Patent US5451576A successfully refreshed from Google Patents.
US5451576A
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Tumor imaging and treatment by water soluble texaphyrin metal complexes
Assignee: Pharmacyclics LLC
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Filing: 1993-08-25
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Granted: 1995-09-19
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Expires: 2013-08-25
Abstract
Abstract The present invention involves water soluble hydroxy-substituted texaphyrins retaining lipophilicity, the synthesis of such compounds and their uses. These expanded porphyrin-like macrocycles are efficient chelators of divalent and trivalent metal ions. Various metal (e.g., transition, main group, and lanthanide) complexes of the hydroxy-substituted texaphyrin derivatives of the present invention have unusual water solubility and stability. They absorb light strongly in a physiologically important region (i.e. 690-880 nm). They have enhanced relaxivity and therefore are useful in magnetic resonance imaging. They form long-lived triplet states in high yield and act as photosensitizers for the generation of singlet oxygen. Thus, they are useful for inactivation or destruction of human immunodeficiency virus (HIV-1), mononuclear or other cells infected with such virus as well as tumor cells. They are water soluble, yet they retain sufficient lipophilicity so as to have greater affinity for lipid rich areas such as atheroma and tumors. They may be used for magnetic resonance imaging followed by photodynamic tumor therapy in the treatment of atheroma and tumors. These properties, coupled with their high chemical stability and appreciable solubility in water, add to their usefulness.
Inventors
- 👤 Jonathan L. Sessler
- 👤 Gregory W. Hemmi
- 👤 Tarak D. Mody
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-29 16:43
CPC Classifications
A; A61; A61K; A61K51/00; A61K51/02; A61K51/04; A61K51/0474; A61K51/0485; A61K41/00; A61K41/0038; A61K41/0057; A61K41/0076; A61K41/10; A61K47/00; A61K47/50; A61K47/51; A61K47/54; A61K47/545; A61K47/546; A61K49/00; A61K49/001; A61K49/0013; A61K49/0017; A61K49/0019; A61K49/0021; A61K49/0036; A61K49/005; A61K49/0058; A61K49/04; A61K49/06; A61K49/08; A61K49/10; A61K49/101; A61K49/106; A61K51/08; A61K51/10; A61K51/1093; A61L; A61L2/00; A61L2/02; A61P; A61P35/00; A61P43/00; C; C07; C07D; C07D487/00; C07D487/22; C07H; C07H17/00; C07H17/02; C07H21/00; A61L2103/00; A61L2103/05
Claims Analysis
Total Claims: 28
Claim 1
Independent Claim
208 words
A method of treating a host harboring atheroma, leukemia., lymphoma, sarcoma, or carcinoma comprising: administering to the host as a first agent a water soluble hydroxy-substituted texaphyrin having structure (A); ##STR12## wherein M is a detectable metal; R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, saccharide, carboxyalkyl or carboxyamidealkyl where at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is hydroxyl, oxyhydroxyalkyl, saccharide, oxyalkyl, carboxyalkyl, carboxyamidealkyl or hydroxyalkyl; the molecular weight of any one of R 1 , R 2 , R 3 , R 4 , or R 5 is less than or equal to about 1000 daltons; N is an integer less than or equal to 2; determining localization sites in the host by reference to the detectable metal; administering to the host as a second agent a water soluble hydroxy-substituted texaphyrin having structure (A) wherein M is a diamagnetic metal, and R 1 , R 2 , R 3 , R 4 , R 5 , the molecular weight and N are as described above; and photoirradiating the second agent in proximity to said atheroma, leukemia, lymphoma, sarcoma, or carcinoma.
Claim 2
Independent Claim
208 words
A method of treating a host harboring atheroma, leukemia., lymphoma, sarcoma, or carcinoma comprising: administering to the host as a first agent a water soluble hydroxy-substituted texaphyrin having structure (A); ##STR12## wherein M is a detectable metal; R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, saccharide, carboxyalkyl or carboxyamidealkyl where at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is hydroxyl, oxyhydroxyalkyl, saccharide, oxyalkyl, carboxyalkyl, carboxyamidealkyl or hydroxyalkyl; the molecular weight of any one of R 1 , R 2 , R 3 , R 4 , or R 5 is less than or equal to about 1000 daltons; N is an integer less than or equal to 2; determining localization sites in the host by reference to the detectable metal; administering to the host as a second agent a water soluble hydroxy-substituted texaphyrin having structure (A) wherein M is a diamagnetic metal, and R 1 , R 2 , R 3 , R 4 , R 5 , the molecular weight and N are as described above; and photoirradiating the second agent in proximity to said atheroma, leukemia, lymphoma, sarcoma, or carcinoma.
Claim 3
Independent Claim
149 words
A method of treating a host harboring leukemia, lymphoma, sarcoma, or carcinoma comprising: administering to the host an effective amount of a water soluble hydroxy-substituted texaphyrin having structure (A); ##STR13## wherein: M is a diamagnetic metal; R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, hydroxyl, alkyl hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, saccharide, carboxyalkyl or carboxyamidealkyl where at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is hydroxyl, oxyhydroxyalkyl, saccharide, oxyalkyl, carboxyalkyl, carboxyamidealkyl or hydroxyalkyl; the molecular weight of any one of R 1 , R 2 , R 3 , R 4 , or R 5 is less than or equal to about 1000 daltons; N is an integer less than or equal to 2; and photoirradiating the water soluble hydroxy-substituted texaphyrin in proximity to the leukemia, lymphoma, sarcoma, or carcinoma.
Claim 4
Independent Claim
149 words
A method of treating a host harboring leukemia, lymphoma, sarcoma, or carcinoma comprising: administering to the host an effective amount of a water soluble hydroxy-substituted texaphyrin having structure (A); ##STR13## wherein: M is a diamagnetic metal; R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, hydroxyl, alkyl hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, saccharide, carboxyalkyl or carboxyamidealkyl where at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is hydroxyl, oxyhydroxyalkyl, saccharide, oxyalkyl, carboxyalkyl, carboxyamidealkyl or hydroxyalkyl; the molecular weight of any one of R 1 , R 2 , R 3 , R 4 , or R 5 is less than or equal to about 1000 daltons; N is an integer less than or equal to 2; and photoirradiating the water soluble hydroxy-substituted texaphyrin in proximity to the leukemia, lymphoma, sarcoma, or carcinoma.
Claim 5
Independent Claim
243 words
A method of treating a host harboring atheroma, leukemia, lymphoma, sarcoma, or carcinoma comprising: administering to the host as a first agent a water soluble hydroxy-substituted texaphyrin having structure (A): ##STR14## wherein: M is a detectable metal; R 1 , R 2 , R 3 , R 4 , and R 5 are independently H, OH, C n H.sub.(2n+1) O Y or OC n H.sub.(2n+1) O y where at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is C n H.sub.(2n+1) O Y or OC n H.sub.(2n+1) O y , having at least one hydroxy substituent; the molecular weight of any one of R 1 , R 2 , R 3 , R 4 , or R 5 is less than or equal to about 1000 daltons; n is a positive integer from 1 to 10; y is zero or a positive integer less than or equal to (2n+1); N is an integer less than or equal to 2; determining localization sites in the host by reference to the detectable metal; administering to the host as a second agent a water soluble hydroxy-substituted texaphyrin having structure (A) wherein M is a diamagnetic metal, and R 1 , R 2 , R 3 , R 4 , R 5 , the molecular weight and N are as described above; and photoirradiating the second agent in proximity to said atheroma, leukemia, lymphoma, sarcoma, or carcinoma.
Claim 6
Independent Claim
243 words
A method of treating a host harboring atheroma, leukemia, lymphoma, sarcoma, or carcinoma comprising: administering to the host as a first agent a water soluble hydroxy-substituted texaphyrin having structure (A): ##STR14## wherein: M is a detectable metal; R 1 , R 2 , R 3 , R 4 , and R 5 are independently H, OH, C n H.sub.(2n+1) O Y or OC n H.sub.(2n+1) O y where at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is C n H.sub.(2n+1) O Y or OC n H.sub.(2n+1) O y , having at least one hydroxy substituent; the molecular weight of any one of R 1 , R 2 , R 3 , R 4 , or R 5 is less than or equal to about 1000 daltons; n is a positive integer from 1 to 10; y is zero or a positive integer less than or equal to (2n+1); N is an integer less than or equal to 2; determining localization sites in the host by reference to the detectable metal; administering to the host as a second agent a water soluble hydroxy-substituted texaphyrin having structure (A) wherein M is a diamagnetic metal, and R 1 , R 2 , R 3 , R 4 , R 5 , the molecular weight and N are as described above; and photoirradiating the second agent in proximity to said atheroma, leukemia, lymphoma, sarcoma, or carcinoma.
Claim 7
Independent Claim
141 words
A method of treating a host harboring atheroma comprising: administering to the host an effective amount of a water soluble hydroxy-substituted texaphyrin having structure (A); ##STR15## wherein: M is a diamagnetic metal; R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, saccharide, carboxyalkyl or carboxyamidealkyl where at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is hydroxyl, oxyhydroxyalkyl, saccharide, oxyalkyl, carboxyalkyl, carboxyamidealkyl or hydroxyalkyl; the molecular weight of any one of R 1 , R 2 , R 3 , R 4 , or R 5 is less than or equal to about 1000 daltons; N is an integer less than or equal to 2; and photoirradiating the water soluble hydroxy-substituted texaphyrin in proximity to the atheroma.
Claim 8
Independent Claim
141 words
A method of treating a host harboring atheroma comprising: administering to the host an effective amount of a water soluble hydroxy-substituted texaphyrin having structure (A); ##STR15## wherein: M is a diamagnetic metal; R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, saccharide, carboxyalkyl or carboxyamidealkyl where at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is hydroxyl, oxyhydroxyalkyl, saccharide, oxyalkyl, carboxyalkyl, carboxyamidealkyl or hydroxyalkyl; the molecular weight of any one of R 1 , R 2 , R 3 , R 4 , or R 5 is less than or equal to about 1000 daltons; N is an integer less than or equal to 2; and photoirradiating the water soluble hydroxy-substituted texaphyrin in proximity to the atheroma.
Claim 9
Dependent Claim
25 words
The method of claim 1 or 3 wherein the detectable metal is a paramagnetic metal and determination of localization sites occurs by magnetic resonance imaging.
Claim 10
Dependent Claim
20 words
The method of claim 5 wherein the paramagnetic metal is Gd(III) and the diamagnetic metal is La(III), Lu(III) or In(III).
Claim 11
Dependent Claim
11 words
The method of claim 5 wherein the paramagnetic metal is Gd(III).
Claim 12
Dependent Claim
26 words
The method of claim 1 or 3 wherein the detectable metal is a gamma emitting metal and determination of localization sites occurs by gamma body scanning.
Claim 13
Dependent Claim
23 words
The method of claim 8 wherein the gamma emitting metal is 111 In/III) and the diamagnetic metal is La(III), Lu(III) or In (III).
Claim 14
Dependent Claim
49 words
The method of claim 1 or 3 wherein the first agent is the Gd(III) complex of 4,5-diethyl-10,23-dimethyl -9,24-bis(3-hydroxypropyl)-16,17-(3-hydroxypropyloxy)-13,20,25,26,27-pentaazapentacyclo heptacosa-1,3,5,7,9,11 (27), 12,14 (19), 15,17,20,22 (25), 23-tridecaene and the second agent is the Lu(III), La(III) or In(III) complex of 4,5-diethyl--10,23-di-methyl-9,24-bis(3-hydroxypropyl)-16,17-(3-hydroxypropyl-oxy)-13,20,25,26,27-pentaazapentacyclo {20.2.1.1 3 ,6.1 8 ,11.0 14 ,19 }hepta-cosa-1,3,5,7,9,11 (27),12,14 (19),15,17,20,22 (25),23-tridecaene.
Claim 15
Dependent Claim
62 words
The method of claim 1, 2, or 4 wherein the oxyhydroxyalkyl is C.sub.(n-x) H.sub.((2n+1)-2x) O x O y or OC.sub.(n-x) H.sub.((2n+1)-2x) O x O y where n is a positive integer from 1 to 10; x is zero or a positive integer less than or equal to n; and y is zero or a positive integer less than or equal to ((2n+1)-2x).
Claim 16
Dependent Claim
197 words
The method of claim 1, 2, or 4 wherein the oxyhydroxyalkyl or saccharide is C n H.sub.((2n+1)-q) O y R a q , OC n H.sub.((2n+1)-q) O y R a q or (CH 2 ) n CO 2 R a where n is a positive integer from 1 to 10, y is zero or a positive integer less than ((2n+1)-q), q is zero or a positive integer less than or equal to 2n+1, R a is independently H, alkyl, hydroxyalkyl, saccharide, C.sub.(m-w) H.sub.((2m+1)-2w) O w O z , O 2 CC.sub.(m-w) H.sub.((2m+1)-2w) O w O z or N(R)OCC.sub.(m-w) H.sub.((2m+1)-2w) O w O z , where m is a positive integer from 1 to 10, w is zero or a positive integer less than or equal to m, z is zero or a positive integer less than or equal to ((2m+1)-2w), R is H alkyl hydroxyalkyl or C m H.sub.((2m+1)-r) O z R b r where m is a positive integer from 1 to 10, z is zero or a positive integer less than ((2m+1)-r), r is zero or a positive integer less than or equal to 2m+1, and R b is independently H, alkyl, hydroxyalkyl, or saccharide.
Claim 17
Dependent Claim
178 words
The method of claim 1, 2, or 4 wherein the carboxyamidealkyl is (CH 2 ) n CONHR a , O(CH 2 ) n CONHR a , (CH 2 ) n CON(R a ) 2 , or O(CH 2 ) n CON(R a ) 2 where n is a positive integer from 1 to 10, R a is independently H, alkyl, hydroxyalkyl, saccharide, C.sub.(m-w) H.sub.((2m+1)-2w) O w O z , O 2 CC.sub.(m-w) H.sub.((2m+1)-2w) O w O z or N(R)OCC.sub.(m-w) H.sub.((2m+1)-2w) O w O z , where m is a positive integer from 1 to 10, w is zero or a positive integer less than or equal to m, z is zero or a positive integer less than or equal to ((2m+1)-2w), R is H, alkyl, hydroxyalkyl, or C m H.sub.((2m+1)-r) O z R b r where m is a positive integer from 1 to 10, z is zero or a positive integer less than ((2m+1)-r), r is zero or a positive integer less than or equal to 2m+1, and R b is independently H, alkyl, hydroxyalkyl, or saccharide.
Claim 18
Dependent Claim
224 words
The method of claim 1, 2, or 4 wherein the carboxyalkyl is C n H.sub.((2n+1)-q) O y R c q or OC n H.sub.((2n+1)-q) O y R c q where n is a positive integer from 1 to 10; y is zero or a positive integer less than ((2n+1)-q), q is zero or a positive integer less than or equal to 2n+1, R c is (CH 2 ) n CO 2 R d , (CH 2 ) n CONHR d or (CH 2 ) n CON(R d ) 2 where n is a positive integer from 1 to 10; R d is independently H, alkyl, hydroxyalkyl, saccharide, C.sub.(m-w) H.sub.((2m+1)-2w) O w O z , O 2 CC.sub.(m-w) H.sub.((2m+1)-2w) O w O z or N(R)OCC.sub.(m-w) H.sub.((2m+1)-2w) O w O z , where m is a positive integer from 1 to 10, w is zero or a positive integer less than or equal to m, z is zero or a positive integer less than or equal to ((2m+1) -2w), R is H alkyl hydroxyalkyl or C m H.sub.((2m+1)-r) O z R b r where m is a positive integer from 1 to 10, z is zero or a positive integer less than ((2m+1)-r), r is zero or a positive integer less than or equal to 2m+1, and R b is independently H, alkyl, hydroxyalkyl, or saccharide.
Claim 19
Dependent Claim
22 words
The method of claim 1, 2, 3, or 4 wherein the photoirradiating is at a wavelength of about 730 to 770 nanometers.
Claim 20
Dependent Claim
16 words
The method of claim 1, 2, 3, or 4 wherein the photoirradiating is from laser light.
Claim 21
Dependent Claim
18 words
The method of claim 1, 2, 3, or 4 wherein the diamagnetic metal is In(III), La(III) or Lu(III).
Claim 22
Dependent Claim
28 words
The method of claim 2 or 4 wherein the texaphyrin is the lanthanum or lutetium complex of 4,5-diethyl-10,23-di-methyl-9,24bis (3-hydroxypropyl)-16,17-(3-hydroxypropyloxy)-13,20,25,26,27pentaazapentacyclo {20.2.1.1 3 ,6.1 8 ,11.0 14 ,19 }heptacosa-1,3,5,7, 9,11(27),12,14(19),15,17,20,22(25),23-tridecaene.
Claim 23
Dependent Claim
28 words
The method of claim 1, 2, or 4 where R 1 is hydroxyalkyl; R 2 , R 3 and R 4 are alkyl; and R 5 is oxyalkyl.
Claim 24
Dependent Claim
68 words
The method of claim 19 where the hydroxyalkyl of R 1 is CH 2 CH 2 CH 2 OH, the alkyl of R 2 and R 3 is CH 2 CH 3 , the alkyl of R 4 is CH 3 , and the oxyalkyl of R 5 is O(CH 2 CH 2 O) 2 CH 2 CH 2 OR', where R' is H or CH 3 .
Claim 25
Dependent Claim
11 words
The method of claim 20 where R' is CH 3 .
Claim 26
Dependent Claim
58 words
The method of claim 1 or 3 where the first agent is the Gd(III) complex of 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis-{2-}2-(2-methoxyethoxy)ethoxy}ethoxyl}-13,20,25,26,27 pentaazapentacyclo {10.2.1.1 3 ,6.1 8 ,11.0 14 ,19 }heptacosa-1,3,5,7,9,-11 (27), 12,14 (19), 15,17,20,22 (25), 23-tridecaene and the second agent is the Lu(III) complex of 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis {2-{2- (2-methoxyethoxy) ethoxyethoxy)ethoxy}ethoxy}-13,20,25,26,27-pentaazapentacyclo {20.2.1.1 3 ,6.1 8 ,11.0 14 ,19 }heptacosa-1,3,5,7,9,11 (27), 12,14(19), 15,17,20,22 (25), 23-tridecaene.
Claim 27
Dependent Claim
13 words
The method of claim 1 or 3 where the host is harboring atheroma.
Claim 28
Dependent Claim
19 words
The method of claim 2 or 4 wherein the texaphyrin is the lutetium complex of 4,5-diethyl-10,23-dimethyl-9,24-bis(3- hydroxypropyl)-16,17-bis-13,20,25,26,27-pentaazapentacyclo heptacosa-1, 3,5,7,9,11(27),12,14(19),15,17,20,22(25),23-tridecaene.
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