47-520C, 84 I b.p. 150-160 C/0.01 IrunHg EXAMPLES 78 to 81.

The following 1,3,4-ozadiazolyl ureas were prepared by methods similar to that of Example 55:

EXAMPLE R1 R3 m.p. 78 n-Butyl Phenyl 70-71 C 79 n-Butyl n-Butyl 60-72 C 80 n-Butyl Phenyl 108-1100C 81 n-Butyl p-Chlorophenyl 126-127 C

EXAMPLES 82 to 84.

The following compounds were prepared by similar methods to that described in Example 63:

EXAMPLE R R m.p. and/or b.p./mmHg Yield % 82 n-Butyl Ethyl 28-38 C, 120-130 C/0.05 mm 80 83 n-Butyl n-Butyl 105-115 C/0.05 mm 49 84 n-Butyl Phenyl 44-480C, 120-1300C/o.04 mm 73 EXAMPLE 85.

Ethyl 2-methyl-5-tetrazolylcarbamate.

A solution of 2-methyl-5-tetrazoleamine (66.6 g, C.067 mole) and ethyl chloro formate (7.2 g, .067 mole) in benzene (35 ml) was heated under reflux for 5 hours.

The title product crystallised out on cooling (Yield 8.9 g, m.p. 101"C).

EXAMPLES 86 to 88.

The following compounds were prepared by the method described in Example 85, products being recrystallised, where necessary, from the solvents shown: n-Butyl 2-methyl-5-tetrazolylcarbamate m.p. 97 C.

i-Propyl 2-methyl-5-tetrazolylcarbamate m.p. 920C. (ethyl acetate-petroleum spirit Phenyl 2-methyl-5-tetrazolylcarbamate m.p. 157--1580C (ethyl acetate) EXAMPLES 89 TO 93.

The following compounds were prepared by the method described in Example 9, the products being distilled in a short path distillation apparatus:

EXAMPLE R R b.p.*/mmHg 89 n-Butyl Ethyl 1100C/0.07 90 n-Butyl i-Propyl 105 C/0.25 91 n-Butyl n-Butyl 1100C/0.1 92 n-Butyl Phenyl 1500C/O.1 93 Benzyl Phenyl 1850C/0.1 * temperatures given are air bath temperatures.

The following Examples illustrate pharmaceutical formulations containing the active compound isopropyl N-n-butyl- (2-t-butylfur-5-yl) carbamate.

EXAMPLE 94.

Soft gelatin capsules were prepared using the following ingredients: Quantity mg/capsule) Active comPound 20 Butylated hydroxyanisole B.P. 0.03 Fractionated Coconut Oil B.P.C. 70 90.03 The above ingredients were mixed and filled into gelatin capsules, the main shell components of which were gelatin and glycerine.

EXAMPLE 95.

The procedure of Example 93 was repeated except that an identical quantity of propyl gallate was used in place of the butylated hydroxyanisole as antioxidant.

EXAMPLE 96.

Hard gelatin capsules were prepared using the following ingredients: Quantity (mg/capsule) Active compound 27 Silicon dioxide (fumed) 27 Lactose 54 Butylated hydroxyanisole B.P. 0.03 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.

Altematively, the solution of butylated hydroxyanisole and active compound can be diluted with an inert solvent, the solution slurried onto the silicon dioxide (fumed) and the inert solvent evaporated off. The lactose is then mixed in and the mixture filled into the hard gelatin capsules EXAMPLE 97.

An injectible solution was prepared containing the following components: Active ingredient 20 mg.

Cremophor EL 20 mg.

Ethanol 20 mg.

Water 20 mg.

Butylated hydroxyanisole B.P. 0.02 mg.

The butylated hydroxyanisole was dissolved in the active ingredient and ethanol, the water and Cremophor (Registered Trade Mark) EL added and the solution sterilised by filtration through a bacteria proof filter into sterile containers.

EXAMPLE 98.

Suppositories containing 25 and 50 mg. of the compound were prepared as follows: Active compound 2.5 g, Henkel base 97.5 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 nominal capacity of 1 g. or 2 g. as desired, to produce suppositories each containing 25 mg. or 50 mg. of the active compound.

EXAMPLE 99.

An aerosol was prepared containing the following ingredients: Quantity per ml.

Active compound 15.00 mg.

Propylene glycol 15.00 mg Dichlorotetrafluoroethane (Propellant 114) 600.00 mg.

Dichlorodifluoromethane (Propellant 12) 850.00 mg.

The active compound was mixed with the propylene glycol and the mix added to the propellant 114, the mixture cooled to - 15 to 2 C. and transferred to a filling device. At the same time a mixture of propellants 114 and 12, previously cooled to - 15 to - 200C. 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 may be equipped with metering device so that approximately 0.15 mg. of the active compound is released by a single actuation of the valve.

EXAMPLE 100.

Tablets were prepared using the following components: Active compound 20.00 mg.

Microcrystalline Cellulose 240.00 mg.

Sodium Carboxymethyl Starch 30.00 mg.

Magnesium Stearate 4.00 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 then the magnesium stearate was mixed in. Finally, the mixture was compressed to form tablets.

In the foregoing Examples 94 to 100 the liquid active compound used may, in accordance with the invention, be replaced wholly or in part by other liquid active compounds of formula (I). If the active compound is a solid, appropriate modification will of course have to be made.

WHAT WE CLAIM IS: 1. A heterocyclic amino derivative of formula:

wherein Ar represents a 5-membered heterocyclic nucleus selected from 2-furyl, 2thienyl, 2-pyrrolyl, 1- (C16 alkyl)-3-pyrazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, oxadiazolyl, 1,2,4-thiadiazolyl and 5-tetrazolyl, the heterocyclic nucleus being optionally substituted by hydrogen, cl-a alkyl or R4; R1 is hydrogen, C38 alkyl, cl-c alkenyl, C,, alkynyl, C,-, cycloalkyl or CH2R4; R2 represents the group OR3 or NHR3; R3 C,, alkyl, C3a alkenyl, C,-, cycloalkyl, admantyl, R4 or CH2R4; and R4 is phenyl optionally substituted by one or more groups selected from halogen, trifluoromethyl, Cl-4 alkyl, C,4 alkoxy and nitro; provided that (i) when the heterocyclic nucleus is 2-furyl or 2-pyrrol, and R2 is OR3, Rl is not hydrogen; (ii) when Ar is unsubstituted 2-thienyl, R1 is not hydrogen; (iii) when the heterocyclic nucleus is 1,2,4- or 1,3,4-oxadiazolyl, 1.2-4-thia diazolyl or 5-tetrazolyl, R1 is not hydrogen; (iv) when the heterocyclic nucleus is 1,2,4-thiadiazolyl, R2 is OR3; (v) when Ar is unsubstituted 2-thienyl, R1 is methyl or benzyl and R2 is OR3, R3 is not methyl;

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. EXAMPLE 99. An aerosol was prepared containing the following ingredients: Quantity per ml. Active compound 15.00 mg. Propylene glycol 15.00 mg Dichlorotetrafluoroethane (Propellant 114) 600.00 mg. Dichlorodifluoromethane (Propellant 12) 850.00 mg. The active compound was mixed with the propylene glycol and the mix added to the propellant 114, the mixture cooled to - 15 to 2û C. and transferred to a filling device. At the same time a mixture of propellants 114 and 12, previously cooled to - 15 to - 200C. 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 may be equipped with metering device so that approximately 0.15 mg. of the active compound is released by a single actuation of the valve. EXAMPLE 100. Tablets were prepared using the following components: Active compound 20.00 mg. Microcrystalline Cellulose 240.00 mg. Sodium Carboxymethyl Starch 30.00 mg. Magnesium Stearate 4.00 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 then the magnesium stearate was mixed in. Finally, the mixture was compressed to form tablets. In the foregoing Examples 94 to 100 the liquid active compound used may, in accordance with the invention, be replaced wholly or in part by other liquid active compounds of formula (I). If the active compound is a solid, appropriate modification will of course have to be made. WHAT WE CLAIM IS:

1. A heterocyclic amino derivative of formula:

(vi) when Ar is 3-methyl-2-thienyl, R1 is hydrogen and R2 is NHR3, R3 is not phenyl; (vii) when Ar is 3,4-diphenylpyrrol-2-yl, R1 is hydrogen and R2 is NHR3, R is not ethyl or phenyl; (viii) when Ar is unsubstituted 1,2,4-thiadiazol-5-yl and R1 is methyl, R3 not ethyl; (ix) when Ar is 5-phenyl-1,3,4-oxadiazol-2-yl, R1 is methyl and R2 is NHR3, is not phenyl; and (x) when Ar is unsubstituted 5-tetrazolyl, R1 is benzyl and R2 is OR3, R3 is not ethyl.

2. A derivative according to Claim 1 wherein Ar is optionally substituted by hydrogen, C1, alkyl or phenyl, R1 is hydrogen, C1-6 alkyl, allyl, propynyl or benzyl and R is C1-6 alkyl, allyl, C5-6 cycloalkyl, adamantyl, phenyl or benzyl.

3. A derivative according to Claim 1 or 2 of formula (II):

where R1 is C1-6 alkyl, allyl, propynl or benzyl, R3 is C14 alkyl, allyl, cyclopentyl or adamantyl and R5 is hydrogen or C14 alkyl.

4. 1-n-Butyl-3 - (2-phenyl-5-thienyl) urea.

5. A derivative according to Claim 1 or 2 of formula (III).

where R is C14 alkyl and R3 is C2-4 alkyl or C,a cycloalkyl.

6. A derivative according to Claim 1 or 2 of formula (IV):

where R1 is C14 alkyl or benzyl and R3 C14 alkyl, phenyl or benzyl.

7. A derivative according to Claim 1 or 2 of formula (V):

where R1 is hydrogen, C14 alkyl or benzyl and R3 is C1a alkyl or phenyl.

8. A derivative according to Claim 1 or 2 of formula (VI):

where K1 is C,4 alkyl or benzyl, R is NHR3 or OR3 and R3 is C1-6 alkyl cyclohexyl or phenyL

9. A derivative according to Claim 8 where R is OR3 and R3 is C,4 alkyl.

10. A derivative according to Claim 8 wherein R1 is n-butyl or benzyl, R is NHR3 and R is n-butyl, cyclohexyl or phenyl.

11. A derivative according to Claim 1 or 2 of formula (VII):

where R1 is butyl or benzyl and R3 is C,4 alkyl.

12. Ethyl N-n-butyl-(3-methyl-1,2,4-thiadiazol-5-yl) carbamate.

13. A derivative according to Claim 1 or 2 of formula (VIII):

where R1 is n-butyl or benzyl and R is C4 alkyl or phenyL

14. A compound of formula (I) as defined in Claim 1 as described in any one of Examples 9 to 51, 55 to 72, 75 to 84 and 89 to 93.

15. A method of preparing a heterocyclic amino derivative of formula (I) as defined in any one of Claims 1 to 14 which comprises: (1) reacting a compound of formula (IX)

wherein Ar and R are as defined in Claim 1, with a compound of formula K"Z (a) wherein (i) Q is hydrogen, R3' is R9 or hydrogen and Z is -NCO, or (ii) Q is COCI, R3' is R3 and Z is NH,; so as to produce a compound of formula (I) in which R2 is NHR3, followed, when R3' is hydrogen, by alkylation to convert R3' to R3; or (b) wherein Q is hydrogen, Z is LCO8- where L is a good leaving group, preferably chlorine, and R3' is R3, so as to produce a compound of formula (I) in which R is OR3, followed where necessary when R is hydrogen by alkylation to form a compound of formula (I) wherein R or OR3 and R1 is other than hydrogen; or (2) reacting a compound of formula Ar-CO-X where Ar is as defined in Claim 1 and X is OH or a good leaving group, preferably chlorine, with diphenylphosphonic azide or alkali metal azide, provided that when X is OH reaction with an alkali metal azide is preceded by reaction with a compound of formula LCOOR6 where L is a good leaving group, preferably chlorine, and RF is Cta alkyl; followed by reaction with a compound of formula R30H wherein R3 is as defined in Claim 1 to give a compound of formula (I) wherein R1 is hydrogen, followed, where necessary, by alkylation to give a compound of formula (I) wherein R1 is not hydrogen.

16. A method according to Claim 15 substantially as hereinbefore described with reference to any of Examples 1 to 93.

17. A derivative of formula (I) as defined in any one of Claims 1 to 14 whenever prepared by a method according to Claim 15 or 16.

18. A pharmaceutical formulation comprising a heterocyclic amino derivative according to any one of Claims 1 to 14 or Claim 17 in association with a prarmameutically acceptable carrier therefor.

19. A pharmaceutical formulation according to Claim 18 substantially as hereinbefore described in any one of Examples 94 to 100.

20. A method of making a pharmaceutical formulation which method comprises bringing a heterocyclic amino derivative according to any one of Claims 1 to 14 or Claim 17 into association with a pharmaceutically acceptable carrier therefor.

21. A method according to Claim 20 substantially as hereinbefore described in any one of Examples 94 to 100.

22. A method of treating an allergic condition in a non-human mammal, which comprises administering a chemotherapeutically effective amount of a heterocyclic amino derivative according to any one of Claims 1 to 14 or Claim 17 to the afflicted non-human mammal.