US Pat. No. 9,855,266

TREATMENT FOR OSTEOARTHRITIS BY INTRA-ARTICULAR ADMINISTRATION OF A CIS-IMIDAZOLINE

Unity Biotechnology, Inc....

1. A method of treating osteoarthritis, comprising administering to a subject in need thereof a therapeutically effective
amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof:

wherein R is selected from saturated and unsaturated 5- and 6-membered rings containing at least one hetero atom, wherein
the hetero atom is selected from S, N and O and is optionally substituted with a group selected from lower alkyl, cycloalkyl,
—C?O—R1, hydroxy, lower alkyl substituted with hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl substituted with —NH2, lower alkyl substituted with —C?O—R1, N-lower alkyl, —SO2CH3, ?O and —CH2C?OCH3;

R1 is selected from hydrogen, lower alkyl, —NH2, —N-lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted with —NH2, and a 5- or 6-membered saturated ring containing at least one hetero atom selected from S, N and O;

X1 and X2 are each independently selected from hydrogen, lower alkoxy, —CH2OCH3, —CH2OCH2CH3, —OCH2CF3, and —OCH2CH2F; and

Y1 and Y2 are each independently selected from —Cl, —Br, —NO2, —C?N, and —C?CH.

US Pat. No. 9,849,128

UNIT DOSE OF A CIS-IMIDAZOLINE FOR TREATING AN OSTEOARTHRITIC JOINT BY REMOVING SENESCENT CELLS

Unity Biotechnology, Inc....

1. A unit dose of a pharmaceutical composition that contains an amount of the compound shown in Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein the composition contains a formulation of the compound suitable for administration into an osteoarthritic joint of
a subject in need thereof; and

wherein the formulation of the composition and the amount of the compound in the unit dose configure the unit dose to be effective
in treating the osteoarthritic joint by decreasing the severity of one or more signs or symptoms of osteoarthritis in the
joint without causing adverse effects when administered to the joint as a single dose.

US Pat. No. 9,980,962

USE OF SULFONAMIDE INHIBITORS OF BCL-2 TO TREAT SENESCENCE-ASSOCIATED LUNG CONDITIONS SUCH AS PULMONARY FIBROSIS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE

UNITY BIOTECHNOLOGY, INC,...

1. A method of selectively eliminating senescent cells to relieve symptoms of a pulmonary disease or disorder that is not a cancer in a subject, the method comprising:administering in or around a lung of a subject in need thereof a therapeutically effective course of therapy of a pharmaceutical composition that contains an aryl sulfonamide that selectively inhibits Bcl-xL;
wherein the pharmaceutical composition is formulated such that the aryl sulfonamide contacts senescent cells located in or around the lung that are causing symptoms of the pulmonary disease or disorder,
wherein the senescent cells are defined as non-cancerous cells that express p16,
wherein the therapeutically effective course of therapy includes:
(1) a treatment phase during which one or more doses of the pharmaceutical composition are administered to the subject so as to contact and selectively eliminate the senescent cells from the lung, followed by
(2) a therapeutic phase lasting at least two months, during which the pharmaceutical composition is not administered, and the symptoms of the pulmonary disease or disorder are relieved in the subject as a result of the selective elimination of the senescent cells by the administration of the one or more doses of the pharmaceutical composition during the treatment phase.
US Pat. No. 9,993,472

TREATMENT FOR OSTEOARTHRITIS IN A JOINT BY ADMINISTERING A MEANS FOR INHIBITING MDM2

UNITY BIOTECHNOLOGY, INC....

1. A method for treating an osteoarthritic joint in a subject, comprising administering to the joint a pharmaceutical composition that contains a senolytic agent and a pharmaceutically compatible excipient such that the senolytic agent contacts and eliminates senescent cells in or around the joint, thereby relieving symptoms of osteoarthritis in the joint,wherein the senolytic agent is a means for inhibiting MDM2.
US Pat. No. 9,969,776

DRUG CONJUGATES FOR DELIVERING COMPOUNDS TO SENESCENT CELLS

UNITY BIOTECHNOLOGY, INC....

1. A method for specifically delivering a compound to a senescent cell, the method comprising:obtaining a conjugate, wherein the conjugate includes the compound conjugated to a senescent cell binding peptide that contains a senescent cell binding sequence; and
contacting the cell with the conjugate; thereby specifically delivering the compound to the senescent cell;
wherein the senescent cell binding peptide configures the conjugate to bind preferentially to senescent cells characterized as expressing senescence associated beta-galactosidase, in comparison with cells not expressing senescence associated beta-galactosidase; and
wherein the senescent cell binding sequence is selected from SEQ. ID NOS: 1, 2, and 3.
US Pat. No. 10,010,546

TREATMENT OF OPHTHALMIC CONDITIONS BY SELECTIVELY REMOVING SENESCENT CELLS FROM THE EYE

Unity Biotechnology, Inc....

1. A method of treating an ophthalmic disease or disorder in a subject, comprising:administering in or around an eye of a subject in need thereof a pharmaceutical composition that contains an effective amount of a small-molecule means for selectively inhibiting Bcl-2 or Bcl-xL,
thereby killing senescent cells in the eye that are causing symptoms of the ophthalmic disease or disorder in the subject,
wherein the senescent cells are defined as non-cancerous cells that express p16,
the pharmaceutical composition is administered intraocularly or intravitreally, and
the pharmaceutical composition is administered in a therapeutically effective course of therapy that includes a period of treatment followed by a non-treatment interval of at least two weeks.

US Pat. No. 9,988,368

CHIRAL SYNTHESIS METHOD FOR PRODUCING CIS-IMIDAZOLINE COMPOUNDS FOR PHARMACEUTICAL USE

UNITY BIOTECHNOLOGY, INC....

1. A method for chemically synthesizing a cis-imidazoline with an enantiomeric excess (ee) of at least 90%, the method comprising:(a) combining a racemic mixture of a precursor according to Formula (A) with a chiral aromatic acid according to Formula (B);
(b) separating a stereoisomer of the precursor that is associated with the chiral aromatic acid from the enantiomorph of the stereoisomer;
(c) selectively derivatizing one of the two nitrogen atoms shown in Formula (A) with a first substituent;
(d) selectively derivatizing the other of the two nitrogen atoms shown in Formula (A) with a second substituent; and then
(e) performing a ring closing reaction in which the first substituent joins with the second substituent, thereby forming the cis-imidazoline with an enantiomeric excess (ee) of at least 90%;
wherein X1 and X2 are both halogen, R1 is —C(?O)—R2 or an amine protecting group, R2 is an optionally substituted carbocycle or heterocycle group, and R3 is an optionally substituted aryl or heteroaryl group.
US Pat. No. 10,130,628

TREATMENT OF JOINT PAIN

UNITY BIOTECHNOLOGY, INC....

1. A method for treating osteoarthritis, comprising administering to an osteoarthritic joint in a subject a pharmaceutical composition that contains a therapeutically effective amount of a senolytic agent defined as (4-[(4S,5R)-4,5 bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(1-methylethoxy)phenyl]-1H-imidazol-1-yl]carbonyl]-2-piperazinone) (Nutlin-3A) or a salt thereof, in a pharmaceutically compatible excipient.

US Pat. No. 10,328,073

USE OF SULFONAMIDE INHIBITORS OF BCL-2 AND BCL-XL TO TREAT OPHTHALMIC DISEASE BY SELECTIVELY REMOVING SENESCENT CELLS

Unity Biotechnology, Inc....

11. A method of treating an ophthalmic disease or disorder in a subject who does not have cancer,the method comprising administering intraocularly into an eye of the subject that is affected with the disease or disorder an effective amount of the following compound, or a pharmaceutically acceptable salt thereof

US Pat. No. 10,279,018

IMMUNOGENIC COMPOSITIONS FOR INDUCING AN IMMUNE RESPONSE FOR ELIMINATION OF SENESCENT CELLS

UNITY BIOTECHNOLOGY, INC....

1. A method for removing senescent cells that are causing or promoting adverse symptoms in a subject, the method comprising:administering to the subject an immunogenic composition that contains a polypeptide or a recombinant expression vector encoding said polypeptide;
wherein the polypeptide comprises at least 20 contiguous amino acids of a p16INK4a protein that is autologous to the subject;
wherein the senescent cells are not cancer cells;
wherein the immunogenic composition evokes an immune response in the subject that is specific for the autologous p16INK4a protein, and
wherein the immune response is effective in removing at least some of the senescent cells that are causing or promoting the adverse symptoms.
US Pat. No. 10,213,426

METHOD OF OPTIMIZING CONDITIONS FOR SELECTIVELY REMOVING A PLURALITY OF SENESCENT CELLS FROM A TISSUE OR A MIXED CELL POPULATION

UNITY BIOTECHNOLOGY, INC....

1. A method for treating a subject to relieve or delay progression of symptoms of a disease or disorder by selectively removing p16 positive senescent cells that are not cancer cells from a target tissue in the subject,wherein the method comprising the following steps:
(a) performing a physical examination of the subject to determine a target tissue in the subject from which it is desirable to remove senescent cells that are not cancer cells;
(b) identifying a small molecule compound that is capable of selectively removing senescent cells from the target tissue;
(c) determining a course of treatment that includes a dosage, a formulation, and a route of administration of the small molecule compound that selectively kills senescent cells in the target tissue, compared with non-senescent cells;
(d) administering the small molecule compound identified in step (b) to the subject in accordance with the course of treatment determined in step (c); and
(e) withholding treatment of the subject with the small molecule during a non-treatment interval of at least two weeks that immediately follows the administering in step (d);
whereby at least some of the senescent cells are selectively removed from the target tissue consequent to step (d), resulting in relief or delayed progression of at least one of the symptoms of the disease or disorder during the non-treatment interval of step (e).
US Pat. No. 10,328,058

TREATING ATHEROSCLEROSIS BY REMOVING SENESCENT FOAM CELL MACROPHAGES FROM ATHEROSCLEROTIC PLAQUES

Mayo Foundation for Medic...

1. A method of inhibiting progression of atherosclerosis in a subject, comprising treating the subject with a course of therapy using a pharmaceutical composition that contains a senolytic compound in an amount and in a formulation that is effective in eliminating p 16 positive senescent cells from a plurality of atherosclerotic plaques in the subject,wherein the senolytic compound constitutes a means for selectively inhibiting mouse double minute 2 homolog (MDM2),
wherein the course of therapy includes:
(1) a treatment period during which the composition is administered systemically to the subject such that the compound contacts and selectively removes senescent cells from the atherosclerotic plaques; followed by
(2) a therapeutic period of at least two weeks, during which the composition is not administered to the subject, and progression of the atherosclerosis is inhibited as a result of administration of the composition to the subject during the treatment period.
US Pat. No. 10,195,213

CHEMICAL ENTITIES THAT KILL SENESCENT CELLS FOR USE IN TREATING AGE-RELATED DISEASE

UNITY BIOTECHNOLOGY, INC....

1. A method of killing a senescent cell, the senescent cell being characterized as a non-cancerous cell in replicative arrest, the method comprising contacting the senescent cell with an effective amount of a senolytic compound that is lethal to the senescent cell, wherein the senolytic compound is apogossypol or a pharmaceutical salt thereof.

US Pat. No. 10,329,279

CHIRAL SYNTHESIS METHOD FOR PRODUCING CIS-IMIDAZOLINE COMPOUNDS FOR PHARMACEUTICAL USE

Unity Biotechnology, Inc....

1. A method for chemically synthesizing a cis-imidazoline with an enantiomeric excess (ee) of at least 90%, the method comprising:(a) obtaining a racemic mixture of a precursor according to Formula (A);

wherein X1 and X2 are both halogen, the first nitrogen is bonded to R1 which is a first substituent having the formula —C(?O)—R2 where R2 an optionally substituted carbocycle or heterocycle group, and the second nitrogen is a primary amine;
(b) combining the racemic mixture of the precursor with a chiral aromatic acid according to Formula (B):
HOOC—CH(OH)—R3  (B)
wherein R3 is an optionally substituted aryl or heteroaryl group,
whereby a first stereoisomer of the precursor associates with the chiral aromatic acid, and a second stereoisomer of the precursor does not;
(c) separating and recovering the first stereoisomer from the chiral aromatic acid;
(d) selectively derivatizing the second nitrogen of the first stereoisomer with a second substituent having the formula —C(?O)—R4, wherein R4 is an optionally substituted carbocycle or heterocycle group; and then
(e) performing a ring closing reaction in which the first nitrogen joins with the second nitrogen, thereby forming the cis-imidazoline with an enantiomeric excess (ee) of at least 90%.
US Pat. No. 10,426,788

CHEMICAL ENTITIES THAT KILL SENESCENT CELLS FOR USE IN TREATING AGE-RELATED DISEASE

Unity Biotechnology, Inc....

1. A method of killing a senescent cell, the senescent cell being characterized as a non-cancerous cell in replicative arrest, the method comprising contacting the senescent cell with an effective amount of a senolytic compound that is lethal to the senescent cell, wherein the senolytic compound is gambogic acid or a pharmaceutical salt thereof.
US Pat. No. 10,413,542

METHODS AND COMPOSITIONS FOR KILLING SENESCENT CELLS AND FOR TREATING SENESCENCE-ASSOCIATED DISEASES AND DISORDERS USING AN INHIBITOR OF AKT KINASE

Buck Institute for Resear...

1. A method for treating a disease or disorder that is not a cancer in a target tissue in a subject,wherein symptoms of the disease or disorder are caused at least in part by senescent cells that are located in or around the target tissue,
wherein the senescent cells are defined as non-cancerous cells that express p16,
the method comprising administering in or around the target tissue a course of therapy with a pharmaceutical composition,
wherein the pharmaceutical composition includes a formulation of an amount of senolytic agent that is less than 10,000 mol. wt., the senolytic agent being a means for binding to Akt kinase, thereby directly inhibiting Akt kinase activity,
wherein the amount of the senolytic agent and the formulation of the composition configure the composition such that upon administration to the target tissue in the subject, the senolytic agent contacts the senescent cells located in or around the target tissue, and selectively removes such senescent cells in preference to adjacent non-senescent cells,
wherein the course of therapy includes a treatment period during which the pharmaceutical composition is administered to the subject in one or a plurality of doses, followed by a therapeutic period of at least two weeks during which the pharmaceutical composition is not administered but one or more signs or symptoms of the disease or disorder in the target tissue are alleviated.
US Pat. No. 10,378,002

REPLICATION CONDITIONAL VIRUS THAT SPECIFICALLY KILLS SENESCENT CELLS

Unity Biotechnology, Inc....

1. A senolytic virus, defined as a conditionally replicating virus having a recombinant genome construct in which a replication gene for the virus is placed under transcriptional control of one or more heterologous promoters,wherein one of the heterologous promoters is the p16 promoter,
wherein when the senolytic virus is applied to a mixed cell population comprising senescent cells, the p16 promoter causes the virus to replicate preferentially in the senescent cells, thereby causing lysis of the senescent cells and selectively depleting them from the cell population.
US Pat. No. 10,258,618

TREATING PULMONARY CONDITIONS BY SELECTIVELY REMOVING SENESCENT CELLS FROM THE LUNG USING AN INTERMITTENT DOSING REGIMEN

UNITY BIOTECHNOLOGY, INC....

1. A method of treating a pulmonary disease or disorder that is not a cancer in a lung of a subject in need thereof, the method comprisingapplying to the subject a course of therapy of a compound that constitutes a means for selectively inhibiting Bcl-2 or Bcl-xL in a pharmaceutical composition,
wherein the pharmaceutical composition is formulated such that the compound contacts p16 positive senescent cells located in or around the lung that are promoting symptoms of the pulmonary disease or disorder, thereby selectively eliminating such cells and relieving such symptoms;
wherein the course of therapy includes:
(1) a treatment period during which the compound is administered through a pulmonary airway into the lung of the subject in a manner such that the compound selectively removes senescent cells from the lung, wherein the senescent cells are defined as p16 positive cells that are not cancer cells; followed by
(2) a therapeutic period of at least two weeks, during which the compound is not administered, and the symptoms of the pulmonary disease or disorder in the lung are relieved as a result of administration of the compound to the lung during the treatment period.