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United States Patent (19) (11 Patent Number: 4,866,206 Bey Et Al

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United States Patent (19) (11 Patent Number: 4,866,206 Bey Et Al United States Patent (19) (11 Patent Number: 4,866,206 Bey et al. (45) Date of Patent: Sep. 12, 1989 54 2-HALOMETHYL DERIVATIVES OF 56) References Cited 2-AMNO ACDS U.S. PATENT DOCUMENTS (75) Inventors: Philippe Bey, Strasbourg; Michel 4,288,601 9/1981 Kollonitsch ................ o 562/561 Jung, Illkirch-Graffenstaden, both of 4,325,961 4/1982 Kolonitsch .... France 4,418,077 11/1983 Bey ................. 4,423,073 12/1983 Gerhart ...... .562/56 73) Assignee: Merrell Dow France et Cie, 4,439,619 3/1984 Bey ...................................... 562/561 Strasbourg, France 4,446,151 5/1984 Gerhart ............................... 562/56 Primary Examiner-Michael L. Shippen (21) Appl. No.: 148,806 Attorney, Agent, or Firm-Louis J. Wille (22 Filed: Jan. 27, 1988 (57) ABSTRACT 2-(Fluoromethyl or chloromethyl)-2,5-diaminopen Related U.S. Application Data tanoic acid, 2-(fluoromethyl or chloromethyl)-2,6- 60 Division of Ser. No. 392,052, Jun. 25, 1982, Pat, No. diaminohexanoic acid, and 2-fluoromethyl-2-amino-5- 4,743,691, which is a continuation-in-part of Ser. No. guanidinopentanoic acid, and certain derivatives 53,937, Jul. 2, 1979, abandoned, which is a continuation thereof, are inhibitors of ornithine decarboxylase. Meth of Ser. No. 814,765, Jul. 11, 1977, abandoned. ods of preparing the compounds and derivatives are 51l Int. Cl." .............................................. CO7C 99/00 also described. 52 U.S.C. .................................................... 562/561 58 Field of Search ................................ 562/561, 574 4 Claims, No Drawings 4,866,206 2 In its first composition of matter aspect, the invention 2-HALOMETHYL DERVATIVES OF 2-AMNO sought to be patented comprehends a pharmacologi ACDS cally active chemical compound of the formula: CROSS-REFERENCE TO RELATED I APPLICATION This is a division of application Ser. No. 392,052 filed z-i-cor June 25, 1982, now U.S. Pat. No. 4,743,691, which is a NHR, continuation-in-part of pending application Serial No. 53,937, filed July 2, 1979, now abandoned, which is a 10 wherein: continuation of application Serial No. 814,765, filed Zisy-guanidinopropyl or RNHCCH)n- wherein Ra July 11, 1977, now abandoned. is hydrogen, (C1-C4)alkylcarbonyl, or the group The present invention relates to 2-(fluoromethyl or chloromethyl)-2,5-diaminopentanoic acid and to 2 (fluoromethyl or chloromethyl)-2,6-diaminohexanoic 15 RCHCO acid, and to derivatives thereof, which compounds in NH2 vivo are inhibitors of ornithine decarboxylase, an en zyme which is involved in polyamine formation in or wherein R1 is (C1-C4)alkyl, benzyl, or p-hydroxyben ganisms. The invention also provides pharmaceutical zyl; compositions comprising said compounds, methods of 20 Y is -CH2F or -CH2Cl; medical treatment using said compounds, and processes Rb is hydrogen or (C1-C4)alkylcarbonyl; and for preparing said compounds. R is hydroxy or (C1-C8)alkoxy; In both eukaryotic and prokaryotic cells, the decar or a pharmaceutically acceptable salt thereof; or boxylation of ornithine to putrescine, a reaction cata an individual optical isomer thereof; with the provisos lyzed by ornithine decarboxylase (ODC), is the first 25 that: step in the biosynthesis of the polyamines known as (a) when A is y-guanidinopropyl, Y is -CH2F, R, is spermidine and spermine. Spermidine is formed by the hydrogen, and R is hydroxy; transfer of an activated aminopropyl moiety from S (b) when Y is -CH2Cl, Z is RNHC(CH2)- wherein Ra is hydrogen and n is 3 or 4, and Rh is hydrogen; adenosyl S-methyl homocysteamine to putrescine, 30 while spermine is formed by the transfer of a second and aminopropyl group to spermidine. Ornithine is formed (c) when R, is (C1-C4)alkylcarbonyl, Z is RNHCCH2 from arginine by the action of arginase. S-Adenosyl )- wherein Ra is hydrogen and n is 3 or 4, and R is S-methyl homocysteamine is formed by the decarboxy hydroxy. lation of S-adenosylmethionine (SAM), a reaction cata As employed herein, "(C1-C4)alkyl ' means a lyzed by the enzyme S-adenosylmethionine decarboxyl 35 straight or branched alkyl group having 1 to 4 carbon ase (SAMDC). In mammals, lysine is also decarboxyl atoms. Examples of (C1-C4)alkyl groups are methyi, ated by ODC. In prokaryotic cells, lysine is decarboxyl ethyl, n-propyl, n-butyl, isopropyl, and tert-butyl. ated by lysine decarboxylase. As employed herein, "(C1-C8)alkoxy ' means a In prokaryotic cells and in plant cells, putrescine can 40 group of the formula -O-alkyl, wherein the alkyl moiety also be biosynthesized via an alternative pathway which is straight or branched and contains from 1 to 8 carbon involves the decarboxylation of arginine by arginine atoms. Examples of (C1-C8)alkoxy groups are methoxy, decarboxylase to yield agmatine and the conversion of propoxy, n-butoxy, tert-butoxy, pentyloxy, and oc agmatine to putrescine. tyloxy. The polyamines, which are found in animal tissues 45 As employed herein, "(C1-C4)alkylcarbonyl' means and microorganisms, are known to play an important a group of the formula role in cell growth and proliferation. The onset of cell growth and proliferation is associated with both a O marked increase in ODC activity and an increase in the -C-alkyl levels of putrescine and the polyamines. Although the 50 exact mechanism of the role of the polyamines in cell wherein the alkyl moiety is straight or branched and growth and proliferation is not known, it appears that contains from 1 to 4 carbon atoms. Examples of (C1-C4 the polyamines may facilitate macromolecular pro )alkylcarbonyl groups are acetyl, propionyl, i-butyroyl, cesses such as DNA, RNA, or protein synthesis. or tert-butyroyl. Since, in eukaryotic cells, putrescine is a precursor of 55 As employed herein, the group represented by the the polyamines spermidine and spermine, blockage of formula R1CH(NH2)CO- is an aminocarboxylic acid the conversion of ornithine to putrescine, such as by residue derived by removing the hydroxy group from inhibition of ODC, will prevent new biosynthesis of the carboxy moiety of the appropriate amino acid, for these polyamines. However, the continuous synthesis of example: glycine, alanine, valine, leucine, isoleucine, these polyamines is not vital to cell viability, provided phenylalanine, or tyrosine. Preferably, amino acid resi the preexisting polyamine pool is maintained above a dues are in the natural or L-configuration. certain critical level. Moreover, total blockage of poly Preferred (C1-C8)alkoxy groups are ethoxy and tert amine biosynthesis by inhibition of ODC will be diffi butoxy. The preferred (C1-C4)alkylcarbonyl group is cult to maintain because of the high turnover rate of this acetyl. enzyme. Nevertheless, we have found that blockage of 65 Illustrative examples of pharmaceutically acceptable the conversion of ornithine to putrescine according to salts of the compounds of Formula I include non-toxic this invention can have beneficial effects in certain cell acid addition salts formed with inorganic acids, such as proliferation situations, to be hereinafter discussed. hydrochloric, hydrobromic, sulfuric, and phosphoric 4,866,206 3. 4 acid, and organic acids, such as methane sulfonic, sali cylic, maleic, malonic, tartaric, citric, cyclamic, and -continued ascorbic acids; and non-toxic salts formed with inor CH2F CHF ganic or organic bases, such as those of alkali metals, for example, sodium, potassium, and lithium, alkaline earth H.Nechn-co-oh H.Nechyl-co-oh metals, for example, calcium and magnesium, light met NHRs NHRs als of Group III A, for example aluminium, organic Va. Vb amines, such as primary, secondary, or tertiary amines, for example, cyclohexylamine, ethylamine, pyridine, CH2Cl CH2Cl methylaminoethanol, ethanolamine, and piperazine. 10 h.Nechin-co-oh H.Nechyn-co-oh The salts are prepared by conventional means. NH, h; When in Formula I, Z is RHN-(CH2)n-, wherein VIIa VIIb. Ra is hydrogen and n is 3, and R is (C1-C8)alkoxy, it is preferable to obtain and purify the compounds in the CH2Cl CH2Cl form of a di-acid addition salt, such as the dihydrochlor 15 H.Nechyl-co-r H.Nechyn-co-r ide salt, since protonation of the sidechain amino group H. H, lessens lactam formation. VIIIa VIIIb. In Formula I, Z is either RHN-(CH2)-, wherein n is 3 or 4, or y-guanidinopropyl. Accordingly, NH CHF (a) when Z is RHN-(CH2)-, the compounds are 20 2-(fluoromethyl or chloromethyl)-2,5-diaminopen H.NCNHechir-co-oh tanoic acid, or derivatives thereof, or 2-(fluoromethyl or chloromethyl)-2,6-diminohexanoic acid, or deriva tives thereof, depending upon whether n is 3 or 4, respectively; and 25 In Formula IIIa, IIIb, Va, Vb, VIIIa and VIIIb, R' is (b) when Z is y-guanidinopropyl, the compound is 2 (C1-C8)alkoxy. In Formula IVa, IVb, Va, and Vb, Ra." fluoromethyl-2-amino-5-guanidinopentanoic acid. is (C1-C4)alkylcarbonyl or R1CH(NH2)CO-, wherein 2-(Fluoromethyl or chloromethyl)-2,5-diaminopen R1 is hydrogen, (C1-C4)alkyl, benzyl, or p-hydroxyben tanoic acid can also be named as 2-(fluoromethyl or zyl. In Formula VIa or VIb, Ra is (C1-C4)alkylcarbo 30 nyl. chloromethyl)-2,5-diaminovaleric acids or as a Preferred embodiments are those represented by For (fluoromethyl or chloromethyl)-ornithine. The abbrevi mula IIa, IIIa, IVa, Va, and VIa. Most preferred em ation "a-MFM" may also be employed to refer to bodiments are those of Formula IIa and Va. a-(fluoromethyl)ornithine. 2-(Fluoromethyl or chlo Illustrative examples of the compounds of Formula I romethyl)-2,6-diaminohexanoic acid can also be named are: as 2-(fluoromethyl or chloromethyl)-2,6-caproic acid or 35 2-fluoromethyl-2,5-diaminopentanoic acid, as a-(fluoromethyl or chloromethyl)lysine. 2 2-fluoromethyl-2,6-diaminohexanoic acid, ethyl 2 Fluoromethyl-2-amino-5-guanidinopentanoic acid can fluoromethyl-2,5-diminopentanoate tert-butyl 2 also be named a-fluoromethylarginine.
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