JPH10511977A - Polyazacycloalkane compounds - Google Patents

Abstract

(57) The present invention relates to a tribenzyl cyclene compound represented by the formula (I) wherein R is hydrogen or a C _1-12 alkyl group which may be substituted with a hydroxy, alkoxy or aryl group. Or R is an amphiphilic aralkyl group containing N, S, O or P separated by a C _2-25 alkylene chain (eg, a polyalkylene oxide chain), or R is a second tribenzylcyclene Provides a bridge to the group, provided that R is not benzyl, X is CHR ₁ , or two X groups may each represent a CO group if R is hydrogen. ₁ is an aralkyl group having hydrogen or hydroxy, alkoxy or optionally substituted C _1-6 alkyl group with a carboxy group, or 1-6 carbons in the alkyl moiety, the aryl moiety is an alkyl, a Kokishi, hydroxy or isothiocyanate group may be substituted.) Relates. These compounds are useful for the preparation of DO3A, N-substituted-1,4,7.10-tetraazacyclododecane-N ', N ", N""-triacetic acid and its phosphonsan analogs.

Description

DETAILED DESCRIPTION OF THE INVENTION                       Polyazacycloalkane compounds Technical field   The present invention relates to a novel polyazacycloalkane compound, a method for producing the same and a macrocyclic chelate And its use in the manufacture of reagents. Background art   In the field of diagnostic medical imaging, complexes of paramagnetic metal ions are widely used as contrast agents. Have been used. Lanthanide metal ions, especially Gd (III) and Dy (III), are the most Effective MR contrast enhancer ensures proper biodistribution and bioremoval after imaging To be administered as a chelate complex with a very high stability constant. Used Some of the available chelating reagents have a linear polyamine structure (eg, Schering GdDTPA products DTPA in the case of Magnevist and Nycomed Imaging's G dDTPA-BMA products DTPA-BMA for Omniscan), other clean The reagent has a macrocyclic polyamine structure (eg, Gudet's GdDOTA product Dot DOTA for arem and ProHance for Squibb's GdHP-D03A product HP-D03A).   1,4,7,10-tetraazacyclododecane of DOTA and HP-DO3A (Cyclcn) polyamine skeleton is a pendant in which three or four ring nitrogens can be ionized Especially stable with metal-metal coordination groups (eg carboxylic acid or phosphonic acid groups) Underlying a Series of Lanthanide-Chelating Macrocyclic Chelans . The lanthanide ion of interest is generally in state III, so it has three of the above acid groups. Cyclen-based chelants provide an opportunity for the formation of charge-neutral or nonionic chelate complexes I will provide a. Various side effects of contrast agent compositions are related to high osmolality, This is important because it has only a low contribution to the overall osmolality of the composition. And   Recently, Schering and Nycomed Salutar described two cyclen rings as bridges between ring nitrogens. "Dimeric" Macrocyclic Chelates with Chelating Agents Linked by Aids Suggested. In general, the remaining ring nitrogens in these chelants have metal-coordinating acid groups. And the resulting complex retains two metal ions, but still has an overall charge Neutral It will be.   Cyclen is a macrocyclic ring in which the ring nitrogen is appropriately substituted after formation of the macrocyclic ring. It is a key intermediate in the production of chelating reagents.   Thus, for example, cyclen can be reacted with bromoacetic acid or its t-butyl ester. In the latter case, followed by ester cleavage to give DOTA (1, 4,7,10-tetraazacyclododecane-N, N ', N ", N" "-tetraacetic acid) Can be manufactured.   However, if one of the ring nitrogens should have a different substituent than the other three, The use of detriment leads to reduced yields due to the formation of undesired N-substituted products. One way to solve this is to mono-substitute cyclen before substituting the remaining three nitrogens. Another method is to replace, for example, a triamine with a monoamine, Monosubstituted siloxanes formed by condensation with one of the two amine reagents that retain the group Starting from Clen (see, for example, Dischino et al. Inorg Chem. 30: 1265 (19 91), Pilchowski et al., Tetrahedron 41: 1956 (1981) and Tweedle et al. A-232 751 and EP-A-292689) for the synthesis of N-monosubstituted cyclenes).   The present invention relates to N, N ', N "-tribenzylcyclene (this compound is Is a novel compound), making a particularly simple and flexible route a triacid-substituted cycle. Based on the discovery that it is provided for the production of chelating reagents including ren. Summary of the Invention   Accordingly, one aspect of the present invention provides a tribenzylcyclene compound of Formula I. Offer. (Formula I) [Where R is hydrogen or substituted with a hydroxy, alkoxy or aryl group. C that may be_1-12An alkyl group or R is C_2-25With an alkylene chain Amphiphilic aralkyl groups containing separated N, S, O or P (eg, polyalkyl Or R represents a second tribenzylcyclene group. To provide crosslinking. Provided that R is not benzyl. X is CHR₁so Or if R is hydrogen, the two X groups may each represent a CO group. R₁Is hydrogen or substituted by hydroxy, alkoxy or carboxy group May be C_1-6Alkyl groups or aralkyl having 1 to 6 carbon atoms in the alkyl moiety And the aryl moiety is alkyl, alkoxy, hydroxy or isothienyl. It may be substituted with an ocyanate group. ] Detailed description of the invention   In Formula I, any alkyl or alkylene moieties are unless otherwise specified. Suitably it contains 1 to 12, preferably 1 to 6 carbons, and the aryl group is Each of them preferably has an optionally substituted phenyl group.   An example of an amphiphilic chain R group is the group L-Ar (-AH) n [where each L is C_2-25-Archi Lenlinker, at least one of which CH_TwoPart is X¹Or group X¹(C H_TwoCH_TwoX¹)_u(U is a positive integer) (for example, X¹CH_TwoCH_TwoX¹, X¹CH_TwoC H_TwoX¹CH_TwoCH_TwoX¹, X¹CH_TwoCH_TwoX¹CH_TwoCH_TwoX¹CH_TwoCH_TwoX¹Etc Substituted, L may be interrupted by a metabolizable group M. However , The terminal of L adjacent to the cyclen ring is CH_TwoAnd the end of L adjacent to Ar The end is X¹Or group X¹CH adjacent to_TwoGroup or X¹From 1CH_TwoDistant CH_TwoBased on (Therefore, for example, the L-Ar bond is L¹-X¹-Ar, L¹-CH_Two-Ar, L¹-X¹CH_Two-Ar or L¹-X¹CH_TwoCH_Two-Can be Ar. Here L¹Is the residue of L Part). Each Ar is substituted with or fused to an additional aryl ring. Is an optionally substituted aryl ring. Each AH is a protonic acid group (preferably an oxyacid such as carbon, sulfur or phosphoroxy Acid)) or a salt thereof. Each X¹Is O, S, NR_TwoOr PR_TwoIt is. Each R_TwoIs hydrogen, alkyl or aryl. n is a positive integer (for example, 1, 2, or 3). ].   When a carbonyl X group is present in a compound of formula I, for example, if the compound is N-linked LvCOCH_TwoOr LvCH_TwoCO group (where Lv is a leaving group such as a halogen atom) If the compound is prepared by a cyclization involving an amine having All X is CH_TwoCan be readily reduced to analogous compounds of formula I   Compounds of formula I wherein R is hydrogen are diamine: diamine or monoamine: tria Can be easily prepared by min cyclization. If carbonyl groups are present, replace them And then reacting the tribenzylcyclene product with non-aqueous An elemental R group can be introduced. Next, debenzylation and carboxymethylation or Is an R-DO3A compound (or its phosphonic acid equivalent) by phosphonomethylation Get. This compound can be further deprotected or R group removed if desired, Then the replacement of the free ring nitrogen by the desired final group, It can be converted to O3A compounds.   A significant advantage of the present invention is the selectivity of the debenzylation step and, for example, Tweedle Higher yields compared to the detosylation required for the substituted DO3A synthesis of Easier isolation of macrocyclic end products and commercial level of debenzylation Is quite easy to implement.   Viewed from another aspect, the present invention relates to DO3A, N-substituted-1,4,7,10-tetra Laazacyclododecane-N ', N ", N1"'-triacetic acid and its phosphonic acids There is provided the use of a compound of formula I for the preparation of an analog.   Viewed from yet another aspect, the present invention provides at least one of the following steps. There is provided a process for preparing a compound of formula I comprising: (A) Diamine of formula II   PhCH_TwoNHCHR₁CHR₁NHCH_TwoPh (II) A diamine of the formula III   YN (CH_TwoPh) CHR₁CHR₁NHY (III) (Where Y is CH_TwoCOLv or COCH_TwoLv, where Lv is a halogen atom or O Ts also Is a leaving group such as an OMs group) to give a compound of formula IV or V (Formula IV) (Formula V) (B) Triamine of formula VI   Z₁NHCHR₁CHR₁N (Z_Two) CHR₁CHR₁NHZ_Three    (VI) To a monoamine of formula VII   Z_FourN (CHR₁COLv)_Two    (VII) And reacting with a compound of formula VIII (Formula VIII) (Here Z₁, Z_Two, Z_ThreeAnd Z_FourOne of them is a hydrogen atom and the other is Is a radical) Get (C) replacing a compound of formula IV, V or VIII with a compound of formula IX (Formula IX) Reduce to (D) replacing a compound of formula IX with a compound of formula X   Lv-R¹    (X) (Where Lv is a leaving group (eg, a halogen atom, an OMs group or an OTs group) R¹Is a group R other than hydrogen, or Lv-R¹Is nucleophilic by amine nitrogen Cyclic or unsaturated compounds which can be substituted to give an N-linked R group other than hydrogen (e.g. Poxide)) React with (E) monoamine of formula XI   LvCHR₁CHR₁NR^TwoCHR₁CHR₁Lv (XI) (Here R^TwoIs a group R or a nitrogen protecting group (eg Ms) Is reacted with a triamine of the formula VI and, if necessary, the resulting tribenzyl cycle R in Len^TwoThe substituted nitrogen is deprotected.   The reagents of formulas II and VI are prepared by converting ethylenediamine or diethylenetriamine to benzyl. Reagent (eg, compound PhCH_TwoLv) or benzaldehyde And reacting the resulting imino product with a catalyst.   The reagent of formula III describes ethylenediamine, for example, for compounds of formulas I and IV. And the benzylamine product is converted to, for example, chloroacetylbutane. Lomid or bromoacetyl chloride or other haloacetyl halide or equivalent Production by acylation by reaction with a double activated acetic acid reagent it can.   The iminodiacetic acid derivative of formula VII can be prepared by conventional carboxylic acid activation methods. You.   The amine substitution and carbonyl reduction of steps (c) and (d) may be necessary As well as possible deprotection steps, it can be performed by conventional means.   Each X is CHR₁The subsequent reaction of a compound of formula I is a standard amine displacement method It can be performed using a debenzylation method.   The debenzylation is carried out, for example, at a hydrogen pressure of 10 to 1000 psi, preferably 30 to 200 pi, 0-200 ° C., preferably 25-120 ° C., palladium / charcoal or platinum / Preferably achieved by catalytic hydrogenation with a conventional hydrogenation catalyst such as C right. Debenzylation is based on Rylander's "Catalytic hydrogeneration over plati num metals ", Academic Press, 1967, pages 449-468.   In contrast, N-substituted -N ', N ", N"'-tritosylcyclene The detosylation reaction used by conventional workers to convert to substituted cyclen is generally Requires a 24 hour treatment with concentrated sulfuric acid at 100 ° C. On a commercial scale, High acid concentration conditions and long reaction times are extremely disadvantageous.   An acid group (eg, carboxymethyl group or phosphonomer) to the debenzylated cyclen The addition of a butyl group can also be accomplished by conventional techniques (eg, bromoacetic acid, t-butyl-bromo). Reaction with acetate or with formaldehyde and phosphonic acid Subsequent removal of protecting groups if necessary and amidation if desired). Can be   Accordingly, the present invention relates to cyclens tri-substituted with acid groups (optionally further May be monosubstituted; for example, DO3A HA-DO3A or other hydroxy Alkyl-DO3A and DO3A-DO3A dimer) in high yield To provide an improved route for   Also, diamine: diamine or monoamine: triamine condensation is used To produce an benzyl-cyclene, substituting its three vacant ring nitrogens, debenzylating, Substitution of a vacant ring nitrogen, if desired, may result in a mono / tri-hetero-substituted system. Clen can be manufactured. Therefore, from this aspect, the present invention provides: In A method for producing a DO3A or DO3A analog chelating reagent comprising the steps of Offer. (1) (a) Diamine of formula XII   Z₁NHCHR_TwoCHR₁NH_Two    (XII) With a diamine of formula XIII   YNZ_TwoCHR₁CHR¹NHY (XIII) (Here R₁And Y are as defined above, and Z₁And Z_TwoOne of which is hydrogen And the other is a benzyl group) Or react with (B) Triamine of formula XIV   Z₁NHCHR₁CHR₁NZ_TwoCHR₁CHR₁NH_Two    (XIV) With a monoamine of the formula XV or XVI   Z_ThreeN (CH_TwoCOLv)_Two        (XV)   Z_ThreeN (CHR₁CHR₁Lv)_Two    (XVI) (Here R₁And Lv are as defined above, and Z₁, Z_TwoAnd Z_ThreeOne of them is A benzyl group and the other two are hydrogen atoms) And react with (C) If necessary, the cyclic dione thus prepared is reduced to give N-benzyl- Get Clen; (2) reacting the N-benzyl-cyclene with an acid group (eg, A ruboxoxymethyl group or a phosphonomethyl group); (3) debenzylating the N-acid substituted product; (4) If desired, the debenzylated product is N-alkylated to give, for example, Introduction of a droxy-alkyl group and the like.   According to the method of the present invention, macrocyclic tetraazacycloalkanes are produced, and if necessary, After the reduction of the ring carbonyl group, the product generally produces the desired chelating reagent. To make it, it will be subjected to N-alkylation. Desired alkyl or substituted The N-alkylation step for introducing an alkyl group into the macrocyclic skeleton is a conventional alkylation step. [For example, alkyl halide R^Two-Hal (where Hal is like chlorine or bromine C Rogen atom, R^TwoMay be substituted with a hydroxy or alkoxy group Alkyl group, carboxamide group, carboxyl group or phosphonic acid group (Optionally protected by an ester group). Which is an alkyl group which may be substituted by Can be. R^TwoIt is convenient for the alkyl moiety to have 1 to 12 carbon atoms. Frequently, it will be preferred that the chelant moiety be on the α or β carbon. protected If a chelant group is introduced in this way, it may be later provided, for example, by ester cleavage. This can be deprotected to make groups available for metallization.   The macrocyclic chelating reagent can be used in either a metallized or non-metallized form. The latter In such a case, for example, it can be used as a therapeutic agent in cancer treatment and the like.   Metallization of the macrocyclic chelating reagent is described, for example, in patent applications relating to MR contrast agents. It can be achieved by conventional methods as described (eg EP-A-71564, EP -A-130934, EP-A-165728, EP-A-258616, WO-A-86 / 06605, etc. When).   The choice of metal ion to complex depends on the intended end use of the chelate complex will do. Metals with atomic numbers 22 to 32, 42 to 44, 49 and 57 to 83 (particularly Gd) Are particularly preferred.   If the chelate compound is used as an MR contrast agent, the chelated metal Species are paramagnetic of transition metals or lanthanides with atomic numbers 21-29, 42, 44 or 57-71 Conveniently, it is a zwitterion. Eu, Gd, Dy, Ho, Cr, Mn and F_eThe complex of Particularly preferred, Gd³⁺, Mn²⁺And Dy³⁺Is a particularly preferred ion. MRI To be used as a contrast agent, it is advantageous if the paramagnetic metal species is non-radioactive. No. Radioactivity is not required and is an undesirable feature.   If the chelate complex is used as an X-ray or ultrasound contrast agent, the metal should be 37 ( Non-radioactive metals having an atomic number greater than 50) (eg Dy³⁺) Such heavy metals are preferred.   If the metal complex is used for scintigraphy or radiotherapy, its chelating gold The genus must of course be radioactive, for example^99mTc or¹¹¹Conventional like In Complexable radioactive isotopes can be used. For radiation therapy, for example,¹⁵³Sm ,⁶⁷Cu or⁹⁰Y and the like can be chelated metals.   All publications mentioned herein are incorporated herein by reference. .   Next, embodiments of the present invention will be described with reference to the following non-limiting examples. Example 1: N-benzylethylenediamine1 And N, N'-dibenzylethylene DiamineTwo   (A) Benzyl chloride and ethylenediamine in a molar ratio of 1: 1 or 2: 1 React in the presence of thorium1 When Two Get.   (B) Benzaldehyde and ethylenediamine in a molar ratio of 1: 1 or 2: 1 Reaction in the presence of group metal (such as Ni, Ru or Pd) and reducing agent (such as hydrogen) ,Respectively 1 When Two Get. Example 2: N, N'-bis (chloroacetyl) -N-benzylethylenediamineThree      (A) 1 (7.53 g, 50.1 mmol) in a 250 mL flask, 55 mL of CH_TwoCl_Two, 16.6g (12 0 mmol) K_TwoCO_ThreeAnd 60 mL of water. Cool the resulting biphasic solution to about 5 ° C. Was. CH_TwoCl_TwoA solution of chloroacetyl chloride (10 mL, 126 mmol) in 50 mL was cooled. The solution was added dropwise while maintaining the temperature at 5 to 10 ° C. Bring the solution to ambient temperature After warming, the aqueous solution was separated and CH 2_TwoCl_Two(2 × 25 mL). Match CH_TwoCl_TwoThe solution was washed with water and concentrated. The resulting oilThree In Example 4 (a ) Used directly.¹³C NMR (CDCl_Three): Δ 38.09, 41.04, 42.38, 45.21 , 51.73, 126.30, 127.70, 128.77, 135.30, 166.66, 168.33.   (B) 3.5 kg of K_TwoCO_ThreeWas dissolved in 10 liters of water at ambient temperature. 10.6 liters to this Turtle CH_TwoCl_TwoAnd 1.6kg1 Was added. The mixture was cooled to 5 ° C. separate And CH_TwoCl_Two12.8 liters of a solution consisting of 3.0 kg of chloroacetyl chloride Prepared. The chloroacetyl chloride solution is added to the cooled mixture Was slowly added while maintaining at 5-10 ° C. After the addition is complete, The mixture was warmed to room temperature. CH_TwoCl_TwoSeparate the phases and replace the aqueous phase with fresh CH_TwoCl_TwoWashed with . CH combined_TwoCl_TwoWas washed with water and used directly in Example 4 (b). (this CH_TwoCl_TwoThe solution volume was 30 liters. ) Example 3: N, N'-bis (bromoacetyl) -N-benzylethylenediamineFour    2L 3-neck round bottom with overhead stirrer, dropping funnel and thermometer Add 69.86 g (0.444 mol) of bromoacetyl chloride to Lasco, 750 mL of CH_TwoCl_Two as well as 62 g (0.449 mol) of K_TwoCO_ThreeWas put. After cooling the mixture to 5-10 ° C, C H_TwoCl_TwoIn 250 mL1 28.99 g (0.193 mol) slowly while maintaining the temperature at about 10 ° C. I added it. The reaction mixture was stirred at 10-15 ° C for 1/2 hour. Then water (25 0 mL) was carefully added to the above cooled mixture (5-10 ° C). Separate the organic layer did. 300 mL CH_TwoCl_TwoAnd combine the organic layers to remove 2 x 300 mL Extracted with water. The organic layer is concentrated and the product4Directly to Example 4 (c) used.¹³C NMR (CDCl_Three): Δ 25.99, 28.74, 38.46, 45.10, 52.26 , 126.30, 128.13, 129.14, 135.36, 166.30, 168.73. Example 4: 1,4,7-tribenzyl-1,4,7,10-tetraaza-2,9-dioxocyclodode CanFive   (A) In a 2 liter flask equipped with a nitrogen inlet and a reflux condenser, add acetonitrile The product of Example 2 (a) dissolved in 300 mL of ril (ACN)Three Was put.Two(10.2g , 42 mmol), Na_TwoCO_Three(70 g, 0.66 mol) and 625 mL of fresh ACN Ko. The mixture was refluxed for 3 days. The mixture is cooled to ambient temperature and A Most of the NC was removed under reduced pressure. 300mL of CH in the residue_TwoCl_TwoAnd water. The organic layer was separated. Change the aqueous layer to new CH_TwoCl_TwoAnd washed. Combine organic layers and remove Washed with water. The organic layer was concentrated. The product is precipitated with ethyl acetate and filtered. Collected by filtration and washed with fresh ethyl acetate.Five(M / e = 471) yield is 67% Was.   (B) 21 liters of CH_TwoCl_TwoFrom the product of Example 2 (b) by atmospheric distillation Removed. Add 21 liters of acetonitrile (ACN) and bring head temperature to 82 ° C Distillation was continued until complete. 120 liters ACN, 6.7 kg anhydrous K_TwoCO_ThreeAnd 2.3 l Turtle'sTwo Was added. The mixture was heated to reflux for 6 hours. 120-130 lit Torr of solvent was removed by distillation. To the residue was added 27 liters of water. That The mixture was cooled to less than 40 ° C. and 53 liters of CH_TwoCl_TwoWas added. Phase separated and water To 8 liters of CH_TwoCl_TwoWas back extracted. Combine the organic phases and add 50 L CH_TwoCl_TwoSteam Removed by distillation. Add 21 liters of ethyl acetate and add another 11 liters of CH_Two Cl_TwoWas removed by distillation. The solution is cooled to 20 ° C and the precipitated product is filtered. Wash with ethyl acetate and dryFive (M / e = 471). 2.5 kg yield (53% yield).   (C) 3 x 2L equipped with overhead stirrer, reflux condenser and thermometer 375 mL of dimethylformamide (DMF) and 50 g of K_TwoCO_ThreeTo I put it. The mixture was heated to 50 ° C. 46.3g (0. (193mol) of N, N'-dibenzylethylenediamine and DMF Product of Example 3Four To the warm potassium carbonate suspension in DMF for 1/2 hour. Added over. The resulting suspension was heated for 6 hours. About 1/2 of DMF is distilled under reduced pressure Removed by After adding 300 mL of deionized water to the solution, 300 mL of CH_TwoCl_Two Was added. The material was transferred to a 2 L separatory funnel and the organic layer was separated. 100m water layer L CH_TwoCl_TwoAnd combine the organic layers and wash with 2 x 150 mL of deionized water. Was. The organic layer was concentrated under reduced pressure. ProductFive Was precipitated with ethyl acetate and filtered. And washed with fresh ethyl acetate.FiveThe yield of (m / e = 471) is 47% Was. Example 5: Tribenzylcyclene6   (A) 1L equipped with reflux condenser, overhead stirrer and nitrogen inlet 10.0 g (0.021 mol) of 3-neck round bottom flaskFive And 72 mL of THF. So Was stirred under nitrogen. After cooling to 5-10 ° C, 176 mL of 1.0 M BH_3. THF was added to the suspension [Note: BH_ThreeDuring the addition of H_TwoThere has occurred]. Got The solution was refluxed under nitrogen for 12 hours. A white solid forms during the course of this reaction. So After cooling the mixture to about 25 ° C., the remaining BH_ThreeTo 64 mL of H_TwoBe careful with O (3.55mol) Quenched deeply [Note: BH_ThreeSignificant H during quench_TwoThere has occurred]. 236mL Of THF was removed under reduced pressure and 25 mL of 12 M HCl (0.3 mol) was poured into the solution. [Note: H during the HCl addition_TwoSeemed to have occurred. The solution is about 3 Warmed to 0 ° C and foamed]. The cloudy acidic mixture is refluxed for 3 hours and is clear and colorless. Was obtained. After cooling the solution to ambient temperature, 25 mL of 50% NaOH aqueous solution  The pH was adjusted to about 14. The product is washed with 120 mL of CH_TwoCl_TwoExtracted. Minute aqueous phase Release, 85 mL of new CH_TwoCl_TwoAnd washed. Combine the organic layers with 2 × 50 mL of H_TwoO And washed. That CH_TwoCl_TwoWas removed under reduced pressure to give 9.4 g of crude product.6 Got . This solid was dissolved in about 40 mL of boiling acetonitrile. The solution slowly And cooled to 0 ° C. The resulting precipitate was collected by filtration and dried to give 6.1 g of a colorless product. Crystalline product of6 (M / e = 443).6The yield ofFive65% based on.   (B) 1L equipped with reflux condenser, overhead stirrer and nitrogen inlet In a three-necked round bottom flask, add 10.0 g (0.021 mol)Five, 7.45 g (0.197 mol) of NaBH_Four And 300 mL of THF. The suspension was stirred under nitrogen. Another flask Then, dissolve 22 g (0.23 mol) of methanesulfonic acid in 100 mL of cooled THF. [Note: dissolution of this acid in THF is an exothermic reaction]. Add the acid solution to the boro It was added slowly to the hydride suspension with stirring [Note: BH_ThreeDuring the addition of H_TwoDeparts I was born. This suspension thickens during the addition of the acid, but some Will be diluted]. The resulting suspension was refluxed under nitrogen for 12 hours. About 25 ℃ After cooling to_ThreeH to 50mL_TwoCarefully quenched with O (2.87mol) [Note: BH_ThreeSignificant H during quench_TwoThere has occurred]. 1/2 of THF under reduced pressure , And then 100 mL of water was added. Most of the remaining THF is removed by distillation After that, 50 mL of 12 M HCl (0.6 mol) was carefully added to the solution. Its acidic The mixture was refluxed for 3 hours. After cooling the solution to ambient temperature, 50% NaOH aqueous solution The pH was adjusted to 12-13 with the liquid. The product was washed with 2 x 125 mL of CH_TwoCl_TwoExtracted in . Combine the organic layers with 3 x 125 mL of H_TwoWashed with O 2. That CH_TwoCl_TwoReduced most of Removal under pressure gave the crude. Dissolve the solid in about 35 mL of boiling acetonitrile. I understand. The solution was slowly cooled to -5C. The resulting precipitate is filtered Collect, dry and colorless crystalline tribenzylcyclene6(M / e = 443) 7.1g was obtained Was. The yield isFive 75% based on.¹H NMR and¹³According to C NMR, The sample was pure. Example 6: 1,14-dibromo-2,13-dioxo-3,12-diaza-6,9-dioxa-tetrade Can7   Dropping funnel, thermometer and N_TwoIn a 500 mL round bottom flask equipped with an inlet tube, 24.8 g (1 60 mmol) bromoacetyl chloride, 300 mL CH_TwoCl_TwoAnd 25g of K_TwoCO_ThreeEnter Was. The suspension was cooled to 5-10 ° C. in an ice bath,_TwoCl_Two2,2 'in 100mL -(Ethylenedioxy) diethylamine 10.1 g (68 mmol) was added dropwise while cooling (Exothermic reaction). After stirring the reaction mixture at ambient temperature for 1 hour, 250 mL of deionized Water was added. The organic layer was separated from the aqueous layer. The aqueous layer was washed with 2 x 200 mL CH_TwoCl_Two And washed. All organic layers were combined and washed with 3 × 250 mL of deionized water. The organic layer was concentrated to dryness and the thick oil solidified to a colorless solid. Its crude Solid7 Was recrystallized from hot ethanol. The resulting crystalline solid is collected, dried,¹ H NMR,¹³Characterized by C NMR and mass spectrometry (m / e = 391).7Yield of 80 %was. Example 7: 1,14-bis (4,7,10-tribenzyl-1.4.7.10-tetraazacyclodide Decyl) -2,13-dioxo-3,12-diaza-6,9-dioxatetradecane8   7Was reacted with 2 equivalents of tribenzylcyclene as follows. Equipped with a reflux condenser 1.5 g (3.4 mmol) of tribenzylcyclene in a 100 mL round-bottomed flask6, 0. 661 g (1.7 mmol)7 And CH_TwoCl_TwoTetramethylguanidine in 50 mL (TM G) 0.39 g (3.4 mmol) was charged. After stirring the reaction mixture at 55 ° C. for 6 hours, Stirred overnight at ambient temperature. Most of the DMF was removed under vacuum. CH_TwoCl_Two/ H_TwoO To afford the product as a thick pale yellow oil.¹H NMR,¹³ C NMR and mass spectrometry data (m / e = 1114) are pure Product8Matched. Example 8: 1,14-bis- (1,4,7,10-tetraazacyclododecyl) -2,13-dioxo So-3,12-diaza-6,9-dioxatetradecane9   (A) Reflux cooler and N_Two1.09 g (0.98 g) in a 100 mL round bottom flask equipped with an inlet mol) of 8, 30 mL of ethanol and 1.133 g of ammonium formate. That The Lasco was purged with nitrogen for 15 minutes and 216 mg of 10% Pd / C was added. The reaction solution Refluxed overnight. Filter the mixture through a bed of celite and concentrate the filtrate This gave a slightly yellow oil.¹H NMR,¹³C NMR and mass spectrometry data (M / e = 573)9Matched.9Was essentially quantitative.   (B) 9.2 g (83 mmol) of 100 ml autoclave pressure reactor8, 50mL Etano And 3 g of 10% Pd / C. The reactor is heated at 80 ° C. for 3 hours and hydrogen Pressurized to psig. The mixture was filtered and the filtrate was concentrated to a slightly yellow oil I got something.¹H NMR,¹³C NMR and mass spectrometry data9Matched.9Income The rates were essentially quantitative. Example 9: 1,14-bis- (4,7,10-tris (carboxymethyl-benzyl ester) Le) -1,4,7,10-tetraazacyclododecyl) -2,13-dioxo-3,12-diaza-6,9- Dioxa TetradecaneTen   1.84 g (3.2 mmol) of 250 mL round bottom flask equipped with a reflux condenser9, 100mL of D MF, 5.99 g (257 mmol) of benzyl bromoacetate and 2.95 g (25.7 mmol) of TMG Was put. The reaction mixture was heated to 55 ° C. for 5 hours. Initial volume of the mixture Was concentrated under reduced pressure to about 1/2 of the above. The reaction is CH_TwoCl_Two/ H_TwoPost-process from O, raw AdultTenWas obtained as a yellow oil contaminated with residual DMF.¹H NMR,¹³C NM R and mass spectrometry data (m / e = 1461)TenMatched. Example 10: 1,14-bis- (4,7,10-tris (carboxymethyl) -1,4,7,10-te Traazacyclododecyl) -2,13-dioxo-3,12-diaza-6,9-dioxatetrade Can11   4.7 g (3.2 mmol) of 10 and 50 mL of 50% TH is added to a 100 mL autoclave pressure reactor. An aqueous F solution and 1 g of 10% Pd / C were charged. The reactor was heated at 80 ° C for 3 hours with water The pressure was increased to 220 psig with hydrogen. The mixture was filtered and the filtrate was concentrated to a slight yellow A colored glassy oil was obtained.¹H NMR,¹³C NMR and mass spectrometry data (m / e = 922)11Matched.11Was essentially quantitative. Example 11: [1,14-bis- (4,7,10-tris (carboxymethyl) -1,4,7,10-te Traazacyclododecyl) -2,13-dioxo-3,12-diaza-6,9-dioxatetrade Can] Gd (III) chelate compound12   344 g (3.7 mmol) of the flask11 And 200 mL of deionized water. 3.01g (7.5 mmol) gadolinium acetate was added at 40 ° C. Remove solvent to 4.55g white Color solid 1Two I got Elemental analysis: C₃₆H₆₂N_TenO_FifteenGd_Two-4.75H_TwoCalculated value for O (Actual value): C 34.71 (34.99); H 5.48 (5.38); N 10.65 (10.77); Gd 2 3.92 (23.88). Example 12: 1,4,7-Tetraazacyclododecane13(Cyclen)   Tribenzyl cyclene (2.0 g, 4.5 mmol), ethanol (50 mL) and 10% Pd / charcoal Element (1.0 g) was charged to a 100 mL autoclave pressure reactor. 80 of that reactor Pressurized to 100 psig with hydrogen for 3 hours. The mixture is filtered to remove the catalyst By concentrating the filtrate, pure in essentially quantitative yield13I got¹³C NMR (D_TwoO): δ 46.30. Example 13: 1,4,7-tris (carboxymethyl-tert-butyl ester) -1,4,7, 10- Te Traazacyclododecane14   35 g (0.20 mol) of cyclen in 600 mL of dimethylacetamide (DMA) and sodium acetate To a mixture of 50 g (0.61 mol) of thorium was added tert-butyl bromoacetate in 150 mL of DMA. (118.9 g, 0.61 mol) was added. The mixture was stirred at ambient temperature for 19 days Later, the precipitated product was collected by filtration. The filtrate is concentrated and the second product I got a crop. Dissolve the combined crop (118.5g) in chloroform and wash with water Was cleaned. The chloroform was removed under reduced pressure. Ethyl acetate in the yellow oil In addition, a white solid was obtained, which was collected by filtration and washed with ether.14 of The yield was 67.4 g (56%).14.HBr¹³C NMR (CDCL_Three): Δ 28.08 , 28.11, 47.41, 49.11, 51.25, 58.06, 80.97, 81.57, 169.52, 170.40. Example 14: 1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclodide DecaneFifteen   About 400 mL of trifluoroacetic acid / CHCl_Three(1: 1), 0.034 mol of14 Added . After stirring at ambient temperature for 1 hour, the solvent was removed under reduced pressure. Repeat this process three times Return to give a yellow oil. The oil was mixed with methanol (15 mL) and And diluted to 1 liter. The precipitated white solid was collected by filtration, dried in vacuo 11.75g (99%)FifteenI got¹³C NMR (D_TwoO): δ 43.00, 48.48, 49.67 , 52.32, 53.94, 56.92, 170.77, 175.35. Example 15: 1,4,7-tris (carboxymethyl) -10- (2-hydroxypropyl ) -1,4,7,10-Tetraazacyclododecane16   To a solution of 194.0 g (0.56 mol) of 15 in 450 mL of water was added NaOH to bring the pH to 12 Adjust to 0.0-12.5 (keep temperature below 30 ° C during addition). This basic solution Propylene oxide (65 g, 1.12 mol) is added to the liquid. After 6 hours at ambient temperature, Excess propylene oxide and solvent are removed under reduced pressure. Minimize the product with minimal methanol From the16In a yield of 96%. Example 16: [1,4,7-tris (carboxymethyl) -10- (2-hydroxypropyl Le) -1,4,7,10-tetraazacyclododecane] gadolinium17   In 100 mL of water16 9.54 g (0.0263 mol) of Gd in a solution of 20.22 g (0.05 mol)_TwoO_Three Add. The suspension is stirred at 95 ° C. for 20 hours. Solvent is removed under vacuum to form Stuff Was recrystallized from methanol / acetone to give a white solid.17 In a yield of 56%. Example 17: [1,4,7-tris (carboxymethyl) -10- (10- (3,5-dicarboxy) Cyphenyl) -decyl) -1,4,7,10-tetraazacyclododecane]18   In a round bottom flask equipped with a reflux condenser, 0.2 mol of tribenzylcyclene (trib enzylcylen), 0.2 mol of 10- (3,5-dicarboxyphenyl) -1-bromodecane 1 liter of DMF and 0.2 mol of tetramethylguanidine (TMG) You. The reaction mixture is stirred at 60-65 ° C for about 12-16 hours. Most of DMF is true Remove under the air. CH_TwoCl_Two/ H_TwoThe post-treatment from O leads to alkylated tribenz Obtain the lucyclene intermediate.   The alkylated tribenzylcyclene intermediate is debenzylated as follows: Approximately 10 mmol of substrate, 50 mL of ethanol and 3 g are added to a 0 mL autoclave pressure reactor. Add 10% Pd / C. The reactor is heated at 80 ° C for 3 hours with hydrogen at 100-200 psig. Press. The mixture was filtered to remove the catalyst, the filtrate was evaporated and 1- [10- (3,5-dicarboxyphenyl) -decyl] -1,4,7,10-tetraazacyclodide Get the decane.   1- [10- (3,5-dicarboxyphenyl) decyl] -1,4,7,10-tetraazacyclo An aqueous solution of sodium chloroacetate (0.16 mol in 500 mL of water) 0.71 mol of sodium chloroacetate in 68 mL of water) is added. The solution was adjusted to pH 9-1. Stir at 80 ° C overnight while maintaining at 0. After cooling to ambient temperature, the pH of the solution is Adjust to 2.5 with aqueous HCl. The resulting precipitate is collected by filtration and Wash and vacuum dry18 Get. Example 18: [1,4,7-tris (carboxymethyl) -10- (2- (1,3,4-trihydr Roxybutyl)]-1,4,7,10-tetraazacyclododecane19   In a round bottom flask equipped with a reflux condenser, 1 liter of acetonitrile, 0.2 mol Tribenzylcyclene and 0.2 mol of 1,4-dihydroxy-2-butene oxide You. The reaction mixture is stirred at 60-65 ° C for about 12-16 hours. Acetonitrile Most are removed under vacuum. CH_TwoCl_Two/ H_TwoPost-treatment from O A cybutyltribenzylcyclene intermediate is obtained.   The trihydroxybutyltribenzylcyclene intermediate was de-bended as follows: About 100 mmol of substrate, 50 mL of ethanol in a 100 mL autoclave pressure reactor. And 3 g of 10% Pd / C. The reactor was heated at 80 ° C for 3 hours and hydrogen Pressurize to 200 psig. The mixture was filtered to remove the catalyst, and the filtrate was evaporated. 1- [2- (1,3,4-trihydroxybutyl)]-1,4,7,10-tetraazacyclodide Get the decane.   1- [2- (1,3,4-trihydroxybutyl)]-1,4,7,10-tetraazacyclodode To an aqueous solution of can (0.16 mol in 500 mL of water) is added an aqueous solution of sodium chloroacetate (68 m 0.71 mol of sodium chloroacetate in L). Bring the solution to pH 9-10 Stir at 80 ° C. overnight while maintaining. After cooling to ambient temperature, the pH of the solution is adjusted to HCl aqueous Adjust to 2.5 with solution. The resulting precipitate is collected by filtration, washed with acetone, Vacuum drying19 Get. Example 19: 1-benzyl-1,4,7,10-tetraaza-2,9-dioxocyclododecane20   2L 3-neck round equipped with overhead stirrer, reflux condenser and thermometer In a bottom flask, 375 mL of dimethylformamide (DMF) and 50 g of K_TwoCO_ThreeEnter It is. Heat the mixture to 50 ° C. Potassium carbonate suspension in the warm DMF Ethylenediamine (0.2mol) diluted to 125mL with DMF and DMF Of Example 3 diluted to 125 mL with4Over 1/2 hour. Obtained suspension Heat the suspension for 6 hours. About 1/2 of DMF is removed by vacuum distillation. 300mL  Of deionized water is added to the solution, then 300 mL of CH 2_TwoCl_TwoAdd. That thing Transfer the mass to a 2 L separatory funnel and separate the organic layer. Transfer the aqueous layer to 100 mL CH_TwoCl_Twoso Wash, combine organic layers and wash with 2 × 150 mL deionized water. Decompress the organic layer Concentrate down. Product20 Was precipitated with ethyl acetate, collected by filtration and fresh Wash with ethyl acetate. Example 20: N-benzylcyclenetwenty one   1L 3 equipped with reflux condenser, overhead stirrer and nitrogen inlet 10.0g (0.021mol) in a round bottom flask20And 72 mL of THF. That blend The mixture is stirred under nitrogen. After cooling to 5-10 ° C, 176 mL of 1.0 M   BH_ThreeAdd .THF. The resulting solution is refluxed under nitrogen for 12 hours. Of this reaction A white solid forms during the process. After cooling the mixture to about 25 ° C., the remaining BH_Three To 64 mL of H_TwoQuench carefully with O (3.55 mol). Reduce 236mL of THF Remove under pressure Afterwards, carefully add 25 mL of 12 M HCl (0.3 mol) to the solution. Its cloudy The acid mixture is refluxed for 3 hours to obtain a clear colorless solution. Bring the solution to ambient temperature After cooling, the pH is adjusted to about 14 with 25 mL of a 50% aqueous NaOH solution. 120 mL CH_TwoCl_TwoExtract with Separate the aqueous layer and add new CH_TwoCl_TwoWash with 85mL . Combine the combined organic layers with 2 x 50 mL of H_TwoWash with O. CH_TwoCl_TwoMost of under pressure To removetwenty oneGet.

[Procedure for Amendment] Article 184-8, Paragraph 1 of the Patent Act [Date of Submission] May 19, 1997 [Content of Amendment] Claims 1. Tribenzylcyclene of formula I. (Formula I) Here, Ph is phenyl. R is not benzyl, but is hydrogen or a C _1-12 alkyl group optionally substituted with a hydroxy, alkoxy or phenyl group, or R is an amphiphilic group L-Ar (-AH) _n (where Each L is a C _2-25 -alkylene linker, of which at least one CH ₂ moiety is substituted by X ¹ or a group X ¹ (CH ₂ CH ₂ X ¹ ) u (where u is a positive integer) . However, the end of the L adjacent to the cyclen ring is assumed to be CH _2, CH the end of the L adjacent Ar away ₂ group 1CH from CH ₂ group or X ¹ adjacent to X ¹ or a group X ¹ ₂ Each Ar is a phenyl ring which may be substituted with or condensed with a further phenyl ring Each AH is an oxyacid or a salt thereof Each X ¹ is O, S, is NR ₂ or PR _2. each R ₂ represents hydrogen, substituted Is phenyl which is also alkyl or substituted been. N are either a positive integer.), Or R provides a bridge to a second tribenzylidene Cie Clen group. When X is CHR ₁ or R is hydrogen, two X groups may each represent a CO group. R ₁ is hydrogen or a C _1-6 alkyl group optionally substituted with a hydroxy, alkoxy or carboxy group, or an aralkyl group having 1 to 6 carbon atoms in the alkyl portion, wherein the aryl portion is an alkyl, alkoxy, A phenyl group which may be substituted with a hydroxy or isothiocyanate group. 2. A compound according to claim 1 every X is CH ₂ group. 3. A process for the preparation of a compound of formula I as defined in claim 1 comprising at least one of the following steps: (A) Diamine of formula II PhCH ₂ NHGHR ₁ CHR ₁ NHCH ₂ Ph (II) (wherein R ₁ and Ph are as defined in claim 1) are converted to diamine of formula III YN (CH ₂ Ph) CHR ₁ CHR ₁ MHY (III) (where Y is CH ₂ COLv or COCH ₂ Lv and Lv is a leaving group) to give a compound of formula IV or V. (Equation IV) and (Equation V) (B) reacting the triamine Z ₁ NHCHR ₁ CHR ₁ N (Z ₂ ) CHR ₁ CHR ₃ NHZ ₃ (VI) of the formula VI with the monoamine Z ₄ N (CHR ₁ COLv) ₂ (VII) of the formula VII, Compound of formula VIII (formula VIII) (Wherein R ₁ is as defined in claim 1, one of Z ₁ , Z ₂ , Z ₃ and Z ₄ is a hydrogen atom and the other is a benzyl group). (C) reducing a compound of formula IV, V or VIII to obtain a compound of formula IX. (Formula IX) However, R ₁ and Ph are as defined in claim 1. (D) reacting a compound of formula IX with a compound of formula X. Lv-R ¹ (X), however, Lv is a leaving group, R ¹ (not benzyl) is hydroxy, alkoxy or substituted optionally substituted in a phenyl group optionally C _1-12 alkyl Or R ¹ is an amphiphilic group L-Ar (-AH) n, wherein each L is a C _2-25 -alkylene linker, wherein at least one CH ₂ moiety is X ¹ or a group X ¹ (CH ₂ CH ₂ X ¹ ) u (u is a positive integer), provided that the terminal of L adjacent to the cyclen ring is CH ₂ and the terminal of L adjacent to Ar assumed is a CH ₃ group or a CH ₂ group apart ₂ group 1CH from X ¹ adjacent to X ¹ or a group X ^1. each Ar is, or is substituted with a further phenyl ring, or a condensed Each AH is an oxyacid or a salt thereof Each X ¹ Is O, S, NN ₂ or PR _2. Each R ₂ is hydrogen, an optionally substituted alkyl or an optionally substituted phenyl, and n is a positive integer. Or R ¹ provides a bridge to a second tribenzylcyclene group, or Lv-R ¹ is a cyclic or unsaturated compound that can be nucleophilically substituted by an amine nitrogen to give an N-linked R ¹ group. is there. (E) reacting the monoamine of the formula XI with the triamine of the formula VI and, if necessary, deprotecting the R ² -substituted nitrogen in the resulting tribenzylcyclene. LvCHR ₁ CHR ₁ NR ² CHR ₁ CHR ₁ Lv (XI) wherein R ² is hydroxy, alkoxy or a C _1-12 alkyl group which may be substituted by phenyl which may be substituted, or R ² is an amphiphilic group L-Ar (-AH) n (where each L is a C _2-25 -alkylene linker, of which at least one CH ₂ moiety is X ¹ or a group X ¹ (CH ₂ CH ₂ X ¹ ) substituted with u (u is a positive integer), provided that the terminal of L adjacent to the cyclen ring is CH ₂ and the terminal of L adjacent to Ar is X ¹ or a group X ¹ assumed to be CH ₂ groups separated ₂ groups 1CH from CH ₂ group or X ¹ adjacent. each Ar is, or is substituted with a further phenyl ring or a phenyl ring optionally fused to it. each AH is an oxyacid or a salt thereof. each X ¹ is , S, is NR ₂ or PR _2. Each R ₂ is hydrogen, phenyl which is also alkyl or substituted optionally be substituted. N is a positive integer.) Or where the nitrogen Is a protecting group. 4. A method for producing a DO3A or DO3A analog chelating reagent, comprising the following steps: (1) a diamine of formula (a) _{XII Z 1 NHCHR 1 CHR 1 NH} 2 (XII) a diamine of Formula _{XIII YNZ 2 CHR 1 CHR 1 NHY} (XIII) ( although, R ₁ and Y are as defined in claim 4 Or _{one of} Z ₁ and Z ₂ is hydrogen and the other is a benzyl group) or (b) a triamine of formula XIV Z ₁ NHCHR ₁ CHR ₁ NZ ₂ CHR ₁ CHR ₁ NH ₂ (XIV) is a monoamine of formula XV or XVI Z ₃ N (CH ₂ COLv) ₂ (XV) Z ₃ N (CHR ₁ CHR ₁ Lv) ₂ (XVI) (where R ₁ and Lv are as defined above) And one of Z ₁ , Z ₂ and Z ₃ is a benzyl group and the other two are hydrogen atoms.) (C) if necessary, the cyclic dione thus produced To give N-benzyl-cyclene. (2) The N-benzyl-cyclene is reacted to introduce a carboxymethyl group or a phosphonomethyl group into the unsubstituted ring nitrogen. (3) The N-acid substituted product is debenzylated. (4) If desired, N-alkylate the debenzylated product. 5. The method according to claim 4, wherein in step (4), the debenzylated product is N-alkylated to introduce a hydroxyalkyl group.

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, S Z, UG), UA (AM, AZ, BY, KG, KZ, MD , RU, TJ, TM), AL, AM, AT, AU, AZ , BB, BG, BR, BY, CA, CH, CN, CZ, DE, DK, EE, ES, FI, GB, GE, HU, I S, JP, KE, KG, KP, KR, KZ, LK, LR , LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, S D, SE, SG, SI, SK, TJ, TM, TR, TT , UA, UG, US, UZ, VN (72) Inventors Bulls, Alan Ray             Pennsylvania, United States             19807, Wayne, 466 Devon Park             Drive, Nycomed Earl and             Dee Inc.

Claims (1)

[Claims] 1. Tribenzylcyclene of formula I. (Formula I) Wherein R is hydrogen or a C _1-12 alkyl group which may be substituted with a hydroxy, alkoxy or aryl group, or R is N, S, O separated by a C _2-25 alkylene chain. Or is an amphiphilic aralkyl group containing P, or R 2 provides a bridge to a second tribenzylcyclene group. Provided that R is not benzyl. When X is CHR ₁ or R is hydrogen, two X groups may each represent a CO group. R ₁ is hydrogen, a C _1-6 alkyl group optionally substituted with a hydroxy, alkoxy or carboxy group, or an aralkyl group having 1 to 6 carbon atoms in the alkyl portion, wherein the aryl portion is an alkyl, alkoxy, , Hydroxy or isothiocyanate groups. 2. The compound according to claim 1, wherein R is an amphiphilic group L-Ar (-AH) n. _Wherein each L is a C _2-25 -alkylene linker, of which at least one CH ₂ moiety is substituted by X ¹ or a group X ¹ (CH ₂ CH ₂ X ¹ ) u (u is a positive integer). And L may be interrupted by a metabolizable group M. However, the ends of L adjacent the cyclen ring is assumed to be CH _2, CH ₂ group terminus of L is a distance ₂ group 1CH from CH ₂ group or X ¹ adjacent to X ¹ or a group X ¹ adjacent to the Ar It is assumed that Each Ar is an aryl ring that may be substituted with or fused to an additional aryl ring. Each AH is a protonic acid group or a salt thereof. Each X ¹ is O, S, NR ₂ or PR ₂ . Each R ₂ is hydrogen, alkyl or aryl. n is a positive integer. 3. A compound according to claim 1 every X is CH ₂ group. 4. A process for the preparation of a compound of formula I as defined in claim 1 comprising at least one of the following steps: (A) a diamine of the formula II PhCH ₂ NHCHR ₁ CHR ₁ NHCH ₂ Ph (II) (wherein R ₁ and Ph are as defined in claim 1) and a diamine of the formula III YN (CH ₂ Ph) CHR ₁ Reaction with CHR ₁ NHY (III), where Y is CH ₂ COLv or COCH ₂ Lv, and Lv is a leaving group, to give a compound of formula IV or V. (Formula IV) (Formula V) (B) reacting the triamine of formula VI Z ₁ NHCHR ₁ CHR ₁ N (Z ₂ ) CHR ₁ CHR ₁ NHZ ₃ (VI) with the monoamine Z ₄ N (GHR ₁ COLv) ₂ (VII) of formula VII Compound of formula VIII (formula VIII) (Wherein R ₁ is as defined in claim 1 and one of Z ₁ , Z ₂ , Z ₃ and Z ₄ is a hydrogen atom and the others are benzyl groups). (C) reducing a compound of formula IV, V or VIII to obtain a compound of formula IX. (Formula IX) However, R ₁ and Ph are as defined in claim 1. (D) reacting a compound of formula IX with a compound of formula X. Lv-R ¹ (X) (provided that, Lv is a leaving group, or R ¹ is a group other than hydrogen R (as defined in claim 1), or lv-R ¹ is determined by an amine nitrogen Cyclic or unsaturated compounds which can be substituted by a nucleus to give an N-bonded R group other than hydrogen (e) reacting a monoamine of the formula XI with a triamine of the formula VI and, if necessary, Deprotect the R ² substituent in Clen LvCHR ₁ CHR ₁ NR ² CHR ₁ CHR ₁ Lv (XI) where R ² is a group R (as defined in claim 1) or a nitrogen protecting group. . manufacturing method of DO3A or DO3A analogues chelating agents include the following listed steps. (1) (a) diamines of XII Z ₁ NHCHR ₁ CHR ₁ diamine NH ₂ (XII) the formula XIII YNZ ₂ CHR ₁ CHR ₁ NHY (XIII) (although, R ₁ and Y are as defined in claim 4 Ri, one of Z ₁ and Z ₂ is hydrogen and the other is a benzyl group.) And is reacted, (b) formula triamine _{XIV Z 1 NHCHR 1 CHR 1 NZ} 2 CHR 1 CHR 1 NH 2 ( XIV) is converted to a monoamine of the formula XV or XVI Z ₃ N (CH ₂ COLv) ₂ (XV) Z ₃ N (CHR ₁ CHR ₁ Lv) ₂ (XVI) (where R ₁ and Lv are as defined in claim 4) And _one of Z ₁ , Z ₂ and Z ₃ is a benzyl group and the other two are hydrogen atoms.) (C) if necessary, the cyclic compound thus produced Dione is reduced to give N-benzyl-cyclene (2) The N-benzyl-cyclene is reacted to introduce an acid group into the unsubstituted ring nitrogen (3) The N-acid-substituted product is removed (4) If desired, N-alkylate the debenzylated product. (4) The method of claim 5, the debenzylated product was then N- alkylated to introduce a hydroxyalkyl group.