AU8564375A

AU8564375A - Urea or thiourea derivatives

Info

Publication number: AU8564375A
Application number: AU85643/75A
Authority: AU
Inventors: Katsuo Arimura; Mitsuhiro Konishi
Original assignee: Yoshitomi Pharmaceutical Industries Ltd
Current assignee: Tanabe Pharma Corp
Priority date: 1974-10-12
Filing date: 1975-10-10
Publication date: 1977-04-21
Also published as: BE834247A; JPS5152176A; SE7511408L; NL7511857A; DE2545501A1; FR2287228A1

Description

.1 3. 111L11111=m

A

MICROCOPY RESOLUTION TEST CHART N4ATIONAL OFSTANDARDS BUREAU 1963

S-I

Ln FORM 4 COMMONWEALTH OF AUSTRALIA w

0 PATEN"S ACT 196249 x

Convention Application for a ~~n

We YOSHITOMI PHARMACEUTICAL INDUSTRIES, LTD.

Of No.35, Hirano-Machi 3-Chome, Higashi-Ku, Osaka, Japan

hereby apply for the grant of a Patent for an invention entitledI

11UREA OR THIOUREA DERIVATIVES" 94~Y DOLLA 57 F9

which is described in the accompanying complete specification. This application is a Convention Application and is based on the application numbered 117503/74 for a patent or similar protection made in Japan AUSRAUAN

on 12th October, 1974

Our address for service is: [7- to v.~I Care: SPRUSON FERGUSON I jm(/ PATENT ATTORNEYS r ESSO HOUSE, 127 KENT STREET SYDNEY. NEW SOUTH WALES. AUSTRALIA.

Dated this NINTH day of OCTOBER, 19 YOSHITOMI PHARMACEUTICAL IlDUST C,0

-Sivmtwe of-*ppficmW To: Registered Patent Attorney The Commissioner of Patenits

SFORM 8 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69

DECLARATION IN SUPPORT OF A CONVENTION APPLICATION FOR A PATENT OR PATENT OF ADDITION In support of the Convention Application made for a

patent for an invention entitled

"UREA OR THIOUREA DERIVATIVES"

Full name and ad- I, MOTOSUKn TASAKA dress of Declarant. care of YOSHITOMI PHARMACEUTICAL INDUSTRIES, LTD., Hirano-Machi 3-Chome, Higashi-Ku, Osaka, Japan do solemnly and sincerely declare as follows:-

1. r h ^4 a edAi"- (or, in the case of an applicationby a body corporate) 1. I am authorised by YOSHITOMI PHARMACEUTICAL INDUSTRIES, LTD. the applicant for the paten to make this declaration on its behalf.

Insert country and 2. The basic application as defined by Section 141 of the Act was made in date of basic appli- cation and name of Japan on the foreign applicant. S12th day of October, 1974 by YOSHITOMI PHARMACEUTICAL INIUSTRIES, LTD.

3* l 3.4atr tht- trenraMtv en -f-th- en t.rf fe'ed-4e. 4n-le4h-basio-application. (or where a person other than the inventor is the applicant) Full name and ad- dress of Inventor(s) 3. KATSUO ARIMURA of No.488, Oaza-Shimomiyanaga, Nakatsu-Shi, oita, Japan and MITSUHIRO KONISHI of No.647-10, Oaza-Kakize, Nakatsu-Shi;,Oita, "fJapan

1

are it the actual inventois of the invention and the facts lpon which the applicant is/are entitled to make the application are as follows:

The said applicant is the assignee of the actual inventors.

4. The basic application referred to in paragraph 2 of this Declaration was the first application made in a Convention country in respect of the invention the subject of the application. Declared at Tokyo this 26th day -fSeptember, 1975

Signature of Declarant To: I' nocn'o 'askai, ':xrecutive-Vice Presilnt The Commissioner of Patents, SPRUSON FERGUSON, SYDNEY.

APPLICATION

COMPLETE SPECIFICATION .N85643/ LOI)GLD -IN 1U2SPEC7T OF

APPLICATION FOR PATENT Of LODG%1I NT AND) AC'KNOWLLIDIGNENTI OF DOCUMENTS itc \.ipJ\

1hef Ing .CieC I Jcd at the Patrent Office Oil

Arp!:,aion for patent. Deklariiiii In SIport7-

L1tilli ir. nrumbler 'I iiiti il'cip hete,pecificartion inde(riing rilrwings. Adirw itd .py ofidhrmn (ertmed copy ot birie speifieftfitn anrd (rrt ilalton.

Addic' fit wimIe

1"r Ct (j AM lit

IF. Alkaw D. n, Gi vi fment Ftmnhr, (int0crro

DOCUMENTS LODGED WITH THIS APPLICATION ARE UNSUITABLE FOR REPRODUCTION AND MAY BE INSPECTED AT THE PATENT OFFICE A.C.T.

COMMONWEALTH OF AUSTRALIA Form PATENTS ACT 1952-69

COMPLETE SPEOIHOATION (ORIGINAL) FOR OFFICE USE

Class Int. Class Application Number -46L63, 6-L Q 43 C617D Lft/ Lodged 10c. /06

14 6 Complete Specification Lodged i0

Published: c2/ 4 i577/t7

Re.lated Art

Nam ofApiat.*ITM ~RAEUILIDSRELD .0-4rso Aplcn*03,Hrn-ahk3ChmHg~i ,Oaa. aa

*4~ta .ASOAIEtad nets ISER OI

Wd.es fo evc: Srsn& Fruo, aetAtres oHue 12 KetSreSdey.e.ot aes 00Asrla

Co plt Spcfcto*o heivninette *UB .I:U OR ERVTVS

Nae fofllo icsatnt iOsHTN fuDlTlES H fti R A netin E nldn etm Lecito efomn td. it knw to.u

ABSTRACT

Urea or thiourea derivatives of the formula:

R4 X SII 3 C-NH-R R -N N 2

wherein R1 is C1-4 alkyl, C2- 6 alkenyl, C_14 alkoxy-carbonyl,

phenyoxy- C1-4 alkyl, pyridyl- C1-4 alkyl or Ar-(B)m-(CH 2)- (wherein Ar is phenyl or substituted phenyl, B is -CH(OH)- or m is 0 (zero) or 1 and n is O (zero) or an interger of from 1 to R2 is CI 6 alkyl, aralkyl, phenyl, substituted phenyl, naphthyl, pyridyl, furfuryl or thenyl; R is C_ 6 slkyl, C2_ 6 alkenyl, aralkyl, phenyl, substituted phenyl or naphthyl R4 is hydrogen or C1-4 alkyl; and X is e oxygen or sulfur, or pharmaceutically acceptable salts

thereof are useful as analgesics. The present invention relates to novel and therapeutically valua'le compounds of the formula: R4 4 X

C-NH-R R1 N N H 2 LR2 or pharmaceutically acceptable salts thereof, wherein: R 1 is an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkoxy- carbonyl group in which the alkoxy moiety has 1 to 4 carbon

atoms, a phenyoxyalkyl group in which the alkyl moiety has

1 to 4 carbon atoms, a pyridylalkyl group in which the alkyl moiety has 1 to 4 carbon atoms or the group Ar-(B)m

(CH2 (wherein Ar is a phenyl group or a phenyl group substituted by 1-3 substituents each selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms and a hydroxyl group; B is -CH(OH)- or m is 0 (zero) or 1 and n is 0 (zero) or an interger of from 1 to 4); R2 is an alkyl group having 1 to 6 carbon atoms, an aralkyl group, a phenyl group, a phenyl group substituted by 1-3 substituents each selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms and a trifluoro- methyl group, a naphthyl group, a pyridyl group, a furfuryl group or a thenyl group; R 3 is an alky group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an aralkyl

group, a phenyl group, a phenyl group substituted by 1-3 substituents each selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms and a nitro group, or a naphthyl group; R4 is a hydrogen atom or an alkyl group having 1 toc carbon atoms; and X is an oxygen atom or a sulfur atom. The alkyl group or moiety having 1 to 4 carbon atoms may be methyl, ethyl, propyl, isopropyl or butyl. The alkyl group having 1 to 6 carbon atoms may be methyl, ethyl, propyl, isopropyl, butyl, pentyl or hexyl. The alkenyl group may be vinyl, allyl, 2-butenyl, 3-methyl-2-buenyl or 2-hexenyl. The alkoxy group may be methoxy, ethoxy, propoxy, isopropoxy or butoxy. The aralkyl group may be benzyl or phenethyl. The halogen atom may be F, Cl or Br.

The compounds of formula can be produced, for example, by the following methods: by reacting a compound of the formula: R4

R1 N [Il

wherein RI, R and R are as defined above, with a compound of the formula:

R N=C=X IIi] ft. ft oo. f

e e wherein R3 and X are as defined above. *.tf The compound of formula [III is usually in the ft ft

S' eeee 10 ratio of 1-3 moles per 1 mole of the compound of formula eet eee ft ft though in some cases the use of a large excess of ft ft ft.

f the compound of formula [III] produces good results. The reaction is usually carried out in a thoroughly dried ft.

aprotic solvent benzene, toluene, xylene, ethyl ft.

ft acetate, dioxane, pyridine or dimethylformamide) at a ft ft.. temperature of from room temperature to a temperature near f

the boiling point of the solvent for 2-24 hours, preferably J ft oooe** under stirring. The starting compound of formula II can be

f 20 produced, fo example, as follows: R4 R4

R1 N 0 HNR 2 1 N N-R 2

Siv] [vi] R4

reduction R -N NH-R 2

An N-substituted-4-piperidone of formula [IV] and an amine of formula are subjected to dehydration conden- sation, and the thus obtained Schiff base of formula [VI, is treated with a suitable reductant sodium boron hydride or lithium aluminum hydride) to give the compound of formula [IT (ii) by reacting a compound of the formula:

R4 X II R-3 II

R2 wherein each symbol is as defined above, with a compound of 10 the formula: 1

[vii] S: wherein R1 is as defined above and Y is a halogen atom (e.g. Cl, Br or I) or an alkyl- or aryl-sulfonyloxy group (e.g. methylsulfonyloxy, phenylsulfonyloxy or p-tOlylsulfonyloxy). The reaction is usually carried out in a solvent methanol, ethanol, toluene, dimethylformanide, acetone, dioxane or ethyl acetate) in the presence of a deacidifying agent sodium carbonate, potassium car- bonate, triethylamine or pyridine) at 50-200°C, preferably 0 at a temperature near the boiling point of the solvent for 1-20 hours. The starting compound of formula [VII] can be produced, for example, by reducing a compound of the formula:

X R 44 1 3 h S 3 RC-N-R [Ia] \2 wherein each symbol is as defined above. Specific example of the preparation of compound [VIi To a solution of 138 g of l-methyl-3-phenyl-3- (l-benzyl-4-piperidyl)urea in 250 ml of 2 N hydrochloric acid and 800 ml of ethanol is added 15 g of 10% palladium- carbon, and hydrogen gas is introduced to the mixture at 40-50°C for 2 hours. While the introduction of hydrogen gas, the contents are stirred. The palladium-carbon is filtered out, and the filtrate is concentrated under reduced pressure. The residue is recrystallized from ethanol to give 113 g of l-methyl-3-phenyl-3-(4-piperidyl)urea hydro- chloride as colorless crystals melting at 239-2400C with decomposition. The product is dissolved in 200 ml of water, and 85 g of sodium bicarbonate is added to the solution. The crystalline precipitate is filtered off and recrystall- ized from aicnhol to give 95 g of l-methyl-3-phenyl-3-(4- piperidyl)urea as colorless crystals melting at 92-950 C. The compounds of the present invention, except the compounds of formula [II wherein R1 is an acidic group such as an alkoxycarbonyl or an aroyl, can be converted in a conventional manner into the corresponding acid addition salts with various inorganic or organic acids such as hydrochloric, hydrobromic, oxalic, citric, maleic or fumaric acid.

The compounds of formula wherein R4 is an alkyl group include geometrically and optically isomeric

bodies, and they can be separated and resolved in a con- ventional manner.

The compounds of formula and pharmaceutically acceptable acid addition salts thereof have nonnarcotic analgesic action as shown, for example, by the following tests.

Analgesic Activity (Electrical Stimulation Method)

The test was performed essentially in accordance with the methods described in "Journal of the Pharmaceutical Society of Japan", vol. 73, p. 212 ff. (1953) and "Folia Pharmacologica Japonica", vol. 65, p. 378 ff. (1969). Each test compound was administered intraperitone- ally to groups each consisting of ten male mice selected 1 0 from the group where the electrical stimulation without administration of any test compound had produced squeak within 2-3 seconds. The tail of the mouse was electrically stimulated for 5 seconds with interrupted direct current

(25 volts, 40 milliseconds, 1 cycle per second). When no S0# squeak was observed during the electrical stimulation the analgesic effect was evaluated to be positive. The ED 50 effective dose) was determined graphically.

Levallorphan Antagonism Test

The test was performed in accordance with the Electrical Stimulation Method mentioned above. Before minutes of administration of the test compound, 10 mgAg

of levallorphan was administered subcutaneously to the mice. The tail of the mouse was stimulated at 15-minute intervals.

When no squeak was observed by the stimulation, the analgesic effect was evaluated to be positive.

The results are shown in the following Table I. As is seen from the Table I, the analgesic effect was not weaken by the pretreatment of levallorphan. It can there- fore be said that the foregoing compounds of formula I are nonnarcotic.

TABLE I

ED 5 0 mg/g

Compound Alone Levallorphan pretreat-

ment (10 mg/kg s.c.)

A 10 11 B 20

C 50 36

The compounds A, B and C mean the following compounds:

A: 1,3-diphenyl-3- (l-phenethyl-4-piperidyl) thiourea

*.o hydrochloride;

B: trans-1,3-diphenyl-3- (l-phenethyl-3-methyl-4-piperidyl)

urea; C: 1,3-diphenyl-3-(l-phenethyl-4-piperidyl)urea fumarate. In view of various tests including those mentioned above, the compounds of formula and pharmaceutically

*0. acceptable salts thereof can be administered safely as

analgesics, either alone or in the form of a pharmaceutical

composition consisting essentially of a therapeutically *0*

effective amount of the compound in admixture with a suitable

and conventional carrier or adjuvant, administrable orally or by way of injection, without harm to the host.

The pharmaceutical composition can take the form

of tablets, granules, powder or capsules, for oral administration, of injectable solution for subcutaneous or

intramuscular administration, or suppository for topical administration. The choice of carrier is determined by the preferred form of administration, the solubility of the compounds and standard pharmaceutical practice.

The following is an example of formulation when

a compound of the invention is administered for pharmaceut-

ical purposes:

tablets are prepared from the following composition: Compound 25 mg

Lactoae 69

Corn starch Methyl cellulose 1

Talc 4

Magnesium stearate 1

125 mg

The usual daily dose of compound [Ij or a salt

thereof, when orally administered, lies in the range of

about 50-150 milligrams per human adult.

The present invention is further explained by way of the following illustrative examples.

EXAMPLE 1

Phenyl isocyanate (2.4 g) is added to a solution

S of 5.3 g of 1-benzyl-4-anilinopiperidine in 100 ml of benzene, and the mixture is stirred under reflux for e hours. The benzene is distilled off under reduced pressure,

and the residue is washed with isopropyl ether, filtered off

and recrystallized from chloroform to give 5.1 g of 1,3-

diphenyl-3-(l-benzyl-4-piperidyl)urea as colorless crystals melting at 158-161°C. The corresponding hydrochloride melts

at 208-211°C with decomposition.

EXAMPLE 2

Phenyl isocyanate (4.8 g) is added to a solution

of 7.6 g of l-methyl-4-anilinopiperidine in 100 ml of benzene and the miiture is stirred under reflux for 15 hours. During the stirring, 4.8 g of phenyl isocyanate is further added in several parts. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is washed with isopropyl ether, filtered off and recrystallized from alcohol to give 4.9 g of 1,3- diphenyl-3-(l-methyl-4-piperidyl)urea as colorless crystals melting at 134-136 C. The corresponding fumarate melts at 193-194 C with decomposition.

EXAMPLE 3

To a solution of 7 g of l-methyl-3-phenyl-3-(4- piperidyl)urea in 50 ml of ethanol are added 8.3 g of phenethyl bromide and 5 ml of triethylamine, and the mixture is refluxed for 8 hours. The ethanol is distilled off, and

50 ml of water and 50 ml of ethyl acetate are added to the

residue. The mixture is shaken in a separatory funnel. The organic layer is dried over magnesium sulfate, and the

ethyl acetate is distilled off. The crystalline precipitate is filtered off, washed with isopropyl ether and recrystall- ized from chloroform to give 5 g of 1-methyl-3-phenyl-3-(1-

phenethyl-4-piperidyl)urea as colorless crystals melting at 155-157 C. The corresponding fumarate melts at 208-2100 C with decomposition.

Using the procedure set forth in the above examples, but substituting equivalent amounts of appropriate starting

materials, the following compounds are also produced.

i 0 0 0* U U U U U U U U U. U 00 0 0. UU U U U U

c-NH-R

R

No. I M.P.

CH3 Ph Ph 140-1, HUl 175-6 (d) $1 CH3 C(OH3 =CHCH2 CH 3 153-5, fumarate 178-9 It it 171-2, iHo1 219-20 (d) Ph-CH 2 C4 H9 Ph HCl 2H2 0 295-8 (d) 11 Ph-CH 2 CH 2 135-6, HCI 302-4 (d) 11

furfuryl fumarate 194-5 (d)

2 -thenyl Ph OH 3 169-71, HUl 215-6 (d) HCI 204-6 (d)

Ph-OH 2 166-7, Hcl 204-5 (d) Ph 122-3, HCl 180-1 (d)

p-Oh-Ph 170-2, CId215-8 (d)

P-CH 3 -Ph L I .m.

*90 9 0 4* .00 961 9 0 9 U *9o o*9 0,0 00. U 9 9

N~O. I R__1_1 1 R3 J R4 1 x IM.P. Ph-CH 2 Ph Po -Ph 128-9, HUl 231-3 (d) 'I 1I o-N0 2 -Ph 157-9, HC1 221-3 (d) II p-Cl-Ph Ph 168-71, EdI 227-9 (d) I, P-C 3 -Ph 11 150-3, HU 215-7 (d) II p-OCH 3 -Ph CH3 148-9, HU 217-8 (d) II Ph 181-3, HEd 242-5 (d) 149-51, HC1 240-5 (d) It p-Cl-Ph 148-50, HEd 243-7 (d) ,8 -naph%'-hyl Ph 167-9, Ed1 219-20 (d) 2 -pyridyl CH3 oxalate 154-5 (d) 3 -pyridyl Ph 161-3, 2HC1 180-3 (d) p-C1-Ph-CH2 Ph 11 fumarate 175-6 (d) Ph-CH 2 CH 2 of CH 3 II 146-8, Ed1 215-7 (d) 41 to 3-cH3 trans. 144-5.5 cis. 109-11 if of is

of CAH 89-90, fwnarate 157-8 (d)

*O* :6.0 966: 4D** I O 1. 0 4

*0

No. R R R4 x M.P.

Ph-CH 2 CH2 Ph iso-C PIF H S 120-2, HC1 197-9 (d) 31 i tCH 2 =.CHCH 2 it 138-9, HC1 194-6 (d) 32 Ph 0 149-51, ftuuarate 160-2 33 I 1 S 141-3, IuCi 191-3 (d) 34 3-CH 3 0 trans. 130-1

cis. 91-2 IIS

36 p-Cl-Ph H to 147-9 37 p-F-Ph It 0 125-7 38 p-C-ci OH3 U fumarate 196-8 (d) 39 It 01 11 II

itPh 0 168-70 41 of S 149-So 42 It3-CH 3 0 43 p-Br-Ph CH3 H S 175-6, HC1 219-20 (d) 44 p-CH 3 -ph 0 ftumarate 195-7 (d)

5400 *5 S.. 0 00 ea S a so S. S S i5 :5 lb a S S S S S S S S S S S 0 0 *S 00 00 'o S 0 S S S S S 555 S S

Nqo. R R2 R3 RI X Mn.P.

Ph-CH 2 CH2 p-CH 3 -Ph Ph H 159-61, HU1 251-4 (d) furnarate 20 5-8 (d) of be 3 -CH 3 l1 H 154-5 'I 2 ,3-di-CH3 -Ph CH3 furnarate 207 -10 (d) lb p-OCH3 -Ph furnarate 185-6 (d) b1 to 'I

Ph 174-6 of 3-CH 3 cis. 140-3 is H oxalate 137-5 (d) lb rn-CF3 -Ph CH3 furnarate 185-6 (d) It Ph furnarate 150-2 (d) it to 151-3

4 -naphthyl CH3 furarate 172-5 (d) H it 0b

is Ph Is so

S I U U

0 5 0 0 to

0 to 000 :5500

No. Ij R4 x_ IM.P. 61 Ph-CH2 CH2 9-naphthyl 3-CH3

62 2-pyridyl 133.5-5.5

63 it 64 3-CH3 it

66 3-pyridyl H 168-70, 2HC1 218-20 (d)

67 2-pyridy1 3-CH 3 68 3-pyridyl it to 69 Ph to it 71 p-CH -Ph-CH 2 CH2 fumarate 175-6 (d) It 72 citrate 183-5 (d)

73 of

74 41

oxalate 163-5 (d)

76 3, 4--di-OCH 3 -Ph-CR 2CH2 fumarate 188-90 (d) 77 3,4,5-tri-OCH. 4--CH2 CH citrate 152-3 (d)

:go S *50 SS* S* S S S 55 S S S oef S* S S S 55* S S

1 9o. -4 M.P. 4. 4- L 4

7R 2-,pyridyl-C 2 CH2 Ph HU 188-90 (d) CH 3 #I

Ph-O-CH 2 CH2 funarate 163-4 (d) Ph-CH (OH) CH 2 Ph

p-C1-Ph-CH (OH)CH2 fumarate 183-5

p-F- Ph-CH (OH) CH 2 p-OCH 3 -Ph-CR (OH)Cc 2

Ph-COCH2 Ph fumarate 160-1 (d) 11 CHR3 141-3, fumarate 177-9 (d) p-Cl-Ph-COCH 2 102-3 of Ph fumarate 184-6 (d) p-F-Ph-COCH 2 iVumarate 165-6 (d) It CH3 fuinarate 182-3 (d) p-OCR 3 -Ph- COCH2 1/2 fumarate 1 iso-C 3 7 0H 141-3 to ,41 0, 0 *00 0 00 eel At no 1 R R _3 R41x1 ,MP 94 p-OCR 3 -Ph-COCH2 Ph 152-5 Rt 3,4, 5-tri-OCH3 -Ph-COCR CR 3 97-9 2 of 11 96 Ph 111-3 97 3, 4-di-OH-Ph-CICR 2 CR3 Hg 102-3 ,fumarate 204-6 (d) 98 p-F-Ph-CO (CR 2 )3~ 154-7 99 p-F-Ph-CO (CR2 2 100 CR CO Ph 210-1 101 Ph-CO 11 '~196-7

102 3,4, 5-tr-OCR 3-Ph-CO 148-51 103 C2 H 5 OCO 70-2 4

:phenyl

:decomposition

I

Claims

The claims defining the invention are as follows: 1. A compound of the formula:
4 X R 3 C-NH-R R1 N R2 or a pharmaceutically acceptable salt thereof, wherein R 1 is an alkyl group having 1 to 4 carbon atoms, an alkenyl ,I group having 2 to 6 carbon atoms, an alkoxycarbonyl group in which the alkoxy moiety has 1 to 4 carbon atoms, a phenoxyalkyl group in which the alkyl moiety has 1 to 4 carbon atoms, a pyridylalkyl group in which the alkyl moiety has 1 to 4 carbon atoms or the group Ar-(B) -(CH n (wherein Ar is a phenyl group or a phenyl group substituted *by 1-3 substituents each selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms and a hydroxyl group; B is -CH(OH)- or m is O(zero) or 1 and n is (zero) or an interger of from 1 to R is an alkyl group having 1 to 6 carbon atoms, an aralkyl group, a phenyl group, a phenyl group substituted by 1-3 substituents each selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms and a trifluoromethyl group, a naphthyl group, a pyridyl group, a furfuryl group or a thenyl group; R 3 is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an aralkyl group, a phenyl group, a phenyl group substituted by 1-3 substituents each selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms and a nitro group, ox' a naphthyl group; R4is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; and X is an oxygen atom or a sulfur atom. 2. A compound of the formula:
R4 X R1 C-NH-R
0
or a pharmaceutically acceptable salt thereof, wherein R is an alkenyl. group having 2 to 6 carbon atoms or an aralkyl .0
group; R is a phenyl group, a phenyl group substituted by
0 1-3 substituents each selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1.to 4 czprbon atoms and a trifluoro- methyl group, or a pyridyl group; R 3is an alkyl group *having 1 to 6 carbon atoms or a phenyl group; R 4 is a 0%.
hydrogen atom or an alkyl group having 1 to 4 carbon atoms; 000
o 0 and X is an oxygen atom or a sulfur atom. A compound of Claim 1: l-methyl-3-phenyl-3- (3-methyl-2-butenyl) -4-piperidylj urea. 4. A compound ol~tClaim 1: 1-methyl-3-phenyl-3- (3-methyl-2-butenyl) -4-piperidyl] thiourea. A compound o3f Claim 1: 1,3-dipbenyl-3-(l-benzyl- 4-piperidyl) thiour a. 6. A compound of Claim 1: l-methyl-3-pheny.-3- (1-phenethyl-4-piperidyl) i'rea. 7. A compound of Claim 1: l-methyl-3-phenyl-3- (1-phenethyl-4-piperidyl) thiourea.
B. A compound of Claim 1: cis-l-methyl-3-phenyl-3-
(1-phenethyl-3-methyl--4-piperidyl) urea. 9. A compound of Claim 1: trans-l-methyl-3-phenyl- 3- (1-phenethyl-3-methyl-4-piperidyl) urea. A compound of Claim 1: l,3-diphenyl-3-(l- phenethyl-4-piperidyl) urea. 11. A compound of claim 1: 1,3-.dipb.enyl-3-(l- phene-thyl-4-piperidyl) thiourea.
12. A compound of Claim 1: cis-1,3-diphenyl-3- (1-phenethyl-3-methyl-4-piperidyl) urea.
13. A compound of Claim 1: trans-1,3-diphenyl-3- (l-phenethyl-3-methyl-4-piperidyl) urea.
14. A compound of Claim 1: 1-methyl-3-p-chloro- phenyl-3- (1-phonethyl-.4-piperidyl) urea.
A compound of Claim 1: 1-methyl-3-p-bromo- phenyl.'3-(l-phenethyl-4-piperidyl)thiourea.
16. A compound of Claim 1: 1-methyl-3-p-tolyl-3-

(1-phenethyl-.4-piperidyl) urea.
17. A compound of Claim 1: 1-methyl-3-p-methoxy- phenyl-3- (1-.henethyl-4-piperidyl) urea.
18. A compound of Claim 1: 1-methyl-3-(3-pyridyl)- 3- (1-phenethyl-4-piperidyl) urea.
19. A metl.cd of producing a compound of the formula:

4 L 3

wherein R1is an alkyl group having I to 4 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkoxycarbonyl group in which the alkoxy moiety has 1 to 4 carbon atoms, a phenoxyalkyl group in which the alkyl moiety has 1 to 4 carbon atoms, a pyridylalkyl group in which the alkyl moiety has 1 to 4 carbon atoms or the group (C 2)n (wherein Ar is a phenyl group or a phenyl group substituted by 1-3 substituents each selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms and a hydroxyl S* group; B is -CH(OH)- or m is 0 (zero) or 1 and n is O (zero) or an interger of from 1 to R2 is an alkyl se: group having 1 to 6 carbon atoms, an aralkyl group, a phenyl group, a phenyl group substituted by 1-3 substituents each selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms and a trifluoromethyl group, a naphthyl group, a pyridyl group, a furfuryl group or a thenyl 3 group; R is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an aralkyl group, a phenyl group, a phenyl group substituted by 1-3 substituents each selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms and a nitro group, or a naphthyl group; R is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; and X is an oxygen atom or a sulfur atom, which comprises: reacting a compound of the formula:

R4

R1 N NH-R22

wherein each symbol is as defined above, with a compound of the formula:

R -N C X

wherein R 3 and X are as defined above, or

(ii) reacting a compound of the formula

R4 X 3 C-NH-R HN N R2 S! wherein each symbol is as defined above, with a compound of the formula: **00 :0 Y

R -Y wherein R is as defined above and Y is a halogen atom or

an alkyl- or aryl- sulfonyloxy group. A pharmaceutical composition comprising at least one compound defined in Claim 1 in combination with

a pharmaceutically acceptable inert carrier or adjuvant,

said compound being useful as analgesics.

DATED thin EIGHTH day of OCTOBER, 1975 *e YOSHITOMI PHARMACEUTICAL INDUSTRIES, LTD.

Patent Attorneys for the Applicant SPRUSON FERGUSON