DE1225649B - Process for the preparation of salts of the nitric acid esters of 7-hydroxyalkylaminoalkyltheophyllines - Google Patents
Process for the preparation of salts of the nitric acid esters of 7-hydroxyalkylaminoalkyltheophyllinesInfo
- Publication number
- DE1225649B DE1225649B DEC25210A DEC0025210A DE1225649B DE 1225649 B DE1225649 B DE 1225649B DE C25210 A DEC25210 A DE C25210A DE C0025210 A DEC0025210 A DE C0025210A DE 1225649 B DE1225649 B DE 1225649B
- Authority
- DE
- Germany
- Prior art keywords
- nitric acid
- salts
- preparation
- acid esters
- straight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 title claims description 14
- 238000000034 method Methods 0.000 title claims description 11
- 150000003839 salts Chemical class 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 10
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 2
- 239000000047 product Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- -1 alkylene radical Chemical class 0.000 description 5
- 239000000006 Nitroglycerin Substances 0.000 description 4
- 229960003711 glyceryl trinitrate Drugs 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- HCYFGRCYSCXKNQ-UHFFFAOYSA-N 2-(1,3-dimethyl-2,6-dioxo-7-purinyl)acetic acid Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CC(O)=O)C=N2 HCYFGRCYSCXKNQ-UHFFFAOYSA-N 0.000 description 3
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 3
- 229960000278 theophylline Drugs 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- LLAPDLPYIYKTGQ-UHFFFAOYSA-N 1-aminoethyl Chemical group C[CH]N LLAPDLPYIYKTGQ-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- POAOYUHQDCAZBD-UHFFFAOYSA-N 2-butoxyethanol Chemical compound CCCCOCCO POAOYUHQDCAZBD-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 206010043087 Tachyphylaxis Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 108010012173 hypophysin Proteins 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- VRZJGNXBSRQZGM-UHFFFAOYSA-N xanthine-8-carboxylic acid Chemical compound N1C(=O)NC(=O)C2=C1N=C(C(=O)O)N2 VRZJGNXBSRQZGM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Verfahren zur Herstellung von Salzen der Salpetersäureester von 7-Hydroxyalkylarninoalkyltheophyllinen Die Erfindung betrifft ein Verfahren zur Herstellung von Salzen der Salpetersäureester von 7-Hydroxyalkylaminoalkyltheophyllinen, das dadurch gekennzeichnet ist, daß man 7-Hydroxyalkylaminoalkyltheophylline der allgemeinen Formel: in der R einen Theophyllinorest, X einen geradkettigen oder verzweigten Alkylenrest mit 2 bis 5 Kohlenstoffatomen in gerader Kette und R1 und R2 Oxyalkylreste mit einer oder mehreren Oxygruppen und geradkettiger oder verzweigter Alkylengruppe bedeuten und R2 außerdem ein Wasserstoffatom oder ein Alkylrest sein kann, in an sich bekannter Weise mit Salpetersäure verestert und gegebenenfalls die erhaltenen Salze in andere Salze umwandelt.Process for the preparation of salts of the nitric acid esters of 7-hydroxyalkylaminoalkyltheophyllines in which R is a theophyllino radical, X is a straight-chain or branched alkylene radical with 2 to 5 carbon atoms in a straight chain and R1 and R2 are oxyalkyl radicals with one or more oxy groups and straight-chain or branched alkylene groups and R2 can also be a hydrogen atom or an alkyl radical, in itself esterified in a known manner with nitric acid and optionally converts the salts obtained into other salts.
Die als Ausgangsstoffe benötigten 7-Hydroxyalkylaminoalkyltheophylline werden in nicht beanspruchter Weise durch Umsetzen der entsprechenden Halogenalkyltheophylline mit den entsprechenden Hydroxyalkylaminen hergestellt, wobei die Umsetzung vorzugsweise bei erhöhter Temperatur mit oder ohne Zugegensein von Lösungsmitteln durchgeführt wird. The 7-hydroxyalkylaminoalkyltheophyllines required as starting materials are not claimed by reacting the corresponding haloalkyltheophylline prepared with the corresponding hydroxyalkylamines, the reaction being preferred carried out at elevated temperature with or without the presence of solvents will.
Die verfahrensgemäße Veresterung dieser Ausgangsstoffe mit Salpetersäure erfolgt z. B. durch Behandeln mit konzentrierter Salpetersäure, vorzugsweise bei niedrigen Temperaturen, gegebenenfalls in Gegenwart von Schwefelsäure oder anderen die Veresterung mit Salpetersäure unterstützenden Zusätzen. The process of esterification of these starting materials with nitric acid takes place z. B. by treating with concentrated nitric acid, preferably at low temperatures, optionally in the presence of sulfuric acid or others the esterification with additives supporting nitric acid.
In der deutschen Patentschrift 924 085 wurde die Herstellung entsprechender Ester von Oxyalkylxanthinen, wie Oxyalkyltheophyllinen, beschrieben. In the German patent specification 924 085, the production was more corresponding Esters of oxyalkylxanthines, such as oxyalkyltheophyllins, are described.
Ferner ist in der deutschen Patentschrift 1090219 und der deutschen Auslegeschrift 1 100 028 die Herstellung von Salpetersäureestern von Xanthincarbonsäureoxyalkylamiden beschrieben. Alle diese Produkte sind jedoch in Wasser unlöslich und deshalb für die Herstellung von Injektionspräparaten weniger geeignet.Furthermore, in the German patent specification 1090219 and the German Auslegeschrift 1 100 028 the production of nitric acid esters of xanthine carboxylic acid oxyalkylamides described. However, all of these products are insoluble in water and therefore for the production of injection preparations less suitable.
Doch auch sonst sind die Verfahrensprodukte etwa dem bekannten Salpetersäureester des Theophyllin-7-essigsäure-(B-oxyäthyl)-amids und anderen bekannten Verbindungen, wie die pharmakologischen Versuche zeigen, weit überlegen. But otherwise the products of the process are, for example, the well-known nitric acid ester of theophylline-7-acetic acid (B-oxyethyl) amide and other known compounds, as the pharmacological tests show, far superior.
Für die Beurteilung, ob eine Verbindung auch beim Menschen eine erwünschte Erhöhung der Coronar- gefäßdurchblutung hervorruft, ist die in der deutschen Patentschrift 1 090 219 und der deutschen Auslegeschrift 1 100 028 angegebene Messung am isolierten Warmblüterherz nach L a n g e n d o r f f nur sehr bedingt geeignet. Es wurden daher entsprechende Untersuchungen am Ganztier (Kaninchen) durchs geführt. Coronardurchflußmessungen am Kaninchen in der Anordnung nach E. Busch (Arch. exp. For assessing whether a connection is also desirable in humans Increase in coronary causes vascular blood flow is that in the German patent 1 090 219 and the German Auslegeschrift 1 100 028 specified measurement on the isolated Warm-blooded heart is only suitable to a very limited extent according to L n g e n d o r f f. There were therefore appropriate studies on the whole animal (rabbit) carried out. Coronary flow measurements on rabbits in the arrangement according to E. Busch (Arch. exp.
Pathol. Pharm., Bd. 237, 1960, S. 565) zeigen, daß gleiche Gewichtsmengen Nitroglycerin und Verfahrensprodukt nach Beispiel 2 eine etwa gleich starke momentane Steigerung des Coronardurchflusses hervorrufen, daß aber darüber hinaus das Verfahrensprodukt nach Beispiel 2 eine zusätzliche Durchflußsteigerung nach einer Latenzzeit von 10 bis 15 Minuten bewirkt, die sich auf einen längeren Zeitraum erstreckt (vgl. Tabelle I). Bei dem Verfahrensprodukt besteht ein weiterer wichtiger Vorteil darin, daß seine Tachyphylaxie weniger ausgeprägt ist als die des Nitroglycerins.Pathol. Pharm., Vol. 237, 1960, p. 565) show that equal amounts by weight Nitroglycerin and process product according to Example 2 an approximately equally strong momentary Cause an increase in the coronary flow, but also the product of the process according to example 2 an additional increase in flow after a latency period of 10 causes up to 15 minutes, which extends over a longer period of time (see table I). Another important advantage of the process product is that its tachyphylaxis is less pronounced than that of nitroglycerin.
Wie Tabelle I zeigt, hatte der bekannte Salpetersäureester des Theophyllin-7-essigsäure-(ß-oxyäthyl)-amids (deutsche Auslegeschrift 1 100 028) unter den Versuchsbedingungen keinen Einfluß auf die Coronardurchblutung. As Table I shows, the known nitric acid ester of theophylline-7-acetic acid (β-oxyethyl) amide had (German Auslegeschrift 1 100 028) no influence under the test conditions on the coronary blood flow.
Tabelle I
Die an der Maus bestimmte Toxizität des Verfahrensproduktes nach Beispiel 2 erwies sich gleichfalls geringer als diejenige der Vergleichssubstanz (Tabelle II). The toxicity of the process product determined on the mouse Example 2 also proved to be less than that of the comparison substance (Table II).
Tabelle II
Beis-piel 1 6,62 g trockenes 7- [B-(N-Hydroxyäthyl-N-äthylaminoäthyl]-theophyllin werden bei 170 C unter .Feuchtigkeitsausschluß in 33 ml Salpetersäure (d= 1,52) emgerührt und unter weiterem Rühren noch 2 Stunden -bei -17 bis -19°C gehalten. Unter weiterer Kühlung wird das Reaktionsprodukt mit 250 ml wasserfreiem -Äther gefällt, der Niederschlag abgesaugt mit 2 1 wasserfreiem Äther nachgewaschen und in 60 mol -Aceton gelöst. Example 1 6.62 g of dry 7- [B- (N-hydroxyethyl-N-ethylaminoethyl] theophylline) are at 170 C with exclusion of moisture in 33 ml nitric acid (d = 1.52) stirred and kept at -17 to -19 ° C for 2 hours with further stirring. With further cooling, the reaction product is mixed with 250 ml of anhydrous ether precipitated, the precipitate filtered off with suction and washed with 2 liters of anhydrous ether dissolved in 60 mol acetone.
Nach kurzer Zeit kristallisiert das salpetersaure Salz des 7-[B(N-Nitroxyäthyl-N-äthyl)-aminoäthyl] theophyllins aus. Der Niederschlag wird isoliert, mit - -emem Gemisch Aceton-Äther 1:1 gewaschen und im Vakuum getrocknet. Ausbeute 7,5 g, F. 129 bis 130°C (unter Zersetzung). After a short time the nitric acid salt of 7- [B (N-nitroxyethyl-N-ethyl) -aminoethyl] crystallizes out. theophyllins from. The precipitate is isolated with an acetone-ether mixture Washed 1: 1 and dried in vacuo. Yield 7.5 g, m.p. 129 to 130 ° C (below Decomposition).
Beispiel 2 6,94 g trockenes 7-{ß-[N-(1',3'-Dihydroxy-2'-methyl)-propyl-(2')]-aminoäthyl}-theophyllin werden wie im Beispiel 1 mit 33 ml Salpetersäure (d = 1,52) behandelt. Das Reaktionsprodukt wird mit 1 1 wasserfreiem Äther gefällt, die überstehende Flüssigkeit abdekantiert und der Niederschlag zweimal mit je 250 ml wasserfreiem Äther durchgeknetet. Dann wird abgesaugt und der Rückstand in 20 ml 400/0iger Salpetersäure gelöst. Man gibt 100 ml Alkohol zu, filtriert und versetzt mit 100 ml Äther. Example 2 6.94 g of dry 7- {β- [N- (1 ', 3'-dihydroxy-2'-methyl) propyl- (2')] aminoethyl} theophylline are treated as in Example 1 with 33 ml of nitric acid (d = 1.52). The reaction product is precipitated with 1 l of anhydrous ether, the supernatant liquid is decanted off and knead the precipitate twice with 250 ml of anhydrous ether each time. then is suctioned off and the residue is dissolved in 20 ml of 400/0 nitric acid. One gives Add 100 ml of alcohol, filter and add 100 ml of ether.
Beim Stehen über Nacht kristallisiert das salpetersaure Salz des 7-{ß-[N-(1',3'-Dinitroxy-2'-methyl)-.propyl-(2')1-aminoäthyl)-theophyllins aus. Der Niederschlag wird abgesaugt, mit einem Äther-Alkohol-Gemisch (2:1) gewaschen und im Vakuum getrocknet. The nitric acid salt of des crystallizes on standing overnight 7- {β- [N- (1 ', 3'-Dinitroxy-2'-methyl) -. Propyl- (2') 1-aminoethyl) -theophylline. The precipitate is filtered off with suction and washed with an ether-alcohol mixture (2: 1) and dried in vacuo.
Ausbeute 4,3 g, F. 146 bis 148°C (unter Zersetzung). Yield 4.3 g, melting point 146 to 148 ° C. (with decomposition).
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEC25210A DE1225649B (en) | 1961-10-05 | 1961-10-05 | Process for the preparation of salts of the nitric acid esters of 7-hydroxyalkylaminoalkyltheophyllines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEC25210A DE1225649B (en) | 1961-10-05 | 1961-10-05 | Process for the preparation of salts of the nitric acid esters of 7-hydroxyalkylaminoalkyltheophyllines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1225649B true DE1225649B (en) | 1966-09-29 |
Family
ID=7017837
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEC25210A Pending DE1225649B (en) | 1961-10-05 | 1961-10-05 | Process for the preparation of salts of the nitric acid esters of 7-hydroxyalkylaminoalkyltheophyllines |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1225649B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE924085C (en) * | 1953-08-01 | 1955-02-24 | Sagitta Werk G M B H | Process for the preparation of nitric acid esters of oxyalkylxanthines |
| DE1090219B (en) * | 1957-01-28 | 1960-10-06 | Arzneimittelfabrik Krewel Leuf | Process for the preparation of nitric acid esters of dimethylxanthine derivatives |
| DE1100028B (en) * | 1956-03-28 | 1961-02-23 | Arzneimittelfabrik Krewel Leuf | Process for the preparation of nitric acid esters of dialkyl-xanthine-carboxylic acidoxyalkylamides |
-
1961
- 1961-10-05 DE DEC25210A patent/DE1225649B/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE924085C (en) * | 1953-08-01 | 1955-02-24 | Sagitta Werk G M B H | Process for the preparation of nitric acid esters of oxyalkylxanthines |
| DE1100028B (en) * | 1956-03-28 | 1961-02-23 | Arzneimittelfabrik Krewel Leuf | Process for the preparation of nitric acid esters of dialkyl-xanthine-carboxylic acidoxyalkylamides |
| DE1090219B (en) * | 1957-01-28 | 1960-10-06 | Arzneimittelfabrik Krewel Leuf | Process for the preparation of nitric acid esters of dimethylxanthine derivatives |
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