Steroid compounds comprising superoxide dismutase mimic groups and nitric oxide donor groups, and their use in the preparation of medicaments

• US 20060247216A1
• Filed: 10/24/2003
• Published: 11/02/2006
• Est. Priority Date: 10/25/2002
• Status: Abandoned Application

• Current Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem)
• Original Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem)
• Inventors: Haj-Yehia, Abdullah I.
• Application Number:
  US10/532,390
• Publication Number:
  US 20060247216A1
• Time in Patent Office: Days
• US Class Current: 514/149
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/655 Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07J 21/00 Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
• CPC Class Codes: C07J 43/00 Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton

Abstract

The present invention relates to multifunctional steroid compounds combining a steroid component with SOD mimic component and optionally also with NO donor component, and to their use in treating and preventing disorders associated with oxidative stress and free radical injury, or disorders in which treatment with steroids is indicated, whereas such combination increases the efficacy of treatment and reduces side effects associated with steroid treatment. The invention further relates to methods and devices for administering the compounds.

Claims

1. Use of a multifunctional steroid compound comprising

i) a steroid component,

ii) at least one SOD mimic component, and optionally

iii) at least one NO donor component in the preparation of a medicament.

2. Use of a multifunctional steroid compound according to claim 1, comprising

i) a steroid component,

ii) at least one SOD mimic component linked to said steroid component, and

iii) at least one NO donor component linked to said steroid component.

3. Use according to claim 1, wherein said steroid comprises cyclopenta[a]phenantrene, said SOD mimic component comprises an antioxidant reacting with superoxide, and said NO donor comprises a group capable of providing nitric oxide in a form selected from uncharged, free radical, and charged.

4. Use according to claim 1, wherein said SOD mimic component comprises a substituted N-oxide free radical.

5. Use according to claim 4, wherein the N-atom of said N-oxide is a member of 3 to 7 membered heterocyclic ring.

6. Use according to claim 2, wherein said NO donor component comprises a group selected from —

ONO₂, —

ONO, —

SNO, and —

NONOate.

7. Use of a multifunctional steroid compound according to claim 1 in the preparation of a medicament for treating or preventing a disorder selected from the group consisting of disorders associated with oxidative stress and free radical injury, disorders in which treatment with steroids or their analogs is indicated, and disorders in which treatment with a smooth muscle relaxant is indicated.

8. Use of a multifunctional steroid compound according to claim 1 in the preparation of a medicament for treating or preventing a disorder selected from the group consisting of respiratory, pulmonary, cardiovascular, inflammatory, and autoimmune disorders.

9. Use of a multifunctional steroid compound according to claim 1 in the preparation of a medicament for treating or preventing a disorder selected from the group consisting of asthma, chronic bronchitis, bronchiectasis, bronchospasms, emphysema, Chronic Obstructive Pulmonary Diseases (COPDs), bronchial hyperreactivity, respiratory distress syndrome or Chronic Obstructive Airway Disease (COADs), allergic conditions, arthritis, autoimmune hematologic disorders, systemic lupus erythematosus, systemic dermatomyositis, thrombocytopenia, psoriasis, contact dermatitis, atopic dermatitis, exfoliative dermatitis, acne, hirsutism, erythema nodosum, inflamed cysts, discoid lupus, bullous diseases, collagen vascular diseases, malignancies, neoplastic disease, trauma, shock, acute and chronic inflammatory conditions, sarcoidosis, Sweet'"'"'s disease, graft-versus-host disease, multiple sclerosis, Alzheimer diseases, Parkinson'"'"'s diseases, amyotrophic lateral sclerosis, convulsive disorders, AIDS-dementia, disorders related to learning, disorders related to olfaction, disorders related to nociception, cerebral edema, migraine, ophthalmic disorders, chronic adrenal insufficiency, congenital adrenal hyperplasia, gastrointestinal diseases, hepatic diseases, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, renal disease, gastric secretory and peristaltic functions, drug and disease-induced neuropathies and nephropathies, pathological uterine contractions, sinus tachycardia, ischaemic heart disease, angina pectoris, myocardial infarction, congestive heart failure, atherosclerosis, rheumatic disorders, hypertension, arrhythmia, hyperthyroidism, cellular defense impairment, hypercholestemia, Reaven'"'"'s Syndrome, vasculitis, arteritis, endothelial dysfunction-induced diseases, diabetes mellitus, insulin-resistance and glucose intolerance in diabetes, ischemia-reperfusion tissue injury, chemotaxis and phagocytic impairment in immunological disorders, aging-mediated changes, cerebrovascular diseases, thyrotoxicosis, aggregation disorders, fertility conditions and reproductive disorders, menopause, ovarian dysfunction, testicular dysfunction, and penile erection.

10. Use of a multifunctional steroid compound according to claim 1, wherein said steroid compound has formula (4)

optical isomers thereof, salts thereof, and solvates thereof;

wherein is a single or double bond, with the proviso that two double bonds are not adjacent;

R² is —

H, —

ONO, —

ONO₂, —

SNO, —

OH, —

CH₃, —

NONOate, —

OC(O)R⁸ wherein R⁸ is C₁-C₅ alkyl or 5- or 6-member heteroaryl, or R² and R⁷ together form a substituted N-oxide free radical;

R³ is —

H, —

OH, or —

CH₃, or R and R³ together form a heterocyclic ring;

R⁴ is —

H or halogen;

R⁵ is —

H, ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate or a substituted N-oxide free radical;

R⁶ is ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate, and

R^6A, if present, is —

H, or R⁶ and R^6A together form a substituted N-oxide free radical;

R⁷ is —

H, —

ONO, —

ONO₂, —

SNO, —

NONOate, or a substituted N-oxide free radical wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring, which ring is optionally substituted by —

OCOCH₂-PEG wherein said PEG may by optionally coupled to another steroid compound, and which ring is further optionally substituted by or one or more independently selected C₁-C₅ alkyl groups which may be further independently substituted by a group selected from an NO donor component, —

SR¹¹, -halogen, and —

OC(O)R¹³ wherein R¹¹ is C₁-C₅ alkyl and wherein R¹³ is C₁-C₅ alkyl or 5- or 6-member heteroaryl, or R² and R⁷ together form a substituted N-oxide free radical; and

wherein NO donor is a group comprising one of —

ONO₂, —

ONO, —

SNO, and —

NONOate, and wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups which may be may be further independently substituted by an NO donor component.

11. Use according to claim 10, wherein said steroid compound has formula (5)

wherein the R², R³, R⁴, R⁵, R⁶, and R^6A are as defined in claim 10;

R⁹ and R¹⁰ are independently, linear or branched C₁-C₅ alkyl groups, or substituted linear or branched C₁-C₅ alkyl groups wherein the alkyl group is independently substituted by an NO donor or —

OC(O)R⁴, wherein R¹⁴ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

X is —

CH₂—

, —

or —

S—

;

Z is —

CH₂—

or —

CH₂—

CH₂—

;

and PEG is a polyethylene glycol of a molecular weight from about 100 to about 4000.

12. Use according to claim 10, wherein said steroid compound has a formula selected from Ia to Id (below) wherein

R² is —

H, —

ONO, —

ONO₂, —

SNO, —

OH, —

CH₃, —

NONOate, or —

OC(O)R⁸, wherein R⁸ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

R³ is —

H, —

OH, or —

CH₃, or R² and R³ together form a heterocyclic ring;

R⁴ is —

H or halogen;

R⁵ is —

H, ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups;

R⁶ is ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate, and

R^6A, if present, is —

H, or R⁶ and R^6A together form a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups which may be may be further independently substituted by an NO donor component;

R⁷ is —

H, —

ONO, —

ONO₂, —

SNO, —

NONOate, or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring optionally substituted by —

OCOCH₂-PEG or one or more independently selected C₁-C₅ alkyl groups which may be further independently substituted by an NO donor component, —

SR¹¹—

halogen, or —

OC(O)R¹³, wherein R¹¹ is C₁-C₅ alkyl, and wherein

R¹³ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl, or R² and R⁷ together form a substituted N-oxide free radical; and

NO donor is a group comprising one of —

NO₂, —

ONO, —

SNO, and —

NONOate;

wherein at least one of R², R⁵, R⁶, or R⁷ comprises an NO donor; and

wherein at least one of R⁵, R⁶, or R⁷ comprises a substituted N-oxide free radical.

13. Use according to claim 10, wherein said steroid compound has a formula selected from IIa to IId (below) wherein

R² is —

H, —

ONO, —

ONO₂, —

SNO, —

OH, —

CH₃, —

NONOate, or —

OC(O)R⁸, wherein R⁸ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

R³ is —

H, —

OH, or —

CH₃, or R² and R³ together form a heterocyclic ring;

R⁴ is —

H or halogen;

R⁵ is —

H, ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups;

R⁷ is —

H, —

ONO, —

ONO₂, —

SNO, —

NONOate, or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by —

OCOCH₂-PEG or by one or more independently selected C₁-C₅ alkyl groups, wherein said alkyl group may be further independently substituted by an NO donor, —

SR¹¹, -halogen, or —

OC(O)R¹³, wherein R¹¹ is C₁-C₅ alkyl, and wherein R¹³ is C₁-C₅ alkyl or 5- or 6-member heteroaryl;

R⁹ and R¹⁰ are independently, linear or branched C₁-C₅ alkyl groups or substituted linear or branched C₁-C₅ alkyl groups wherein said alkyl group may be substituted by an NO donor or —

OC(O)R¹⁴, wherein R¹⁴ is C₁-C₅ alkyl or 5- or 6-member heteroaryl;

X is —

CH₂—

, —

O—

or —

S—

;

Z is —

CH₂—

or —

CH₂—

CH₂—

;

NO donor is a group comprising one of —

ONO₂, —

ONO, —

SNO, and —

NONOate; and

wherein at least one of R², R⁵, R⁷, R⁹ or R¹⁰ comprises an NO donor.

14. Use according to claim 10, wherein said steroid compound has a formula selected from IIIa to IIId (below) wherein

R¹ is —

H, —

OH, —

OCOCH₂-PEG, linear or branched C₁-C₅ alkyl, linear or branched C₁-C₅ alkyl substituted by an NO donor, —

SR¹¹, -halogen, or —

OC(O)R¹⁵, wherein R¹¹ is C₁-C₅ alkyl wherein R¹⁵ is C₁-C₅ alkyl;

R² is —

H, —

ONO, —

ONO₂, —

SNO, —

OH, —

CH₃, —

NONOate, or —

OC(O)R⁸, wherein R⁸ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

R³ is —

H, —

OH, or —

CH₃, or R and R³ together form a heterocyclic ring;

R⁴ is —

H or halogen;

R⁵ is —

H, ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups;

R⁶ is ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate, and R^6A, if present, is —

H, or R⁶ and R^6A together form a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups, wherein said alkyl may be further substituted by an NO donor, or —

OC(O)R¹², wherein R¹² is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

R⁹ and R¹⁰ are independently, linear or branched C₁-C₅ alkyl groups, or substituted linear or branched C₁-C₅ alkyl groups wherein said alkyl group is

independently substituted by —

ONO, —

ONO₂, —

SNO, —

NONOate or —

OC(O)R¹⁴, wherein R¹⁴ is C₁-C₅ alkyl;

X is —

CH₂—

, or —

S—

;

Z is —

CH₂—

or —

CH₂—

CH₂—

;

wherein an NO donor is a group comprising one of —

ONO₂, —

ONO, —

SNO, and —

NONOate; and

wherein at least one of R¹, R², R⁵, R⁶, R⁹ or R¹⁰ comprises at least one NO donor.

15. Use according to claim 10, wherein said steroid compound has formula a formula selected from IVa to IVd (below) wherein

R¹ is —

H, —

OH, —

OCOCH₂-PEG;

linear or branched C₁-C₅ alkyl;

linear or branched C₁-C₅ alkyl substituted by an NO donor, —

SR¹¹, -halogen, or —

OC(O)R⁵, wherein R¹¹ is C₁-C₅ alkyl, and wherein R¹⁵ is C₁-C₅ alkyl;

R² is —

H, —

ONO, —

ONO₂, —

SNO, —

OH, —

CH₃, —

NONOate, or —

OC(O)R⁸, wherein R⁸ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

R³ is —

H, H, or —

CH₃, or R² and R³ together form a heterocyclic ring;

R⁴ is —

H or halogen;

R⁵ is —

H, ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups;

R⁹ and R¹⁰ are independently, linear or branched C₁-C₅ alkyl groups, or substituted linear or branched C₁-C₅ alkyl groups wherein the said group is independently substituted by an NO donor or —

OC(O)R¹⁴,

wherein R¹⁴ is C₁-C₅ alkyl;

X is —

CH₂—

, —

O—

or —

S—

;

Z is —

CH₂—

or —

CH₂—

CH₂—

;

wherein an NO donor is a group comprising one of —

ONO₂, —

ONO, —

SNO, and —

NONOate; and

wherein at least one of R¹, R², R⁵, R⁹ or R¹⁰ comprises at least one NO donor.

16. Use according to claim 10, wherein said steroid compound has a formula selected from Va to Vd (below) wherein

R³ is —

H, —

OH, or —

CH₃;

R⁴ is —

H or halogen;

R⁵ is —

H, ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups;

R⁶ is ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate,

and R^6A, if present, is —

H, or R⁶ and R^6A together form a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups wherein said alkyl groups may be further substituted by an NO donor, or —

OC(O)R¹², wherein R¹² is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

R⁹ and R¹⁰ are independently, linear or branched C₁-C₅ alkyl groups, or substituted linear or branched C₁-C₅ alkyl groups wherein the alkyl group is independently substituted by an NO donor or —

OC(O)R¹⁴, wherein R¹⁴ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

X is —

CH₂—

, —

O—

or —

S—

;

Z is —

CH₂—

or —

CH₂—

CH₂—

;

wherein an NO donor is a group comprising one of —

ONO₂, —

ONO, —

SNO, and —

NONOate; and

wherein at least one of R⁵, R⁶, R⁹ or R¹⁰ comprises an NO donor.

17. Use according to claim 11, wherein said steroid compound has a formula selected from VIa to VId (above) wherein

R² is —

H, —

ONO, —

ONO₂, —

SNO, —

OH, —

CH₃, —

NONOate, or —

OC(O)R⁸, wherein R⁸ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

R³ is —

H, —

OH, or —

CH₃, or R² and R³ together form a heterocyclic ring;

R⁴ is —

H or halogen;

R⁵ is —

H, ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups;

R⁹ and R¹⁰ are independently, linear or branched C₁-C₅ alkyl groups, or substituted linear or branched C₁-C₅ alkyl groups wherein the alkyl group is independently substituted by an NO donor or —

OC(O)R¹⁴, wherein R¹⁴ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

X is —

CH₂—

, —

O—

or —

S—

;

Z is —

CH₂—

or —

CH₂—

CH₂—

;

wherein an NO donor is a group comprising one of —

ONO₂, —

ONO, —

SNO, and —

NONOate; and

wherein at least one of R², R⁵, R⁹ or R¹⁰ comprises at least one NO donor.

18. Use according to claim 10 wherein R³ is —

H, —

OH, or —

CH₃;

R⁴ is —

H, F, or Cl; and

R⁵ is —

H, ═

O, or —

ONO₂.

19. Use according to claim 11 wherein X is —

CH₂—

or —

O—

, Z is —

CH₂—

, and R⁹ and R¹⁰ are independently methyl or ethyl.

20. Use according to claim 10 wherein R² is —

H or —

ONO₂.

21. Use according to claim 10 wherein R⁶ is ═

O, —

ONO₂, and R^6A, if present, is —

H, or R⁶ and R^6A together form a substituted N-oxide free radical selected from substituted pyrrolidinyloxy N-oxide free radical, substituted piperidinyloxy N-oxide free radical, substituted oxazolidinyloxy N-oxide free radical, substituted oxazinyloxy N-oxide free radical, substituted thiazolidinyloxy N-oxide free radical and substituted thiazinyloxy N-oxide free radical.

22. Use according to claim 10 wherein R⁷ is —

ONO₂ or a substituted N-oxide free radical selected from substituted pyrrolidinyloxy N-oxide free radical, substituted piperidinyloxy N-oxide free radical, substituted oxazolidinyloxy N-oxide free radical, substituted oxazinyloxy N-oxide free radical, substituted thiazolidinyloxy N-oxide free radical and substituted thiazinyloxy N-oxide free radical.

23. Use according to claim 10 wherein said N-oxide free radical is selected from the substituted 5- or 6-member rings of general formulae 3a and 3b

wherein X is —

CH₂—

, —

O—

or —

S—

;

Z is —

CH₂—

or —

CH₂—

CH₂—

;

R¹ is —

H, —

OH, —

OCOCH₂-PEG, linear or branched C₁-C₅ alkyl, linear or branched C₁-C₅ alkyl substituted by —

ONO, —

ONO₂, —

SNO, or —

NONOate or —

OC(O)R¹⁵, wherein R¹⁵ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl; and

R⁹ and R¹⁰ are independently, linear or branched C₁-C₅ alkyl groups, or substituted linear or branched C₁-C₅ alkyl groups, wherein said alkyl group may be is independently substituted by —

ONO, —

ONO₂, —

SNO, —

NONOate or —

OC(O)R¹⁴, wherein R¹⁴ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl.

24. A multifunctional steroid compound comprising

i) a steroid component,

ii) at least one SOD mimic component, and

iii) at least one NO donor component, for use as a medicament.

25. A multifunctional steroid compound according to claim 24, wherein said steroid component is selected from corticosteroids, estrogens, progesterones, androgens, analogs thereof, and derivatives thereof.

26. A method of treating or preventing a disorder selected from the group consisting of asthma, chronic bronchitis, bronchiectasis, bronchospasms, emphysema, Chronic Obstructive Pulmonary Diseases (COPDs), bronchial hyperreactivity, respiratory distress syndrome or Chronic Obstructive Airway Disease (COADs), allergic conditions, arthritis, autoimmune hematologic disorders, systemic lupus erythematosus, systemic dermatomyositis, thrombocytopenia, psoriasis, contact dermatitis, atopic dermatitis, exfoliative dermatitis, acne, hirsutism, erythema nodosum, inflamed cysts, discoid lupus, bullous diseases, collagen vascular diseases, malignancies, neoplastic disease, trauma, shock, acute and chronic inflammatory conditions, sarcoidosis, Sweet'"'"'s disease, graft-versus-host disease, multiple sclerosis, Alzheimer diseases, Parkinson'"'"'s diseases, amyotrophic lateral sclerosis, convulsive disorders, AIDS-dementia, disorders related to learning, disorders related to olfaction, disorders related to nociception, cerebral edema, migraine, ophthalmic disorders, chronic adrenal insufficiency, congenital adrenal hyperplasia, gastrointestinal diseases, hepatic diseases, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, renal disease, gastric secretory and peristaltic functions, drug and disease-induced neuropathies and nephropathies, pathological uterine contractions, sinus tachycardia, ischaemic heart disease, angina pectoris, myocardial infarction, congestive heart failure, atherosclerosis, rheumatic disorders, hypertension, arrhythmia, hyperthyroidism, cellular defense impairment, hypercholestemia, Reaven'"'"'s Syndrome, vasculitis, arteritis, endothelial dysfunction-induced diseases, diabetes mellitus, insulin-resistance and glucose intolerance in diabetes, ischemia-reperfusion tissue injury, chemotaxis and phagocytic impairment in immunological disorders, aging-mediated changes, cerebrovascular diseases, thyrotoxicosis, aggregation disorders, fertility conditions and reproductive disorders, menopause, ovarian dysfunction, testicular dysfunction, and penile erection, in a mammal in need thereof comprising administering to said mammal an effective amount of a a multifunctional steroid compound comprising

i) a steroid component,

ii) at least one SOD mimic component, and optionally

iii) at least one NO donor component.

27. A method according to claim 26, wherein said administration or treatment is selected from the group consisting of topical, oral, and parenteral.

28. A method according to claim 26, wherein said administration or treatment is selected from the group consisting of suppository, by way of injection, and by way of infusion.

29. A method according to claim 26, wherein said multifunctional steroid compound is administered by a route selected from intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, implant, inhalation spray, nasal, vaginal, rectal, sublingual, and urethral.

30. A method according to claim 26, wherein said mammal is human.

31. A multifunctional steroid compound of formula (4)

optical isomers thereof, salts thereof, and solvates thereof;

wherein is a single or double bond, with the proviso that two double bonds are not adjacent;

R² is NO donor, —

H, —

OH, —

CH₃, —

OC(O)R⁸ wherein R⁸ is C₁-C₅ alkyl or 5- or 6-member heteroaryl, or R² and R⁷ together form a substituted N-oxide free radical;

R³ is —

H, —

OH, or —

CH₃, or R² and R³ together form a heterocyclic ring;

R⁴ is —

H or halogen;

R⁵ is —

H, ═

O, NO donor or a substituted N-oxide free radical;

R⁶ is ═

O or NO donor, and

R^6A, if present, is —

H, or R⁶ and R^6A together form a substituted N-oxide free radical;

R⁷ is —

H, NO donor, or a substituted N-oxide free radical wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring, which ring is optionally substituted by —

OCOCH₂-PEG wherein said PEG may by optionally coupled to another steroid compound, and which ring is further optionally substituted by or one or more independently selected C₁-C₅ alkyl groups which may be further independently substituted by a group selected from an NO donor component, —

SR¹¹, -halogen, and —

OC(O)R¹³ wherein R¹¹ is C₁-C₅ alkyl and wherein R¹³ is C₁-C₅ alkyl or 5- or 6-member heteroaryl, or R² and R⁷ together form a substituted N-oxide free radical; and

wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups which may be further independently substituted by an NO donor component; and

wherein said NO donor is a group comprising one of —

ONO₂, —

ONO, —

SNO, and —

NONOate; and

with the proviso that said compound contains at least one N-oxide free radical and at least one NO donor.

32. A multifunctional steroid compound according claim 31, wherein said PEG links two identical structures selected from the group consisting of Ia to Id, IIa to IId, IIIa to IIId, and IVa to IVd.

33. A compound according to claim 32, having formula (5)

wherein the R², R³, R⁴, R⁵, R⁶, and R^6A are as defined in claim 31;

R⁹ and R¹⁰ are independently, linear or branched C₁-C₅ alkyl groups, or substituted linear or branched C₁-C₅ alkyl groups wherein the alkyl group is independently substituted by an NO donor or —

OC(O)R¹⁴, wherein R¹⁴ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

X is —

CH₂—

, —

O—

or —

S—

;

Z is —

CH₂—

or —

CH₂—

CH₂—

;

and PEG is a polyethylene glycol of a molecular weight from about 100 to about 4000.

34. A compound according to claim 31, having a formula selected from Ia to Id (page 106) wherein

R² is —

H, —

ONO, —

ONO₂, —

SNO, —

OH, —

CH₃, —

NONOate, or —

OC(O)R⁸, wherein R⁸ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

R³ is —

H, —

OH, or —

CH₃, or R² and R³ together form a heterocyclic ring;

R⁴ is H or halogen;

R⁵ is —

H, ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups;

R⁶ is ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate, and

R^6A, if present, is —

H, or R⁶ and R^6A together form a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide

 

free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups which may be may be further independently substituted by an NO donor component;

R⁷ is —

H, —

ONO, —

ONO₂, —

SNO, —

NONOate, or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring optionally substituted by —

OCOCH₂-PEG or one or more independently selected C₁-C₅ alkyl groups which may be further independently substituted by an NO donor component, —

SR¹¹—

halogen, or —

OC(O)R¹³, wherein R¹¹ is C₁-C₅ alkyl, and wherein R¹³ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl, or R² and R⁷ together form a substituted N-oxide free radical; and

 

NO donor is a group comprising one of —

ONO₂, —

ONO, —

SNO, and —

NONOate;

wherein at least one of R², R⁵, R⁶, or R⁷ comprises an NO donor; and

wherein at least one of R⁵, R⁶, or R⁷ comprises a substituted N-oxide free radical.

35. A compound according to claim 31, having a formula selected from IIa to IId (page 108) wherein

R² is —

H, —

ONO, —

ONO₂, —

SNO, —

OH, —

CH₃, —

NONOate, or —

OC(O)R⁸, wherein R⁸ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

R³ is —

H, —

OH, or —

CH₃, or R² and R³ together form a heterocyclic ring;

R⁴ is —

H or halogen;

R⁵ is —

H, ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups;

R⁷ is —

H, —

ONO, —

ONO₂, —

SNO, —

NONOate, or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by

 

—

OCOCH₂-PEG or by one or more independently selected C₁-C₅ alkyl groups, wherein said alkyl group may be further independently substituted by an NO donor, —

SR¹¹—

, -halogen, or —

OC(O)R¹³, wherein R¹³ is C₁-C₅ alkyl, and wherein R¹³ is C₁-C₅ alkyl or 5- or 6-member heteroaryl;

R⁹ and R¹⁰ are independently, linear or branched C₁-C₅ alkyl groups or substituted linear or branched C₁-C₅ alkyl groups wherein said alkyl group may be substituted by an NO donor or —

OC(O)R¹⁴, wherein R¹⁴ is C₁-C₅ alkyl or 5- or 6-member heteroaryl;

X is —

CH₂—

, —

O—

or —

S—

;

Z is —

CH₂—

or —

CH₂—

CH₂—

;

NO donor is a group comprising one of —

ONO₂, —

ONO, —

SNO, and —

NONOate; and

wherein at least one of R², R⁵, R⁷, R⁹ or R¹⁰ comprises an NO donor.

36. A compound according to claim 31, having a formula selected from IIIa to IIId (page 110) wherein

R¹ is —

H, —

OH, —

OCOCH₂-PEG, linear or branched C₁-C₅ alkyl, linear or branched C₁-C₂ alkyl substituted by an NO donor, —

SR¹¹, -halogen, or —

OC(O)R¹⁵, wherein R¹¹ is C₁-C₅ alkyl, wherein R¹⁵ is C₁-C₅ alkyl;

R² is —

H, —

ONO, —

ONO₂, —

SNO, —

OH, —

CH₃, —

NONOate, or —

OC(O)R⁸, wherein R⁸ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

R³ is —

H, —

OH, or —

CH₃, or R² and R³ together form a heterocyclic ring;

R⁴ is —

H or halogen;

R⁵ is —

H, ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups;

R⁶ is ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate, and R^6A if present is —

H, or R⁶ and R^6A together form a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups, wherein said alkyl may be further substituted by an NO donor, or —

OC(O)R¹², wherein R¹² is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

R⁹ and R¹⁰ are independently, linear or branched C₁-C₅ alkyl groups, or substituted linear or branched C₁-C₅ alkyl groups wherein said alkyl group is independently substituted by —

ONO, —

ONO₂, —

SNO, —

NONOate or —

OC(O)R¹⁴, wherein R⁴ is C₁-C₅ alkyl

X is —

CH₂—

, —

O—

or —

S—

;

Z is —

CH₂—

or —

CH₂—

CH₂—

;

wherein an NO donor is a group comprising one of —

ONO₂, —

ONO, —

SNO, and —

NONOate; and

wherein at least one of R¹, R², R⁵, R⁶, R⁹ or R¹⁰ comprises at least one NO donor.

37. A compound according to claim 31, having a formula selected from IVa to IVd (page 112) wherein

R¹ is —

H, —

OH, —

OCOCH₂-PEG;

linear or branched C₁-C₅ alkyl;

linear or branched C₁-C₅ alkyl substituted by an NO donor, —

SR¹¹, -halogen, or —

OC(O)R¹⁵, wherein R¹⁵ is C₁-C₅ alkyl and wherein R¹⁵ is C₁-C₅ alkyl;

R² is —

H, —

ONO, —

ONO₂, —

SNO, —

OH, —

CH₃, —

NONOate, or —

OC(O)R⁸, wherein R⁸ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

R³ is —

H, —

OH, or —

CH₃, or R and R³ together form a heterocyclic ring;

R⁴ is —

H or halogen;

R⁵ is —

H, ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups;

R⁹ and R¹⁰ are independently, linear or branched C₁-C₅ alkyl groups, or substituted linear or branched C₁-C₅ alkyl groups wherein the said group is independently substituted by an NO donor or —

OC(O)R¹⁴,

wherein R¹⁴ is C₁-C₅ alkyl;

X is —

CH₂—

, —

O—

or —

S—

;

Z is —

CH₂—

or —

CH₂—

CH₂—

;

wherein an NO donor is a group comprising one of —

ONO₂, —

ONO, —

SNO, and —

NONOate; and

wherein at least one of R¹, R², R⁵, R⁶ or R¹⁰ comprises at least one NO donor.

38. A compound according to claim 31, having a formula selected from Va to Vd (page 114) wherein

R³ is —

H, H, or —

CH₃;

R⁴ is —

H or halogen;

R⁵ is —

H, ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups;

R⁶ is ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate,

 

and R^6A, if present, is —

H, or R⁶ and R^6A together form a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups wherein said alkyl groups may be further substituted by an NO donor, or —

OC(O)R¹², wherein R¹² is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

R⁹ and R¹⁰ are independently, linear or branched C₁-C₅ alkyl groups, or substituted linear or branched C₁-C₅ alkyl groups wherein the alkyl group is independently substituted by an NO donor or —

OC(O)R¹⁴, wherein R¹⁴ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

X is —

CH₂—

, —

O—

or —

S—

;

Z is —

CH₂—

or —

CH₂—

CH₂—

;

wherein an NO donor is a group comprising one of —

ONO₂, —

ONO, —

SNO, and —

NONOate; and

wherein at least one of R⁵, R⁶, R⁹ or R¹⁰ comprises an NO donor.

39. A compound according to claim 32, having a formula selected from VIa to VId (page 115) wherein

R² is —

H, —

ONO, —

ONO₂, —

SNO, —

OH, —

CH₃, —

NONOate, or —

OC(O)R⁸, wherein R⁸ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

R³ is —

H, —

OH, or —

CH₃, or R² and R³ together form a heterocyclic ring;

R⁴ is —

H or halogen;

R⁵ is —

H, ═

O, —

ONO, —

ONO₂, —

SNO, —

NONOate or a substituted N-oxide free radical, wherein the nitrogen of the N-oxide group in the substituted N-oxide free radical is within a 5- or 6-member ring substituted by one or more independently selected C₁-C₅ alkyl groups;

R⁹ and R¹⁰ are independently, linear or branched C₁-C₅ alkyl groups, or substituted linear or branched C₁-C₅ alkyl groups wherein the alkyl group is independently substituted by an NO donor or —

OC(O)R⁴, wherein R⁴ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl;

X is —

CH₂—

, —

O—

or —

S—

;

Z is —

CH₂—

or —

CH₂—

CH₂—

;

wherein an NO donor is a group comprising one of —

ONO₂, —

ONO, —

SNO, and —

NONOate; and

wherein at least one of R², R⁵, R⁹ or R¹⁰ comprises at least one NO donor.

40. A compound according to claim 31 wherein R³ is —

H, —

OH, or —

CH₃;

R⁴ is —

H, F, or Cl; and

R⁵ is —

H, ═

O, or —

ONO₂.

41. A compound according to claim 33 wherein X is —

CH₂—

or —

O—

, Z is —

CH₂—

, and R⁹ and R¹⁰ are independently methyl or ethyl.

42. A compound according to claim 31 wherein R² is —

H or —

ONO₂.

43. A compound according to claim 31 wherein R⁶ is ═

O, —

ONO₂, and R^6A, if present, is —

H, or R⁶ and R^6A together form a substituted N-oxide free radical selected from substituted pyrrolidinyloxy N-oxide free radical, substituted piperidinyloxy N-oxide free radical, substituted oxazolidinyloxy N-oxide free radical, substituted oxazinyloxy N-oxide free radical, substituted thiazolidinyloxy N-oxide free radical and substituted thiazinyloxy N-oxide free radical.

44. A compound according to claim 31 wherein R⁷ is —

ONO₂ or a substituted N-oxide free radical selected from substituted pyrrolidinyloxy N-oxide free radical, substituted piperidinyloxy N-oxide free radical, substituted oxazolidinyloxy N-oxide free radical, substituted oxazinyloxy N-oxide free radical, substituted thiazolidinyloxy N-oxide free radical and substituted thiazinyloxy N-oxide free radical.

45. A compound according to claim 31 wherein said N-oxide free radical is selected from the substituted 5- or 6-member rings of general formulae 3a and 3b

wherein X is —

CH₂—

, —

O—

or —

S—

;

Z is —

CH₂—

or —

CH₂—

CH₂—

;

R¹ is —

H, —

OH, —

OCOCH₂-PEG, linear or branched C₁-C₅ alkyl, linear or branched C₁-C₅ alkyl substituted by —

ONO, —

ONO₂, —

SNO, or —

NONOate or —

OC(O)R¹⁵, wherein R¹⁵ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl; and

R⁹ and R¹⁰ are independently, linear or branched C₁-C₅ alkyl groups, or substituted linear or branched C₁-C₅ alkyl groups, wherein said alkyl group may be is independently substituted by —

ONO, —

oNO₂, —

SNO, —

NONOate or —

OC(O)R¹⁴, wherein R¹⁴ is C₁-C₅ alkyl, or 5- or 6-member heteroaryl.

46. A pharmaceutical composition comprising a compound according to claim 31.

47. A pharmaceutical composition according to claim 46, further comprising a component selected from carrier, binding agent, stabilizer, adjuvant, diluent, excipient, surfactant, odorant, and second pharmaceutically active agent.

48. A pharmaceutical composition according to claim 46, for use as a medicament in treating and preventing a disorder selected from the group consisting of asthma, chronic bronchitis, bronchiectasis, bronchospasms, emphysema, pneumonia, Chronic Obstructive Pulmonary Diseases (COPDs), bronchial hyperreactivity, respiratory distress syndrome or Chronic Obstructive Airway Disease (COADs), allergic conditions, arthritis, autoimmune hematologic disorders, systemic lupus erythematosus, systemic dermatomyositis, thrombocytopenia, psoriasis, contact dermatitis, atopic dermatitis, exfoliative dermatitis, acne, hirsutism, erythema nodosum, inflamed cysts, discoid lupus, bullous diseases, collagen vascular diseases, malignancies, neoplastic disease, trauma, shock, acute and chronic inflammatory conditions, sarcoidosis, Sweet'"'"'s disease, graft-versus-host disease, multiple sclerosis, Alzheimer diseases, Parkinson'"'"'s diseases, amyotrophic lateral sclerosis, convulsive disorders, AIDS-dementia, disorders related to learning, disorders related to olfaction, disorders related to nociception, cerebral edema, migraine, ophthalmic disorders, chronic adrenal insufficiency, congenital adrenal hyperplasia, gastrointestinal diseases, hepatic diseases, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, renal disease, gastric secretory and peristaltic functions, drug and disease-induced neuropathies and nephropathies, pathological uterine contractions, sinus tachycardia, ischaemic heart disease, angina pectoris, myocardial infarction, congestive heart failure, atherosclerosis, rheumatic disorders, hypertension, arrhythmia, hyperthyroidism, cellular defense impairment, hypercholestemia, Reaven'"'"'s Syndrome, vasculitis, arteritis, endothelial dysfunction-induced diseases, diabetes mellitus, insulin-resistance and glucose intolerance in diabetes, ischemia-reperfusion tissue injury, chemotaxis and phagocytic impairment in immunological disorders, aging-mediated changes, cerebrovascular diseases, thyrotoxicosis, aggregation disorders, fertility conditions and reproductive disorders, menopause, ovarian dysfunction, testicular dysfunction, and penile erection.

49. A kit for administration of a multifunctional steroid compound comprising i) a dosage amount of at least one multifunctional steroid compound that comprises a steroid component, at least one SOD mimic component, and optionally at least one NO donor component;

ii) instructions for use; and

iii) optionally means for the delivery of said compound.

50. A kit according to claim 49 comprising one of items selected from inhaler, spray dispenser, syringe, or suppositories.