Europaisches Patentamt J European Patent Office (p) Publication number: 0 414 422 A2 Office europeen des brevets EUROPEAN PATENT APPLICATION C07D © Application number: 90308785.6 © int. ci.5: C07D 491/10, 498/10, A61K 31/54, //(C07D491/10, @ Date of filing: 09.08.90 31 7:00,221 :00),(C07D498/1 0, 263:00,221 :00) © Priority: 10.08.89 HU 409389 Inventor: Palosi, Eva, Dr. Vend u. 21 (§) Date of publication of application: H-1025 Budapest(HU) 27.02.91 Bulletin 91/09 Inventor: Gro , D ra, Dr. Napraforg u. 17 © Designated Contracting States: H-1021 Budapest(HU) AT BE CH DE DK ES FR GB GR IT LI LU NL SE Inventor: Laszlovszky, Istvan, Dr. Bart k B. u. 16 © Applicant: RICHTER GEDEON VEGYESZETI H-1111 Budapest(HU) GYAR R.T. Inventor: Lapis, Erzsebet, Dr. Gyomroi ut 19-21 Abaliget u. 86 H-1475 Budapest X(HU) H-1173Budapest(HU) Inventor: Sarkadi, Adam, Dr. @ Inventor: T th, Edit Thokoly ut 85 Szabolcska M.U. 1 H-1146 Budapest(HU) H-1114 Budapest(HU) Inventor: Ambrus Andras, Dr. Inventor: Torley, J zsef Lenin krt. 23 Katona J. u. 41 H-1073 Budapest(HU) H-1137Budapest(HU) Inventor: Laszy, Judit, Dr. Inventor: Hegedus, Bela, Dr. Beregsuasz u. 40 Bartok B. u. 82 H-1112 Budapest(HU) H-1113Budapest(HU) Inventor: Szporny, Laszl , Dr. Szabolcska M. u. 7 Representative: Pett, Christopher Phineas et H-1114 Budapest(HU) al Inventor: Kiss, Bela Frank B. Dehn & Co. European Patent Gergely u. 48 Attorneys Imperial House 15-19 Kingsway H-1103 Budapest(HU) London WC2B 6UZ(GB) Q © 2-Oxo-1-oxa-8-azaspiro [4,5] decane derivatives, processes for their preparation and pharmaceutical ^ compositions thereof. <M (M *tf" © The invention relates to 2-oxo-1-oxa-8-azaspiro [4,5] decane derivatives of formula (I), © Q- LU Xerox Copy Centre EP 0 414 422 A2 <cH2)n (I) wherein X represents an oxygen atom or a NR group, wherein R represents a hydrogen atom or a C1-12 alky! or C3-Gcycloalkyl group, or a carbocyclic Cs-ioaryl or carbocylic Cs-ioaryl-Ci-/i.alkyl group optionally substituted on the aromatic ring by one or more halogen atoms, C1 -4. alkyl or C1 -4alkoxy groups; R1 and R2 together represent a methylene group or when X is a >NR group, one of R1 and R2 may additionally represent a hydroxyl group and the other represent a methyl group; Z represents a hydrogen or halogen atom or a trihalomethyl or a C2-^alkanoyl group; and n is 2 or 3; and all optical isomers and mixtures thereof and all acid addition and quartemary ammonium salts thereof. The invention further relates to pharmaceutical compositions containing these compounds and processes for their preparation. The compounds of formula (I) possess psychotropic and antiallergic properties and a low toxicity. Thus, they may be useful for the treatment of psychiatric and allergic diseases. EP 0 414 422 A2 2-OXO-1-OXA-8-AZASPIRO [4,5] DECANE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THEREOF This invention relates to 1-oxa-2-oxo-3,8-diazaspiro [4-5] decane derivatives, processes for their preparation and pharmaceutical preparations thereof. A number of therapeutically useful 2-oxo-1 -oxa-3,8-diazaspiro [4-5] decane derivatives have been described in the literature e.g. C.A. 71 , 91359d (1969); C.A. 78 , 719668t (1973); C.A. 78 , 2387q (1973); DE 5 C.A. 81 , 33153c and 105368b (1974); C.A. 95 , 161765e (1981); as well as in the patent specifications Nos. 27013,729, 2,013, 668, and 2,163,000; irTBE patent specifications Nos. 775,984, 774,170, 786, 631 and 825,444; in the GB patent specification No. 1,100,218; in the published NL patent application No. 7,214,689 as well as in the US patent specifications Nos. 3,555,033, 3,594,386, 4,244,961 and 4,255,432. We have now developed a novel range of compounds based on this ring system but for which the w substituents bound in 4-position and optionally in the 3-position of the spirodecane skeleton are substan- tially different. According to one aspect of the present invention, there are provided compounds of formula (I) 75 20 (CH2)n (I) 25 wherein X represents an oxygen atom or a NR group, wherein 30 R represents a hydrogen atom or a C1-12 alkyl or C3-Gcycloalkyl group, or a carbocyclic Cs-ioaryl or carbocylic C6-ioaryl-Ci-4alkyl group optionally substituted on the aromatic ring by one or more halogen atoms, C1-4. alkyl or Ci-<.alkoxy groups; R1 and R2 together represent a methylene group or when X is a >NR group, one of R1 and R2 may additionally represent a hydroxyl group and the other represent a methyl group; 35 Z represents a hydrogen or halogen atom or a trihalomethyl or C2-4alkanoyl group, and n is 2 or 3; and optical isomers and mixtures thereof and all acid addition and quartemary ammonium salts thereof. The compounds of formula (I) may exist in various stereoisomeric forms such as geometrical isomers as well as racemates, individual optical isomers and their mixtures, all of which may also occur in the form 40 of various solvates and hydrates. All these compounds and mixtures are within the scope of the present invention. According to another aspect of the present invention, there is provided a process for the preparation of compounds of the formula (I) and their acid addition and quaternary ammonium salts, which comprises a) for the preparation of compounds of formula (I) wherein N is a group NR, reacting a 2-oxo-3,8- 45 diazaspiro [4-5] decane derivative of formula (II), 50 EP 0 414 422 A2 (") w wherein R,R1 and R2 are as hereinbefore defined with a phenothiazine derivative of the formula (III), 75 (in) 20 (CH2)n-Y wherein n and Z are as hereinbefore defined and Y represents a halogen atom or a Ci-+alkylsulfonyloxy or arylsulfonloxy group; 25 or b) for the preparation of compounds of formula (I) as defined in process (a) above, reacting a 2-oxo-3,8- diazaspiro [4,5] decane derivative of formula (IV), 30 Y-(CH2)n— N 35 (IV) wherein R, n, R1, R2 and Y are as defined above with a phenothiazine derivative of formula (V), 40 (V) 45 50 wherein Z is as defined above; or c) for the preparation of compounds of formula (I) wherein Ri and R2 together are a methylene group, reacting a compound of formula (VI) 55 EP 0 414 422 A2 <CH2>n (VI) 10 wherein n and Z are as defined above, with an isocyanate of formula R-NCO, wherein R is as defined above, to obtain a 4-carbamoyloxy-4-ethynylpiperdine derivative of the formula (VII), 75 20 y yO-CO-NHR N\_X N ' C=CH 25 (VII) wherein R, n and Z are defined above followed by either; a) for compounds wherein X is a oxygen atom, cyclizing in an acidic medium the compound of the salt formula (VIII), 30 formula (VII) as prepared and defined above and reacting resulting 35 40 0 CH2 (VIII) wherein R, and Z are as defined above with water; 45 n or $) for compounds wherein X is a NR group, cyclizing in a basic medium the compound of formula (VII) as prepared and defined above; or for the of compunds of formula (I) as defined in process (c) (a) above, cyclizing in an 50 d) preparation acidic medium a 4-carbamoyloxy-4-ethynylpiperdine derivative of formula (VII) as defined above and reacting the obtained salt of formula (VIII) as defined above with water; or e) for the preparation of compounds of formula (I) as defined in process (c) (0) above, cyclizing in a basic medium 4-carbamoyloxy-4-ethynylpiperidine derivative of formula (VII) as defined above; 55 a or f) for the preparation of compounds of formula (I) wherein X is a >NR group and one of R1 and R2 is hydroxyl group and the other is a methyl group, reacting a 4-acetyl-4-hydroxypiperidine derivative of EP 0 414 422 A2 formula (X), OH 10 (X) 75 wherein n and Z are as defined above, with an isocyanate of formula R-NCO, wherein R is as defined above, to obtain a 4-acetyl-4-carbamoyloxypiperidine derivative of the formula (IX), 20 0-CO-NHR 25 30 (IX) wherein R, n and Z are as defined above, which is then cyclized; or 35 g) for the preparation of compounds of formula (I) wherein X is a >NR group and one of R1 and R2 is a hydroxyl group and the other is a methyl group, cyclizing a 4-acetyl-4-carbamoyloxypiperdine derivative of formula (IX) as defined above; followed if desired or necessary, by reacting a compound of the formula (I) as prepared above, wherein X is an oxygen atom and R1 and R2 together are a methylene and n and Z are as defined above, with an amine of formula R-NH2, 40 group wherein R is as defined above, in order to prepare a compound of the formula (I), wherein X is a NR group and one of R1 and R2 is a hydroxyl group and the other is a methyl group; and/or if desired or necessary, transforming a functional group of a compound of formula (I) as prepared above into another compound of formula (I) as hereinbefore defined; 45 and/or if desired or necessary, reacting a compound of formula (I) as prepared above with an acid to obtain the acid addition salt thereof and/or reacting with a base salt of a compound of formula (I) as prepared above to liberate the free basic form thereof and/or converting a thus prepared compound of formula (I) into its quaternary ammonium salt.