阅读说明：本技术 调节血管性血友病因子水平的化合物及其在治疗血液疾病中的用途 (Compounds that modulate von Willebrand factor levels and their use in treating hematologic disorders ) 是由 J·克利奇巴杜 A·M·普勒 C·里克尔 于 2019-01-30 设计创作，主要内容包括：本发明涉及具有式(I)的结构的化合物,该化合物用于预防或治疗血液疾病,具体地讲是通过调节血管性血友病因子水平来预防或治疗血液疾病。还提供了包含本发明的化合物的营养品产品或食品产品。(The present invention relates to compounds having the structure of formula (I) for use in the prevention or treatment of hematological disorders, in particular by modulating von willebrand factor levels. Also provided are nutraceutical or food products comprising the compounds of the invention.)

1. Triterpene compounds of the formula (I)

Wherein the content of the first and second substances,

bond b is a single or double bond;

r1, R4, R9, R13, R14, R17 and R20a are each independently optionally substituted and/or optionally branched C1 to C10 alkyl; optionally substituted and/or optionally branched C2 to C10 alkenyl; or optionally substituted and/or optionally branched C2 to C10 alkynyl;

r3 and R20b are each independently selected from H, OH, -CO2H, C1 to C5 alkyl groups substituted with 1 to 5-OH, -CO2H groups;

r6, R16 are independently H or OH;

r7 is independently H, OH or carbonyl;

r12 is independently H or methyl;

r11, R19 are independently H or Br;

r15 is independently H, OH or carbonyl;

r18 is independently H, methyl or OH;

r21a is independently H, methyl, OH, carbonyl, or oxime;

r21b is independently absent, H, OH or CO 2H; and

r22 is independently an ester derivative of H, OH, carbonyl or OH,

for the prevention or treatment of a hematological disorder in an individual.

2. The compound for use according to claim 1, wherein R1, R4, R9, R13, R14, R17 and R20a are each independently optionally substituted and/or optionally branched C1 to C5 alkyl; optionally substituted and/or optionally branched C2 to C5 alkenyl; or optionally substituted and/or optionally branched C2 to C5 alkynyl.

3. A compound for use according to any preceding claim, wherein R1, R4, R9, R13, R14, R17 and R20a are each independently a branched or straight chain saturated hydrocarbon chain having 1,2,3,4, 5 or 6 carbon atoms.

4. A compound for use according to any preceding claim, wherein R1, R4, R9, R13, R14, R17 and R20a are each independently a methyl group.

5. A compound for use according to any preceding claim, for use in the prevention or treatment of a hematological disease by reducing the level of von willebrand factor in a human subject.

6. A compound for use according to any preceding claim, wherein the compound is a triterpenoid quinone methide selected from celastrol, pristimerin and dulcitone.

7. A compound for use according to any preceding claim, wherein the compound is celastrol.

8. A compound for use according to any preceding claim, wherein the hematological disorder is one or more of von willebrand factor disease, thrombosis, physiological haemostasis, hypercoagulable state, abnormal blood flow and endothelial cell dysfunction.

9. The compound for use according to claim 8, wherein the hematological disorder is peripheral thrombosis, cardiac thrombosis or cerebral thrombosis.

10. The compound for use according to claim 9, wherein the individual has an ApoE4 allele, cardiovascular disease, type I diabetes, type 2 diabetes, systemic lupus erythematosus, active ulcerative colitis, rheumatoid arthritis, or physiological and acute stress including surgery, exercise, anxiety, systemic inflammation, pregnancy.

11. A nutraceutical or food product for use in the prevention or treatment of a hematological disorder in an individual, wherein said product comprises a triterpene or diterpene quinone methide compound.

12. The nutraceutical or food product for use according to claim 11, wherein said product comprises a triterpene quinone methide compound.

13. The nutraceutical or food product for use according to claim 11 or 12, wherein said compound is a triterpenoid quinone methide compound selected from one or more of celastrol, cork triterpenone, pristimerin and dulcitone.

14. A nutraceutical or food product for use according to claims 11 to 13, wherein the compound is tripterine.

15. A nutraceutical or food product for use according to claims 11 to 14, wherein von willebrand factor levels in the individual are reduced.

16. A pharmaceutical formulation for use in the prevention or treatment of a hematological disorder in a subject, wherein the formulation comprises a triterpene or diterpene quinone methide compound and a pharmaceutically acceptable excipient.

Drawings

Fig. 1 is a graph showing the results of human endothelial cells in the experimental examples disclosed herein.

Detailed Description

The present invention provides a compound, in particular a terpene, in particular a triterpene, more in particular a triterpene comprising a quinone methide, for use in the prevention or treatment of a hematological disorder in an individual.

In particular, the present invention relates to compounds of formula (I) for use in the prevention or treatment of a hematological disorder in an individual.

Wherein:

the bond b is a single bond or a double bond.

R1, R4, R9, R13, R14, R17 and R20a are each independently optionally substituted and/or optionally branched C1 to C10 alkyl, preferably C1 to C5 alkyl; optionally substituted and/or optionally branched C2 to C10 alkenyl, preferably C2 to C5 alkenyl; or optionally substituted and/or optionally branched C2 to C10 alkynyl, preferably C2 to C5 alkynyl.

More preferably, R1, R4, R9, R13, R14, R17, and R20a are each independently a branched or straight saturated hydrocarbon chain having 1,2,3,4, 5, or 6 carbon atoms. The term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl.

More preferably, at least three of R1, R4, R9, R13, R14, R17, and R20a are methyl groups. More preferably, at least four of R1, R4, R9, R13, R14, R17, and R20a are methyl groups. Most preferably, all of R1, R4, R9, R13, R14, R17, and R20 are methyl groups.

R3 and R20b are each independently selected from H, OH, -CO2H, C1 to C5 alkyl groups substituted with 1 to 5-OH, -CO2H groups.

Preferably, R3 is selected from the substituents listed in table 1.

R6, R16 are independently H or OH.

R7 is independently H, OH or carbonyl.

R12 is independently H or methyl.

R11, R19 are independently H or Br.

R15 is independently H, OH or carbonyl.

R18 is independently H, methyl or OH.

R21a is independently H, methyl, OH, carbonyl, or oxime.

R21b is independently absent, H, OH or CO 2H.

R22 is independently an ester derivative of H, OH, carbonyl, or OH.

TABLE 1：

In a preferred embodiment, the bond b is a double bond.

In a preferred embodiment, R3 is OH.

In a preferred embodiment, R20 is CO 2H.

In a preferred embodiment, R3 is OH and R20 is CO 2H.

In a preferred embodiment, the compound of formula (I) is a triterpene comprising a quinone methide.

In a preferred embodiment, the quinone methide-containing triterpene compound of formula (I) is celastrol and has the structure of compound 1:

tripterine has the empirical formula (Hill representation) C29H38O 4. It has a molecular weight of 450.61. CAS number 34157-83-0. It has the synonyms 10-hydroxy-2, 4a,6a,9,12b,14 a-hexamethyl-11-oxo-1, 2,3,4,4a,5,6,6a,11,12b,13,14,14a,14 b-decatetrahydro-picene-2-carboxylic acid.

In one embodiment of formula (I), R3 is OH and R20 is COOH.

In one embodiment, the compound of formula (I) has the structure of compound 2:

in one embodiment of formula (I), R3, R4, R6 are independently OH; and R20 is COOH.

In one embodiment, the compound of formula (I) has the structure of compound 3:

the present invention also relates to a triterpene compound of formula (IIIa) for use in the prevention or treatment of a hematological disorder in a subject:

wherein:

ring a is aromatic;

r2 is independently OH, methoxy, an O-linked derivative selected from ether, ester, carbonate or glycoside. Preferably, R2 is selected from the substituents listed in table 2 a;

r3 is the same as R2 or is acetyl;

R2-R3 may form a ring;

r4 is independently H, methyl, CH2OH, OH, CO2H, CO2CH3, or formyl;

r6 is independently H, OH, carbonyl, acetyl, nitrile, allyl, or OH-containing alkyl, amino, keto, or ester groups, S-linked groups, heteroaryl, or as defined in table 2 b;

r7 is independently H or OH;

r17 is independently H or methyl;

r20a are independently methyl, CH2OH or acetyl-ester derivatives, or as defined in table 2 c; and R20b is independently H, OH, CH2OH, or an acyl derivative, including carboxylic acids, amides, esters; or nitrile, N-linked groups including amines, amides, ureas and derivatives thereof, or as defined in table 2 d;

r21 is independently H, OH, carbonyl, or O linked acetate; and

r22 is independently H, methyl, OH or O linked acetate.

TABLE 2a (examples of substituents R2)：

Table 2b (examples of substituents R6)：

Table 2c (examples of substituents R20 a)：

TABLE 2d (examples of substituents R20 b)：

In one embodiment, the compound of formula (IIIa) has the structure of compound 6:

in one embodiment, the compound of formula (IIIa) has the structure of compound 7:

in a preferred embodiment, R2 is OH.

In a preferred embodiment, R3 is OH.

In a preferred embodiment, R4 is CO.

In a preferred embodiment, R6 is CO.

In a preferred embodiment, R20 is COOH.

In a preferred embodiment, R2 and R3 are OH, R4 and R6 are CO, and R20 is COOH.

In a particularly preferred embodiment, the compound of formula (IIIa) is not a quinone methide compound.

In a particularly preferred embodiment, the compound of formula (IIIa) has the structure of compound 8:

compound 8 has the empirical formula (hilt representation) C29H36O 6. It has a molecular weight of 480.601.

In one embodiment, the compound of formula (IIIa) has the structure of compound 9:

in a preferred embodiment, R2 is OH.

In a preferred embodiment, R3 is OH.

In a preferred embodiment, R6 is COH.

In a preferred embodiment, R20 is COOH.

In a preferred embodiment, R2 and R3 are OH, R6 is COH, and R20 is COOH.

In a particularly preferred embodiment, the compound of formula (IIIa) is not a quinone methide compound.

In one embodiment, the compound of formula (IIIa) has the structure of compound 10:

compound 10 has the empirical formula (hill notation) C31H44O 5. It has a molecular weight of 496.688. It is not a quinone methide compound.

In one embodiment, the compound of formula (IIIa) has the structure of compound 11:

the invention also relates to a triterpene compound of formula (IIIb) for use in the prevention or treatment of a hematological disorder in a subject:

wherein

R2, R3 are independently OH, methoxy or O linked acetyl ester;

r4 is independently H, methyl, CHO, or CO 2H;

r6a is independently: h or carbonyl, and R6b is independently H or sulfonate;

r7a is independently H or carbonyl, and R7b is independently H or OH;

r15 is independently H or OH;

r17 is independently H or methyl;

r20a is independently methyl, OH, or CO2H, and R20b is independently H, carbonyl, CO2H, or CO2CH 3;

r21 is independently H or carbonyl; and

r22 is independently H, OH or an O-linked acetyl ester.

The present invention also relates to a triterpene compound of formula (IVa) for use in the prevention or treatment of a hematological disorder in a subject:

wherein

R6 and R22 are independently H or OH;

r20a is methyl, and R20b is independently H or CO 2H;

r21 is independently H or carbonyl.

In one embodiment, the compound of formula (IVa) has the structure of compound 12:

in one embodiment, the present invention provides a triterpene compound of formula (IVb) for use in preventing or treating a hematological disorder in a subject:

wherein

R2 is independently OH or O linked acetyl ester

R9, R10, R13, R19 are independently H or methyl

R17 is methyl

R17, R19 may also form intramolecular rings containing ether or ester groups

R20a is methyl and R20b is independently methyl or forms an intramolecular ring comprising an ester with respect to position 17

In one embodiment, the present invention provides a triterpene compound of formula (IVc) for use in preventing or treating a hematological disorder in a subject:

wherein

R6 is independently H or OH

R8, R10 and R14 are methyl

R11, R12 are epoxides

R13 to R17 are ester-containing rings

R19 is independently H or methyl

R20a is independently methyl or methylene, and R20b is independently H, methyl or OH

In one embodiment, the present invention provides a triterpene compound of formula (V) for use in preventing or treating a hematological disorder in a subject:

wherein

R20a is methyl and R20b is independently CO2H or ester and amide derivatives.

The present invention provides a compound, in particular a diterpene, more particularly a diterpene comprising a quinone methide compound of the formula (II):

wherein:

the bond b being a single or double bond

R1 is independently H, OH or O linked acetate (OAc)

R3 may be selected from the substituents listed in Table 3

R4 independently is H, methyl, isopropyl, OH, methoxy, OAc or CH2CH2OH R3, R4 may also form ether containing rings

R6 is independently H, OH, methoxy, NH2 or (CH2)4C (═ O) CH3, diterpenes

R7 is independently H, OH, OMe, carbonyl or Br

R7, R14 may also form ether-containing rings

R9 is independently methyl, CO2Me or CH2CO2Me

R12 is independently H, OH, carbonyl, O-linked acetate or O-linked benzoate (derivative)

R13 is independently H, OH, carbonyl, O-linked formate, O-linked benzoate, or O-linked cinnamate

R14a is independently methyl, CH2OH or CH2O linked ester, and R14b is methyl

R3 may be further defined as follows:

TABLE 3

In one embodiment, the compound of formula (II) has the structure of compound 4:

in a preferred embodiment, R6 is O

In a preferred embodiment, R11 is OH

In a preferred embodiment, R12 is O

In a preferred embodiment, R6 and R12 are O, and R11 is OH

In a particularly preferred embodiment, the compound of formula (IIIa) is a quinone methide compound.

In a particularly preferred embodiment, the compound of formula (II) is a diterpene quinone methide and has the structure of compound 5:

compound 5 has the empirical formula (hilt representation) C20H26O 4. It has a molecular weight of 330.424.

In one embodiment, the present invention provides a diterpene compound of formula (VIIa):

wherein:

r2 is independently OH, methoxy, allyloxy or O-linked acetyl ester

R3 is independently H, n-propyl, isopropyl, allyl, or isopropyl derivative having an acetyl ester group

R8 is independently H or OH

R9 is methyl

R13 is independently H, OH or O linked formate

R14 is independently methyl or CH2OH and its formate

R9, R14 may be ester-containing rings

In one embodiment, the compound of formula (VIIa) has the structure of compound 13:

in one embodiment, the present invention provides a diterpene compound of formula (VIIb):

wherein:

r2 is independently OH, methoxy, ether derivative or ester derivative

R3 is independently H, isopropyl, allyl, isopropenyl or n-propyl, and isopropyl derivatives containing hydroxyl, ether and ester groups

R6 is independently H, methyl, OH, methoxy, ethoxy, carbonyl, O-linked formate, acetate, glycolate or fatty acid ester

R7 is independently H, OH, carbonyl, O-linked formate, acetate, propionate, butyrate or benzoate and derivatives thereof

R8 is independently H or methoxy

R9 is independently methyl, CH2OH or carboxylic acid

R9, R14 are independently a ring containing a hydroxyl, ether or ester group

R12 is independently H or OH

R13 is independently H, OH, carbonyl or O linked formate or acetate

R14 is independently methyl, CH2OH or its formate or acetate, or CO2CH3

In one embodiment, the compound of formula (VIIb) has the structure of compound 14:

in one embodiment, the compound of formula (VIIb) has the structure of compound 15:

in a preferred embodiment, R12 is OH.

In a particularly preferred embodiment, the compound of formula (VIIb) is not a quinone methide compound.

In a particularly preferred embodiment, the compound of formula (VIIb) is a diterpene and has the structure of compound 16:

compound 16 has the empirical formula (hill notation) C20H26O 4. It has a molecular weight of 330.424. It is not a quinone methide compound.

In one embodiment, the compound of formula (VIIb) has the structure of compound 17:

in one embodiment, the compound of formula (VIIb) has the structure of compound 18:

in one embodiment, the compound of formula (VIIIb) has the structure of compound 19:

in one embodiment, the compound of formula (VIIIb) has the structure of compound 20:

in one embodiment, the compound of formula (VIIIb) has the structure of compound 21:

in one embodiment, the compound of formula (VIIb) has the structure of compound 22:

in one embodiment, the compound of formula (VIIb) has the structure of compound 23:

in one embodiment, the compound of formula (VIIb) has the structure of compound 24:

in one embodiment, the compound of formula (VIIb) has the structure of compound 25:

in one embodiment, the present invention provides a diterpene compound of formula (VIIIa) for use in the prevention or treatment of a hematological disorder in a subject:

wherein:

r1, R2, R4 are independently OH, methoxy or O linked acetates

R3 is independently H, isopropyl, propen-1-yl, propen-2-yl or acetyl ester derived n-propyl

R6 is independently H or acetyl

R7 is H

R7, R14 may be ether containing rings

R9 is independently methyl or CO2H

R14 is methyl

In one embodiment, the present invention provides a diterpene compound of formula (VIIIb):

wherein:

r1 is independently OH, methoxy or O linked acetate

R2 is independently OH, methoxy, O-linked acetate or benzoate

R3 is independently: H. straight-chain and branched alkyl or alkenyl groups, and derivatives containing OH, ether or ester groups

R2, R3 may be ether containing rings

R4 is independently OH, methoxy or O linked acetate

R3, R4 may be ether containing rings

R6 is independently H, OH, methoxy, carbonyl or O linked acetate

R6, R7, R8, R9 and R14 may independently be ester-containing rings

R7 is independently H, OH, methoxy, carbonyl, O linked acetate

R8 is independently H, methyl, CH2OH or formyl

R9, R14 may be ether-containing or ester-containing rings

R12 is independently H, OH or O linked acetate

R13 is independently H, OH, carbonyl, methylene or O linked formate or acetate

R14 is independently methyl, methylene, CH2OH formate or CO2CH3

In a preferred embodiment, R1 is OH

In a preferred embodiment, R2 is OH

In a preferred embodiment, R4 is OH

In a preferred embodiment, R6 is CO

In a preferred embodiment, R7 is CO

In a preferred embodiment, R1, R2 and R4 are OH; and R6 and R7 are CO

In a particularly preferred embodiment, the compound of formula (VIIb) is not a quinone methide compound.

In a particularly preferred embodiment, the compound of formula (VIIIb) has the structure of compound 26:

compound 26 has the empirical formula (hill notation) C20H26O 5. It has a molecular weight of 346.423. It is not a quinone methide compound.

In one embodiment, the compound of formula (VIIIb) has the structure of compound 27:

in one embodiment, the compound of formula (VIIIb) has the structure of compound 28:

in one embodiment, the compound of formula (VIIIb) has the structure of compound 29:

in one embodiment, the present invention provides diterpenoid compounds of formula (IX) for use in the prevention or treatment of a hematological disorder in a subject:

wherein:

r4 is independently OH or methoxy

R6 is independently OH or O linked acetyl ester

R7 is H

R9 is methyl

R7, R9 may be ester-containing rings

In one embodiment, the present invention provides diterpenoid compounds of formula (X) for use in the prevention or treatment of a hematological disorder in an individual:

wherein:

r1 is independently H, OH, carbonyl or O-linked acetyl ester

R2 is independently OH, epoxide or O-linked acetyl ester

R3 is independently H, methyl, epoxide, isopropyl or 1, 2-propene and its ester derivatives R6 is independently H, OH, ethoxy, carbonyl, O-linked formate, acetate or benzoate derivatives

R7 is independently H, OH or O linked acetyl ester

R9 is methyl

R13 is independently H, OH, carbonyl, 1, 4-butene derivative, O-linked formate or acetate

R6, R9 may be rings containing double bonds

R14 is independently methyl, 1, 4-butene derivative, CH2OH or its formate or acetate, or CO2CH3

In one embodiment, a compound according to the invention is provided for use in the prevention or treatment of a hematological disease by modulating the level of von willebrand factor in an individual.

In one embodiment, a compound according to the invention is provided for use in preventing a hematologic disease by modulating the level of von willebrand factor in an individual.

In one embodiment, a compound according to the invention is provided for use in treating a hematologic disease by modulating von willebrand factor levels in an individual.

In one embodiment, a compound according to the invention is provided for use in preventing or treating a hematologic disease by reducing the level of von willebrand factor in an individual.

In one embodiment, there is provided a compound for use according to the invention, wherein said compound is a triterpene compound selected from the group consisting of compounds 1,2,3, 6, 7, 8, 9, 10, 11 and 12 as described herein.

In one embodiment, there is provided a compound for use according to the present invention, wherein said compound is a triterpenoid quinone methide selected from the group consisting of celastrol (compound 1), cork triterpenoid ketone, pristimerin and dulcitone.

In one embodiment, there is provided a compound for use according to the invention, wherein the compound is tripterine (compound 1).

In one embodiment, there is provided a compound for use according to the present invention, wherein said compound is a triterpene non-quinone methide compound.

In one embodiment, there is provided a compound for use according to the present invention, wherein said triterpene non-quinone methide compound is selected from the group consisting of compounds 8 and 10. Compound 8 can be described as having a molecular weight of the formulae C31H44O 5and 480.601. Compound 10 can be described as having a molecular weight of the formulae C31H44O 5and 496.688.

In one embodiment, there is provided a compound for use according to the invention, wherein said compound is a diterpene selected from the group consisting of compounds 4, 5,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 and 29 as described herein.

In one embodiment, there is provided a compound for use according to the present invention, wherein said compound is diterpene non-quinone methide compound 5. Compound 5 can be described as having a molecular weight of the formulae C20H26O4 and 330.424.

In one embodiment, there is provided a compound for use according to the invention, wherein the compound is a diterpene non-quinone methide compound.

In one embodiment, there is provided a compound for use according to the present invention, wherein said compound is a diterpene non-quinone methide selected from the group consisting of compounds 16 and 26. Compound 16 can be described as having a molecular weight of the formulae C20H26O4 and 330.424. Compound 26 can be described as having a molecular weight of the formulae C20H26O 5and 346.423.

In one embodiment, a compound for use according to the invention is provided, wherein the hematological disorder is one or more of von willebrand factor disease, thrombosis, physiological hemostasis, hypercoagulable state, abnormal blood flow, and endothelial cell dysfunction.

In one embodiment, a compound for use according to the invention is provided, wherein the hematological disorder is thrombosis, in particular peripheral thrombosis, cardiac thrombosis or cerebral thrombosis.

In one embodiment, there is provided a compound for use according to the invention, wherein the hematological disorder is physiological hemostasis.

In one embodiment, a compound for use according to the invention is provided, wherein the individual has a condition associated with higher levels of von willebrand factor.

In one embodiment, there is provided a compound for use according to the invention, wherein the higher level of von willebrand factor is due to one or more of the following causes: there is an ApoE4 allele, cardiovascular disease, type I diabetes, type 2 diabetes, systemic lupus erythematosus, active ulcerative colitis, rheumatoid arthritis, physiological stress and acute stress including surgery, exercise, anxiety, systemic inflammation, pregnancy.

In one embodiment, there is provided a compound for use according to the invention, wherein the higher level of von willebrand factor is due to the presence of the ApoE4 allele in the individual. ApoE4 is a well-known genetic risk factor for cardiovascular disease. In one embodiment, the individual has an ApoE4/ApoE4 genotype. In one embodiment, the individual has an ApoE3/ApoE4 genotype. In one embodiment, the individual has an ApoE3/ApoE3 genotype.

In one embodiment, the compound or composition thereof is administered orally. In one embodiment, the compound or composition thereof is administered by intravenous injection.

In one embodiment, the subject is a human, e.g., an elderly human.

Also provided is a nutraceutical or food product comprising a triterpene or diterpene compound, in particular a triterpene quinone methide or diterpene quinone methide.

In one embodiment, the compound is selected from the group consisting of celastrol (10-hydroxy-2, 4a,6a,9,12b,14 a-hexamethyl-11-oxo-1, 2,3,4,4a,5,6,6a,11,12b,13,14,14a,14 b-decatetrahydro-picene-2-carboxylic acid), cork triterpene ketone, pristimerin and dulcitone.

In one embodiment, the compound is tripterine (10-hydroxy-2, 4a,6a,9,12b,14 a-hexamethyl-11-oxo-1, 2,3,4,4a,5,6,6a,11,12b,13,14,14a,14 b-decatetrahydro-picene-2-carboxylic acid).

There is also provided the use of a nutraceutical or food product according to the invention for the prevention or treatment of a hematological disorder in an individual.

In one embodiment, the hematologic disorder is thrombosis. In another embodiment, the hematological disorder is physiological hemostasis.

In one embodiment, the subject has an ApoE3/ApoE4 genotype. In another embodiment, the subject has an ApoE4/ApoE4 genotype.

Definition of

All percentages expressed herein are by weight of the total weight of the composition, unless otherwise indicated. As used herein, "about" and "substantially" are understood to mean a number within a range of values, for example in the range of-10% to + 10% of the number referred to, preferably-5% to + 5% of the number referred to, more preferably-1% to + 1% of the number referred to, most preferably-0.1% to + 0.1% of the number referred to. All numerical ranges herein should be understood to include all integers or fractions within the range. Additionally, these numerical ranges should be understood to provide support for claims directed to any number or subset of numbers within the range. For example, a disclosure of 1 to 10 should be understood to support a range of 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, and so forth.

As used in this disclosure and the appended claims, the singular forms "a," "an," and "the" ("a," "an," and "the") include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a component" or "the component" includes two or more components.

The term "alkyl" refers to a monovalent branched or straight saturated hydrocarbon chain having 1 to 20 carbon atoms, or 1 to 15 carbon atoms, or 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. The term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-decyl, tetradecyl.

The term "substituted alkyl" refers to:

1) alkyl as defined above having 1,2,3,4 or 5 substituents (in some embodiments, 1,2 or 3 substituents) selected from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, amido, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S (O) -alkyl, -S (O) -cycloalkyl, -S (O) -heterocyclyl, -S (O) -arylthio, amino, nitro, -S (O) -aryl, amino, heteroaryl, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxy, nitro, -S (O) -alkyl, -S (O) -cycloalkyl, -S (O) -heterocyclyl, S (O) -aryl, -S (O) -heteroaryl, -S (O) 2-alkyl, -S (O) 2-cycloalkyl, -S (O) 2-heterocyclyl, -S (O) 2-aryl and-S (O) 2-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1,2 or 3 substituents selected from alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl and-s (o) n R < a >, wherein R < a > is alkyl, aryl or heteroaryl and n is 0, 1 or 2; or

2) An alkyl group as defined above interrupted by 1 to 10 atoms (e.g. 1,2,3,4 or 5 atoms) independently selected from oxygen, sulphur and NR < a >, wherein R < a > is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. All substituents may be optionally further substituted with alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl and-s (o) n R < a > wherein R < a > is alkyl, aryl or heteroaryl and n is 0, 1 or 2; or

3) An alkyl group as defined above having 1,2,3,4 or 5 substituents as defined above and further interrupted by 1 to 10 atoms (e.g. 1,2,3,4 or 5 atoms) as defined above.

The term "heterocyclyl", "heterocycle" or "heterocyclic" refers to a monovalent saturated group having a single ring or multiple condensed rings, which has 1 to 40 carbon atoms and 1 to 10 and 1 to 4 heteroatoms selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring. In some embodiments, a "heterocyclyl", "heterocycle", or "heterocyclic" group is attached to the remainder of the molecule through one of the heteroatoms within the ring.

Some of the compounds exist as tautomeric isomers. The tautomeric isomers are in equilibrium with each other. For example, an amide-containing compound can exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown, and regardless of the nature of the balance between tautomers, one of ordinary skill in the art would understand that compounds include both amide and imidic acid tautomers. Thus, it is understood that amide-containing compounds include their imidic acid tautomers. Also, it is understood that the imine acid containing compounds include their amide tautomers.

The words "comprise", "comprises" and "comprising" are to be construed as inclusive and not exclusive. Likewise, the terms "including" and "or" ("include," and "or") should be considered inclusive, unless the context clearly prohibits such interpretation. However, the compositions disclosed herein may be free of any elements not specifically disclosed herein. Thus, disclosure of embodiments using the term "comprising" includes disclosure of embodiments "consisting essentially of and embodiments" consisting of the indicated components. A composition "consisting essentially of …" comprises at least 50% by weight of the reference component, preferably at least 75% by weight of the reference component, more preferably at least 85% by weight of the reference component, and most preferably at least 95% by weight of the reference component.

The term "and/or" as used in the context of "X and/or Y" should be interpreted as "X" or "Y" or "X and Y". As used herein, the terms "example" and "such as" (especially when followed by a list of terms) are merely exemplary and illustrative and should not be considered exclusive or comprehensive.

"preventing" includes reducing the risk and/or severity of a condition or disorder. The terms "treat," "alleviate," and "alleviate" include both prophylactic or preventative treatment (prevention and/or slowing of the development of the pathological condition or disorder of interest) and curative, therapeutic, or disease modifying treatment, including curative, slowing, lessening the symptoms of, and/or interrupting the progression of, a diagnosed pathological condition or disorder; and includes treating patients at risk of contracting a disease or suspected of contracting a disease, as well as treating patients who are ill or have been diagnosed as having a disease or medical condition. The term does not necessarily mean that the individual is treated until complete recovery. These terms also refer to the maintenance and/or promotion of health in individuals who do not have the disease but may be prone to developing an unhealthy condition. These terms are also intended to include the enhancement or otherwise enhancement of one or more primary preventative or therapeutic measures. The terms "treat," "alleviate," and "alleviate" are also intended to include dietary management of a disease or condition or dietary management of preventing or preventing a disease or condition. The treatment may be patient-related or physician-related.

The term "individual" refers to any animal, including humans, that may suffer from cognitive aging and thus benefit from one or more of the methods disclosed herein. Generally, the subject is a human or avian animal, bovine, canine, equine, feline, caprine, wolf, murine, ovine, and porcine animal. A "companion animal" is any domesticated animal and includes, but is not limited to, cats, dogs, rabbits, guinea pigs, ferrets, hamsters, mice, gerbils, horses, cows, goats, sheep, donkeys, pigs, and the like. Preferably, the subject is a human or a companion animal, such as a dog or cat. In the human context, the term "elderly" means at least 60 years of age, preferably 63 years of age or older, more preferably 65 years of age or older, and most preferably 70 years of age or older, from birth. In the context of humans, the term "elderly" refers to an age of at least 45 years, preferably over 50 years, more preferably over 55 years, from birth and includes elderly individuals. For other animals, "elderly" means having exceeded 50% of the average lifespan of their particular species and/or species within. Animals are considered "elderly" if they exceed 66% of the average life expectancy, preferably over 75% of the average life expectancy, more preferably over 80% of the average life expectancy. The senior cat or dog is at least about 7 years of age from birth.

As used herein, an "effective amount" is an amount that prevents a deficiency, treats a disease or medical condition in an individual, or more generally, reduces symptoms, manages disease progression, or provides a nutritional, physiological, or medical benefit to an individual. The relative terms "improve," "increase," "enhance," and the like refer to the effect of a composition disclosed herein relative to a composition lacking one or more ingredients and/or having a different amount of one or more ingredients, but otherwise being the same.

As used herein, it is believed that "reducing" the level of von willebrand factor in an individual refers to a reduction in the level of von willebrand factor as a result of the use of a compound or composition of the invention. In other words, the level of von willebrand factor is lower in the treated same individual compared to the level of von willebrand factor observed in an untreated individual.

The term "hematological disease" includes disorders, diseases or conditions due to abnormalities associated with red blood cells, white blood cells, or platelets, or a combination thereof.

Compounds or compositions thereof

It is to be understood that according to certain embodiments, the compounds of the present invention or compositions thereof may be nutraceutical compositions, pharmaceutical compositions, functional foods, functional nutritional products, medical foods, medical nutritional products, or dietary supplements.

The term "nutraceutical" combines the words "nutrition" and "drug". It is a food or food product that provides health and medical benefits, including prevention and treatment of disease. Nutraceuticals are products that are isolated or purified from food that is typically sold in the form of pharmaceuticals that are not normally associated with food. Confirming that the nutritional product has a physiological beneficial effect or providing prophylaxis against chronic disease. Such products can range from isolated nutrients, dietary supplements and special diets to genetically engineered foods, herbal products and processed foods such as cereals, soups and beverages.

As used herein, the term "nutraceutical" denotes the usefulness in the fields of nutritional and pharmaceutical applications. Thus, the novel nutritional compositions may be used as supplements for food and beverages, and as pharmaceutical formulations for enteral or parenteral administration, which may be solid formulations such as capsules or tablets, or liquid formulations such as solutions or suspensions.

The nutraceutical compositions according to the present invention may further comprise protective hydrocolloids (such as gums, proteins, modified starches), binders, film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilising agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, co-compounds, dispersing agents, wetting agents, processing aids (solvents), flowing agents, taste masking agents, weighting agents, gelling agents, gel forming agents, antioxidants and antimicrobials.

In addition, vitamin complex and mineral supplements may be added to the nutraceutical compositions of the present invention to obtain sufficient amounts of essential nutrients that are missing in some diets. The multivitamin and mineral supplement can also be used to prevent disease and to prevent loss and deficiency of nutrients due to lifestyle patterns.

The nutraceutical compositions of the present invention may be in any galenic form suitable for administration to the body, in particular in any form conventionally used for oral administration, e.g. in solid form such as (additives/supplements for) food or feed, food or feed premixes, fortified food or feed, tablets, pills, granules, dragees, capsules and effervescent preparations such as powders and tablets; or in liquid form such as solutions, emulsions or suspensions, such as, for example, beverages, pastes and oily suspensions. The paste may be incorporated into hard or soft shell capsules, whereby the capsules are characterized by a matrix of e.g. (fish, pig, poultry, cattle) gelatin, vegetable protein or lignosulfonate. Examples of other forms of application are those for transdermal, parenteral or injection administration. The dietary and pharmaceutical compositions may be in the form of controlled (sustained) formulations.

Beverages encompass non-alcoholic and alcoholic beverages as well as liquid formulations to be added to drinking water and liquid food products. Non-alcoholic beverages are for example soft drinks, sports drinks, fruit juices, tea and milk based beverages. Liquid food products are for example soups and dairy products. The nutraceutical composition comprising the compounds of the present invention may be added to soft drinks, energy bars or candies.

If the nutraceutical composition is a Pharmaceutical formulation, the composition may further comprise pharmaceutically acceptable excipients, diluents or adjuvants, and may be formulated using standard techniques, as disclosed, for example, in Remington's Pharmaceutical Sciences,20th edition, Williams publishing Co., Williams, Pa., USA, Remington's Pharmaceutical Sciences,20th edition Williams & Wilkins, USA. For oral administration, preference is given to using tablets and capsules which comprise suitable binders (for example gelatin or polyvinylpyrrolidone), suitable fillers (for example lactose or starch), suitable lubricants (for example magnesium stearate) and optionally further additives.

"functional food", "functional nutritional product", "medical food" and "medical nutritional product" relate to any health food which claims to have health condition-promoting or disease-preventing properties in addition to the essential function of supplying nutrients. The general category of functional foods includes processed foods or foods fortified with health-promoting additives, such as "vitamin-rich" products.

Dietary supplements, also known as food supplements or nutritional supplements, are preparations intended to supplement the diet and provide nutrients (such as vitamins, minerals, fiber, fatty acids or amino acids) that are missing or may be ingested in insufficient amounts in the human diet. Some countries define dietary supplements as food products, while others define dietary supplements as drugs or natural health products. Supplements containing vitamins or dietary minerals are included as a class of food products in the international food codex, which is an internationally recognized collection of standards, practice specifications, guidelines, and other recommendations relating to food, food production, and food safety. These texts are prepared by the international food codex committee, an organization subsidized by the Food and Agriculture Organization (FAO) and the World Health Organization (WHO) of the united nations.

Administration of Compounds or compositions thereof

The compounds of the present invention or compositions thereof can be administered orally, intravenously, topically, parenterally, intraperitoneally, intramuscularly, intrathecally, intralesionally, intracranially, intranasally, intraocularly, intracardially, intravitreally, intraosseously, intracerebrally, intraarterially, intraarticularly, intradermally, transdermally, transmucosally, sublingually, enterally, sublabially, by insufflation, by suppository, by inhalation, or subcutaneously.

It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. Accordingly, such changes and modifications are intended to be covered by the appended claims.