The United States of America As Represented by the Department of Health

The United States of America

The Government of the United States of America

Glen R Gale

Paul Steven Schwartz

Sandra J Meischen

Marion B Naff

##STR1## where X is Na.sup.+, K.sup.+, Li.sup.+ or H (N-phosphonacetyl-L-asparato) (1,2-diaminocyclohexane)platinum(II) or alkali metal salt thereof has shown antitumor activity in animals such as activity against murine leukemia L1210. Additionally, this agent is used against B-16 and Colon 38 tumors and also Ehrlich ascites tumor. It is effective in dosages of 5-60 mg/kg of body weight and is potentiated in a treatment with cyclophosphamide (CY) (50 mg/kg of body weight) to which may be added hydroxyurea (HU) (1000-1500 mg/kg of body weight). In binary treatment with cis-dichlorodiamine-platinum(II) (or cisplatin) the preferred ratio of the present compound to cisplatin is about 10:1 with a range of about 10:1 to 1:10 in mg/kg of body weight. As to the variations in the formula on the left hand side of the formula, it may be varied as monodentate, such as cisplatin containing a single amine group proceeding from the ring, or bidentate, such as the present compound. The saturated cyclo ring may be C.sub.4 or C.sub.5 -C.sub.7 in addition to the present cyclohexane. The present platinum compound may be prepared by reacting the known L-aspartic acid, N-(phosphonacetyl-)disodium salt (PALA; NSC-224131), with dinitrato(1,2-diaminocyclohexane)platinum(II) (NSC-239851). This compound N-phosphonacetyl-L-asparato (1,2-diaminocyclohexane)platinum(II) may be combined in multiple drug regimen with substantially improved yield cures over the parent compounds. For example, the compound denoted Pt-268 may be combined in a dual regimen with cyclophosphamide (CY), hydroxyurea (HU), and cisplatin.

(N-Phosphonacetyl-L-aspartato) (1,2-diaminocyclohexane)platinum(II) or

##STR1## where X is Na.sup.+, K.sup.+, Li.sup.+ or H (N-phosphonacetyl-L-aspartato)(1,2-diaminocyclohexane)platinum(II) or alkali metal salt thereof has shown antitumor activity in animals such as activity against murine leukemia L1210. Additionally, this agent is used against B-16 and Colon 38 tumors and also Ehrlich ascites tumor. It is effective in dosages of 5-60 mg/kg of body weight and is potentiated in a treatment with cyclophosphamide (CY) (50 mg/kg of body weight) to which may be added hydroxyurea (HU) (1000-1500 mg/kg of body weight). In binary treatment with cis-dichlorodiamine-platinum(II) (or cisplatin) the preferred ratio of the present compound to cisplatin is about 10:1 with a range of about 10:1 to 1:10 in mg/kg of body weight. As to the variations in the formula on the left hand side of the formula, it may be varied as monodentate, such as cisplatin containing a single amine group proceeding from the ring, or bidentate, such as the present compound. The saturated cyclo ring may be C.sub.4 or C.sub.5 -C.sub.7 in addition to the present cyclohexane. The present platinum compound may be prepared by reacting the known L-aspartic acid, N-(phosphonacetyl-) disodium salt (PALA; NSC-224131), with dinitrato(1,2-diaminocyclohexane)platinum(II) (NSC-239851). This compound N-phosphonacetyl-L-aspartato(1,2-diaminocyclohexane)platinum(II) may be combined in multiple drug regimen with substantially improved yield cures over the parent compounds. For example, the compound denoted Pt-268 may be combined in a dual regimen with cyclophosphamide (CY), hydroxyurea (HU), and cisplatin.

(N-Phosphonacetyl-L-aspartato)(1,2-diaminocyclchexane)platinum(II) or

##STR1## 4-Carboxyphthalato(1,2-diaminocyclohexane)platinum(II) (and alkali metal salts thereof) has shown antileukemic activity in mice against murine leukemia L1210. It is effective in dosages of 5-60 mg/kg of body weight and is potentiated in a treatment with cyclophosphamide (CY) (50 mg/kg of body weight) to which may be added 5-fluorouracil (5-FU) (75 mg/kg of body weight) or hydroxyurea (HU) (1000 mg/kg of body weight). Some previous platinum chelate compounds show dosage limitation due to renal impairment but the free carboxyl of the present Pt compound offers a possible route of oral administration and absorption by the stomach. The Pt compound may be prepared by reacting the known dichloro(1,2-diaminocyclohexane)platinum(II) (NSC 194814) with silver nitrate to replace chloro with nitro. Subsequently, benzene tricarboxylic acid is added to form an off-white precipitate (2 hrs, dark, 5.degree. C.) of the desired product which is preferably utilized as the alkali metal salt. The 4-carboxyphthalato(1,2-diaminocyclohexane)platinum(II) and alkali metal salts thereof may be combined in multiple drug regimen with substantially improved yield cures over the parent compound. For example, the compound denoted Pt-307 may be combined in a dual regimen with cyclophosphamide (CY) and in a triple drug regimen of Pt-307 plus cyclophosphamide (CY) and either 5-fluorouracil (5-FU) or hydroxyurea (HU) as the third component. Additionally, the present compound (NSC 271674) has shown superior results in testing for renal toxicity against the parent compound (NSC 119875, cis-dichlorodiamino platinum II) and further the present compound appears to be active against strains of murine leukemia wherein the same NSC 119875 has exhausted its activity.

Use of 4-carboxy-phthalato(1,2-diaminocyclohexane)-platinum (II) and

Use of 4-carboxy-phthalato(1,2-diaminocyclohexane)-platinum(II) and

##STR1## Y=H, alk met 4-Carboxyphthalato(1,2-diaminocyclohexane) platinum(II) (and alkali metal salts thereof) has shown antileukemic activity in mice against murine leukemia L1210. It is effective in dosages of 5-60 mg/kg of body weight and is potentiated in a treatment with cyclophosphamide (CY) (50 mg/kg of body weight) to which may be added 5-fluorouracil (5-FU) (75 mg/kg of body weight) or hydroxyurea (HU) (1000 mg/kg of body weight). Some previous platinum chelate compounds show dosage limitation due to renal impairment but the free carboxyl of the present Pt compound offers a possible route of oral administration and absorption by the stomach. The Pt compound may be prepared by reacting the known dichloro(1,2-diaminocyclohexane) platinum(II) (NSC 194814) with silver nitrate to replace chloro with nitro. Subsequently, benzene tricarboxylic acid is added to form an off-white precipitate (2 hrs, dark, 5.degree. C.) of the desired product which is preferably utilized as the alkali metal salt. The 4-carboxyphthalato(1,2-diaminocyclohexane)-platinum(II) and alkali metal salts thereof may be combined in multiple drug regimen with substantially improved yield cures over the parent compound. For example, the compound denoted Pt-307 may be combined in a dual regimen with cyclophosphamide (CY) and in a triple drug regimen of Pt-307 plus cyclophosphamide (CY) and either 5-fluorouracil (5-FU) or hydroxyurea (HU) as the third component. Additionally, the present compound (NSC 271674) has shown superior results in testing for renal toxicity against the parent compound (NSC 119875, cis-dichlorodiamino platinum II) and further the present compound appears to be active against strains of murine leukemia wherein the same NSC 119875 has exhausted its activity.

Use of 4-carboxy-phthalato-(1,2-diaminocyclohexane)-platinum(II) and

4-Carboxy-phthalato(1,2-diaminocyclohexane)-platinum(II) and alkali

Organoplatinum complexes having antineoplastic activity against the L1210 mouse leukemia test system and having sufficient water-solubility for use in aqueous i.v. fluids. The organoplatinum complexes include malonato (1,2-diaminocyclohexane) platinum (II), hydroxymalonato (1,2-diaminocyclohexane) platinum (II), dinitrato (1,2-diaminocyclohexane) platinum (II), sulfato (1,2-diaminocyclohexane) platinum (II), and hydroxonitrato (1,2-diaminocyclohexane) platinum (II).

1,2-Diaminocyclohexane platinum (II) complexes having antineoplastic

##STR1## 4-Carboxyphthalato (1,2-diaminocyclohexane)platinum(II) (and alkali metal salts thereof) has shown antileukemic activity in mice against murine leukemia L1210. It is effective in dosages of 5-60 mg/kg of body weight and is potentiated in a treatment with cyclophosphamide (CY) (50 mg/kg of body weight) to which may be added 5-fluorouracil (5-FU) (75 mg/kg of body weight) or hydroxyurea (HU) (1000 mg/kg of body weight). Some previous platinum chelate compounds show dosage limitation due to renal impairment but the free carboxyl of the present Pt compound offers a possible route of oral administration and absorption by the stomach. The Pt compound may be prepared by reacting the known dichloro(1,2-diaminocyclohexane)platinum(II) (NSC 194814) with silver nitrate to replace chloro with nitro. Subsequently, benzene tricarboxylic acid is added to form an off-white precipitate (2 hrs, dark, 5.degree. C) of the desired product which is preferably utilized as the alkali metal salt. The 4-carboxyphthalato(1,2-diaminocyclohexane)-platinum(II) and alkali metal salts thereof may be combined in multiple drug regimen with substantially improved yield cures over the parent compound. For example, the compound denoted Pt-307 may be combined in a dual regimen with cyclophosphamide (CY) and in a triple drug regimen of Pt-307 plus cyclophosphamide (CY) and either 5-fluorouracil (5-FU) or hydroxyurea (HU) as the third component.

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Charleston, SC, United States of America

Glen R Gale